CLINICAL GASTROENTEROLOGY GEORGE Y. WU, SERIES EDITOR
For further volumes: http://www.springer.com/series/7672
Chronic Viral Hepatitis DIAGNOSIS AND THERAPEUTICS Edited by
KIRTI SHETTY, MD Georgetown University Medical Center, Washington, DC
and
GEORGE Y. WU, MD University of Connecticut Health Center, Farmington, CT, USA
Editors Kirti Shetty, MD Georgetown University Hospital, 2 Main 3800 Reservoir Road, NW Washington DC 20007
[email protected]
George Y. Wu, MD University of Connecticut Health Center 236 Farmington Ave. Farmington CT 06030-1845 USA
[email protected]
ISBN 978-1-934115-81-7 e-ISBN 978-1-59745-565-7 DOI 10.1007/ 978-1-59745-565-7 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2009921504 c Humana Press, a part of Springer Science+Business Media, LLC 2001, 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
I wish to dedicate this book to my students and patients who have taught me so much and to my family who make this all worthwhile. K.S. I would like to dedicate this book to my family for their patience, our students who inspire us, and especially Roy Lopata, Sigmund, and Jenny Walder who have been so supportive for our efforts in research, teaching, and treating liver disease. G.Y.W.
PREFACE Since the publication of the first edition in 1991, a great deal of new information has become available regarding pathogenesis and treatment of chronic viral hepatitis. While the armamentarium for use against viral hepatitis has expanded, especially for the treatment of hepatitis B, in many ways the evaluation and therapeutic decision making has become more complex. Problematic issues not previously addressed include the appearance of resistance, side effects some of which are irreversible, and their management. Chronic viral hepatitis still affects hundreds of millions of people worldwide, and millions more new infections occur every year. This edition is intended to provide the readership with the most current information, concentrating on clinically useful practical information and new advances in diagnostic and therapeutic technology. Special attention is devoted to reactivation of hepatitis B with chemotherapy and immunosuppression, herbal and nontraditional therapies, HCV extrahepatic manifestations and their treatment, chronic viral hepatitis in the pediatric population, and immunology and immunotherapy of HCV. As in the previous edition, the authors have strived to make this volume focused on clinically relevant information, presented in a practical and convenient format. It has been a pleasure to work with this group of expert authors in producing this volume. We hope the readers will find the information useful and helpful. Kirti Shetty George Y. Wu
vii
CONTENTS
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vii
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
xi
Molecular Virology of Hepatitis B and C: Clinical Implications . . . Marcy Coash and George Y. Wu
1
Contributors
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nalini K. Sharma and Averell H. Sherker
33
. . . . . . . .
71
Hepatitis C in Special Populations . . . . . . . . . . . . . . . . . Douglas Dieterich, Marie-Louise Vachon and Damaris Carriero
97
Extrahepatic Manifestations of Chronic Hepatitis C Infection . . . . Douglas Meyer and Henry C. Bodenheimer Jr.
135
Anti-HCV Agents in Development . . . . . . . . . . . . . . . . . . Ketan Kulkarni and Ira M. Jacobson
159
Current and Future Therapy of Chronic Hepatitis C Mohammad Ashfaq and Gary Davis
Epidemiology, Screening, and Natural History of Chronic Hepatitis B Infection . . . . . . . . . . . . . . . . . . . . . . . Shiv K. Sarin and Manoj Kumar
185
. . . . . . . . . . . . .
243
Current Treatment of Chronic Hepatitis B Walid S. Ayoub and Emmet B. Keeffe
Management of Patients Co-Infected with Chronic Hepatitis B (CHB) and the Human Immunodeficiency Virus (HIV) . . . . . . . . . . . . . . . . . . . . . . . . . . . Edward Doo and Marc Ghany Management of Antiviral Resistance in Chronic Hepatitis B . . . . . Edward Doo and Marc Ghany
ix
259 273
x
Contents
Herbal and Non-Traditional Therapies for Viral Hepatitis . . . . . . Veronika Gagovic and Paul Kwo
289
Hepatitis B Reactivation in the Setting of Chemotherapy and Immunosuppression . . . . . . . . . . . . . . . . . . . . . Halim Charbel and James H. Lewis
307
Support of Patients During Antiviral Therapy for Hepatitis B and C . . . . . . . . . . . . . . . . . . . . . . Alyson N. Fox and Thomas W. Faust
337
. . . . . . . . . . . .
353
Chronic Viral Hepatitis and Liver Transplantation . . . . . . . . . Kirti Shetty
375
Treatment of Viral Hepatitis in Children – 2008 . . . . . . . . . . . Zachary R. Schneider and Parvathi Mohan
405
Viral Hepatitis and Hepatocellular Carcinoma . . . . . . . . . . . Jorge A. Marrero
431
Hepatitis B Vaccines . . . . . . . . . . . . . . . . . . . . . . . . Oren Shibolet and Daniel Shouval
449
Viral Hepatitis, A Through E, In Pregnancy Eashen Liu and Jacqueline Laurin
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard C. Duke, Alex Franzusoff and David Apelian
471
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
491
CONTRIBUTORS DAVID A PELIAN , MD , PHD • GlobeImmune, Louisville, CO M OHAMMAD A SHFAQ , MD • Baylor University Medical Center, Dallas, TX WALID S. AYOUB , MD • Stanford University, Palo Alto, CA H ENRY C. B ODENHEIMER • Albert Einstein College of Medicine, New York, NY DAMARIS C ARRIERO , MD • Mount Sinai School of Medicine, New York, NY H ALIM C HARBEL , MD • Georgetown University Medical Center, Washington, DC M ARCY C OASH , MD • University of Connecticut Health Center, Farmington, CT G ARY DAVIS , MD • Baylor University Medical Center, Dallas, TX D OUGLAS D IETERICH , MD • Mount Sinai School of Medicine, New York, NY E DWARD D OO , MD • National Institutes of Health, Bethesda, MD R ICHARD C. D UKE , PHD • GlobeImmune, Louisville, CO T HOMAS W. FAUST • University of Pennsylvania, Philadelphia, PA A LYSON N. F OX • University of Pennsylvania, Philadelphia, PA A LEX F RANZUSOFF , PHD • GlobeImmune, Louisville, CO V ERONIKA G AGOVIC • Indiana University School of Medicine, Indianapolis, IN M ARC G HANY, MD • National Institutes of Health, Bethesda, MD I RA M. JACOBSON , MD • Weill Medical College of Cornell University, New York, NY E MMETT B. K EEFFE , MD • Stanford University, Palo Alto, CA K ETAN K ULKARNI , MD • Weill Medical College of Cornell University, New York, NY M ANOJ K UMAR , MD • G. B. Pant Hospital, New Delhi, India PAUL K WO • Indiana University School of Medicine, Indianapolis, IN JACQUELINE L AURIN , MD • Georgetown University Medical Center, Washington, DC JAMES H. L EWIS , MD , FACP, FACG • Georgetown University Medical Center, Washington, DC xi
xii
Contributors
E ASHEN L IU , MD • Georgetown University Medical Center, Washington, DC J ORGE A. M ARRERO , MD , MS • University of Michigan, Ann Arbor, MI D OUGLAS M EYER , MD • Albert Einstein College of Medicine, New York, NY PARVATHI M OHAN • Children’s National Medical Center, Washington, DC S HIV K. S ARIN , MD • G.B. Pant Hospital, New Delhi, India Z ACHARY R. S CHNEIDER • Children’s National Medical Center, Washington, DC NALINI K. S HARMA , MD • Washington Hospital Center, Washington, DC K IRTI S HETTY, MD , FACG • Georgetown University Medical Center, Washington, DC AVERELL H. S HERKER , MD , FRCP ( C ) • Washington Hospital Center, Washington, DC O REN S HIBOLET, MD • Hadassah-Hebrew University Hospital, Jerusalem, Israel DANIEL S HOUVAL , MD • Hadassah-Hebrew University Hospital, Jerusalem, Israel M ARIE -L OUISE VACHON , MD • Mount Sinai School of Medicine, New York, NY G EORGE Y. W U , MD , PHD • University of Connecticut Health Center, Farmington, CT
Molecular Virology of Hepatitis B and C: Clinical Implications Marcy Coash, MD and George Y. Wu, MD, PhD CONTENTS I NTRODUCTION H EPATITIS B V IRUS H EPATITIS C V IRUS C ONCLUSION : F UTURE T REATMENT S TRATEGIES ACKNOWLEDGMENTS R EFERENCES Key Principles
• • • • • •
HBV and HCV are hepatotropic, noncytotoxic viruses. Both viruses mutate rapidly to produce quasispecies. HBV, but not HCV, can integrate into the host genome. Both viruses require viral and host proteins for replication. Few animal models for HBV and HCV are available. Specialized features of viral replication may offer targets for new antiviral agents.
1. INTRODUCTION Despite fundamental differences in genome structure, hepatitis B (HBV) and C (HCV) viruses use many of the same strategies to achieve
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 1, C Humana Press, a part of Springer Science+Business Media, LLC 2009
1
2
Coash and Wu
high-level replication and persistence of infection in hepatocytes. The limited genome size of these viruses necessitates an efficient use of host cell machinery to carry out viral gene expression. This strong dependence on virus–host interactions restricts HBV and HCV cell tropism to the hepatocytes of higher primates and previously precluded their reliable and reproducible propagation in cell culture. Recent studies have begun to overcome this experimental limitation, so as to permit a more complete understanding of the molecular basis for viral replication, and the concomitant induction or evasion of the host antiviral immune response. Some of the important molecular biological properties of these viruses, as well as how they are reflected in the clinical manifestations of viral infection, are presented below.
2. HEPATITIS B VIRUS HBV is a member of the Hepadnavirus family, a group of hepatotropic mammalian and avian DNA viruses, which replicate via reverse transcription of a full-length genomic RNA intermediate carried out by reverse transcriptase activity present in the viral DNA polymerase (1–3). The frequency of mutation during HBV genome replication is 10-fold higher than the normal rate for DNA viruses due to the fact that RTs do not correct errors of transcription. HBV populations may evolve more quickly than most DNA viruses as a result of environmental factors allowing the development of viral HBV mutants. Diversification of HBV strains has produced genotypes, subgenotypes, and HBsAg subtypes. They have emerged in specific populations and migrated with their hosts to other areas of the world. Based on sequence divergence in the entire genome of >8%, human HBV strains have been classified into eight genotypes (A–H), further divided into 24 subgenotypes that differ by at least 4% from each other. Additionally, nine different serologic subtypes exist as determined by HBsAg epitopes. Each of the various genotypes exhibits a characteristic serotype profile and geographical distribution, allowing an evaluation of HBV phylogenetic evolution and possible genotypic influence on the natural course of HBV infection (4). The sequencing of clinical isolates has even been used as an epidemiological marker to trace routes of transmission. HBV infection is highly cell type- and species-specific: hepatocytes of the great apes are the only confirmed site of HBV replication. Reported infection of other cell types, e.g., lymphocytes, is controversial and generally thought to be of little clinical relevance. The lack of infection models to study the mechanisms of hepadnaviral entry and disease has been a significant problem in the past. Other hepadnaviruses, particularly duck and woodchuck hepatitis viruses, provided
Molecular Virology of Hepatitis B and C: Clinical Implications
3
convenient model systems for HBV infection and associated liver disease. With regard to cell culture models for HBV, recently primary hepatocytes from tree shrews, i.e., Tupaia belangeri, and a human hepatoma cell line (HepaRg) have been demonstrated to have susceptibility for HBV infection, the latter upon induction of differentiation in vitro (5). Besides the chimpanzees, which are extremely expensive and in short supply, a SCID mouse model based on primary human hepatocytes (PHH) and more recently an immunocompetent human hepatocyte-tolerant rat model have been described (6–8).
2.1. Structure of HBV HBV is a 42-nm-coated DNA virus with a partially double-stranded 3.2-kb genome. The virion is composed of a nucleocapsid covered with the envelope proteins. The nucleocapsid, or core particle (also known as Dane particle), is a 27-nm icosahedron made up of the core protein HBcAg, an incomplete double-stranded viral DNA, and a DNA polymerase. The envelope is composed of lipids derived from the host in combination with the viral surface antigen (HBsAg), which is made up of three related proteins (S, M, L), variably glycosylated. Excess HBsAg can aggregate to form noninfectious quasispherical particles 20 nm in diameter as well as tubular structures 22 nm in diameter (9, 10).
2.2. Replication Cycle HBV commonly achieves infection in virtually 100% of the hepatocyte population. The HBV replication cycle is complicated. Viral entry involves various components of the large and middle HBsAg proteins and annexins as well as other hepatocellular membrane proteins. Following entry into the host cell, the virus uncoats and the 3.2-kb partially double-stranded (pdsDNA) HBV genome is transported to the nucleus and converted by host RNA polymerase to a covalently closed circular (cccDNA) template, which is then organized into viral minichromosomes from which all viral mRNAs are transcribed, including the pregenomic RNA (pgRNA), which is essential for HBV replication (Fig. 1). Although the viral genome is a 3.2-kb partially double-stranded DNA molecule, it is generated by the reverse transcription of a longer-than-genome length 3.5-kb pregenomic RNA (11). The pgRNA is translated to produce the core protein and DNA polymerase and plays a role in nucleocapsid formation. The viral pgRNA transcript, encompassing the entire genome sequence, is subsequently encapsidated and reverse-transcribed into the pdsDNA form by a viral DNA polymerase, which functionally resembles that of a retrovirus.
4
Coash and Wu
Fig. 1. HBV life cycle. After cell entry, HBV nucleocapsids transport the partially double-standed circular genomic HBV DNA to the nucleus, where the DNA is converted into covalently closed circular (ccc) DNA. The cccDNA functions as the template for the transcription of four viral RNAs, which are exported to the cytoplasm and used as mRNAs for the translation of the HBV proteins. The longest pregenomic RNA also functions as the template for replication, which occurs within nucleocapsids in the cytoplasm. Nucleocapsids are enveloped during their passage through the ER or Golgi complex and are secreted through the cell. Adapted from Rehermann et al. (45).
Although direct cytopathic liver injury is seen under conditions of very high viral load—as in fibrosing cholestatic hepatitis, a rare condition observed in some patients with recurrent posttransplantation hepatitis B—the virus itself is generally noncytolytic. Rather, HBV-associated injury is attributed to the lysis of infected hepatocytes by the host immune response (12).
2.3. Cellular Entry Virion endocytosis, uncoating, and nuclear transport of the pdsDNA genome remain poorly understood, although the host cell contribution to these events is believed to be a major determinant of HBV-cell
Molecular Virology of Hepatitis B and C: Clinical Implications
5
tropism. Interaction of the viral envelope protein with a specific cell surface receptor is considered the initial step of HBV infection. Aside from host-derived phospholipids, the envelope of an HBV virion contains virus-derived (S), (M), and (L) surface proteins that are translated from distinct initiation codons, but share a common carboxyl domain. A generally accepted view is that the pre-S domain which resides on the N-terminal domain of the LHBs of the HBV envelope protein, specifically residues 21–47, is involved in mediating HBV attachment to a viral receptor on hepatocytes. The putative cellular receptor of HBV is still an enigma in the field of HBV research although studies with duck hepatitis B virus suggest the involvement of a carboxypeptidase receptor. More than 10 proteins including interleukin-6, human squamous cell carcinoma antigen 1, immunoglobulin A receptor, asialoglycoprotein receptor, transferrin receptor, apolipoprotein H, polymerized serum albumin, annexin V, fibronectin and more recently lipoprotein lipase have been demonstrated to interact with the HBV PreS or S proteins in vitro and may be potential receptor candidates although none of them has been experimentally proven to be the true receptor (13). Nuclear import of pdsDNA may be facilitated by the covalently attached HBV polymerase, or by the noncovalently associated capsid protein, which bears a nuclear localization signal. Host components involved in this nucleocytoplasmic transport have yet to be determined. Interestingly, the translocation event does not occur in transgenic mouse models of HBV infection, despite the ability of mouse hepatocytes to support subsequent steps in HBV replication.
2.4. cccDNA The mechanism by which HBV pdsDNa is converted to covalently closed circular form is not known, but presumably involves host cell DNA-repair pathways. Conversion of the relaxed circular DNA genomes of the incoming virus to covalently closed circular (ccc) DNA within the nucleus of an infected hepatocyte is the first marker of a productive infection, but is difficult to detect (14). Once formed, the cccDNA does not undergo semiconservative replication in the nucleus, as the intracellular HBV DNA pool can be supplemented only by reverse transcription in the cytoplasm, as described below. In contrast to serum HBV DNA which has a half-life of just 1–3 d, cccDNA is a remarkably stable species in hepatocyte nuclei despite the fact that it is not integrated into the cellular genome. It is resistant to direct elimination by antiviral agents and serves as a reservoir for viral reactivation when antiviral therapy is interrupted. The half-life of infected hepatocytes is quite long, 10–100 d or more, depending on the extent of liver injury. Accordingly, antiviral therapy with reverse transcriptase inhibitors requires an extended course of treatment to achieve
6
Coash and Wu
complete clearance, especially in mild disease with a relatively low rate of hepatocyte turnover.
2.5. Transcription In contrast to other DNA viruses, HBV appears not to utilize posttranscriptional alternative mRNA splicing to maximize its coding capacity. Instead, HBV makes exquisitely economical use of its genome at the transcriptional level by embedding regulatory elements—even overlapping open-reading frames (ORFs) (C, P, S, and X)—within concise protein coding sequences for seven viral proteins (Fig. 2). Despite its small size, the HBV cccDNA genome is sufficient to direct the synthesis of four classes of RNA transcripts by host RNA polymerase II. A pair of –3.5-kb RNAs, differentially regulated by the core promoter, function as templates for HBV DNA synthesis and serve as mRNAs for precore (HBeAg) which contains the full amino acid sequence of the core protein, and is not incorporated into the virus particle, but is secreted
Fig. 2. Structure of HBV DNA and genes. Four genes (S, C, X, and P) are encoded and these partially overlap. The pre-S gene is located upstream of the S gene and consists of the pre-S1 and pre-S2 genes. The precore region is upstream of the core gene.
Molecular Virology of Hepatitis B and C: Clinical Implications
7
in a soluble form by the infected cell, core (HBcAg), and polymerase (DNA-pol) proteins. The 2.4-kb and 2.1-kb pre-S1/pre-S2/S mRNAs encode the three envelope proteins. A 0.7-kb transcript directs the synthesis of the HBV X protein (HBxAg), which is a transactivator of virus replication that is not incorporated into the virion. The mature viral particle is composed of a single core protein, three envelope glycoproteins, and the viral DNA polymerase (2). Transcription of each HBV RNA initiates from one or more unique promoters, which are regulated by two shared enhancer elements, EN I and II. Activity of liver-enriched transcription factors (TFs) at these sites is thought to contribute to tissue specificity of HBV infection, as the observed multifactorial cis-regulation of viral promoters takes place only in well-differentiated liver cells (15). Additionally, the HBV genome also contains two 11-base direct repeats (DR1 and DR2) located at the 5 -end of both strands, a polyadenylation signal, and a site for glycocorticoid response (GRE). All transcripts terminate at a common polyadenylation signal, which is located in the core ORF. This signal is read-through during transcription of the pregenomic RNA, generating a terminally redundant greater-than-genome length transcript. Hepatitis delta RNA selectively inhibits transcription of pregenomic HBV RNA in vitro. This effect likely contributes to the frequently observed precore antigen seroconversion in carriers superinfected with HDV.
2.6. Translation Efficient use of coding sequences, the hallmark of HBV biology, is also apparent during translation. The surface antigens are generated by three different in-phase start codons. Translation of the precore/core ORF originates from one of two in-frame start codons; initiation from the upstream site generates the precore polypeptide containing a signal for secretion, which is posttranslationally modified to form the hepatitis B e-antigen. Translation of the polymerase gene initiates from an outof-frame start codon located in the C-terminal coding region of the core ORF. The inefficiency of this unconventional and, as yet, poorly understood process yields a core:polymerase molar ratio of 250:1. Interaction between the HBV polymerase and the 5 -end of its own mRNA is sufficient to block further translation and to precipitate the events of genomic replication.
2.7. Encapsidation and Reverse Transcription HBV RNA packaging and reverse transcription have been well characterized (16). Among the viral transcripts made from cccDNA, the
8
Coash and Wu
3.5-kb pregenomic RNA (pgRNA) encodes the core and polymerase proteins, and carries at its 5 -end a stem and loop structure known as epsilon that directs its encapsidation into the viral replication complex. The N-terminal domain of the polymerase protein binds to “epsilon” and is facilitated by host cell chaperones, such as p23 and heat-shock protein (Hsp)70; inhibitors of Hsp90 have been shown to block HBV RNA packaging and subsequent DNA synthesis. Formation of the polymerase–RNA complex triggers assembly of the viral nucleocapsid. The capsid is composed of 120 disulfide-linked core dimers, which collectively bind RNA via a C-terminal domain of the core polypeptide. The N-terminal domain is responsible for core protein dimer formation and capsid assembly (17). Reverse transcription occurs within the nucleocapsid, which contains small pores to allow influx of deoxynucleotides and other small molecules. Initiation of reverse transcription is accomplished by a protein-priming mechanism, utilizing an amino-terminal tyrosine residue of the polymerase and the epsilon structure as a replication origin. The C-terminal catalytic domains of the HBV polymerase protein exhibit reverse transcriptase, DNA-dependent DNA polymerase, and RNase H activities. In the presence of requisite host cell chaperones, and possibly other cofactors, the polymerase carries out synthesis of viral pdsDNA and nearly complete degradation of the pregenomic RNA template. Phosphorylated metabolites of the antiviral compounds lamivudine, famciclovir, lobucavir, and adefovir dipivoxil inhibit this step of HBV replication by competing with deoxynucleotide triphosphates for incorporation into HBV DNA, thereby causing premature termination of nascent polynucleotide chains. One notable feature of the HBV polymerization process is its discontinuous nature. pdsDNA synthesis requires dissociation of the polymerase, and nascent DNA from the RNA template, and annealing to a homologous direct repeat sequence on the 3 -end of the pregenome. Polymerization from primers that fail to undergo template switching (“in situ priming”) results in the formation of double-stranded linear (dslDNA) genomes. Although illegitimate recombination events can convert dslDNA into cccDNA, they may also cause integration of HBV sequences into host DNA.
2.8. Integration The integration of the HBV DNA is apparently a common event that occurs early during HBV infection even after acute self-limiting hepatitis. It is not essential for the viral replication, but it allows persistence of the viral genome. Transcription from integrated DNA accounts for
Molecular Virology of Hepatitis B and C: Clinical Implications
9
hepatitis B surface antigen HBsAg secretion observed in the absence of viral replication. Even in the majority of patients who develop spontaneous or treatment-induced HBeAg seroconversion and normalization of aminotransferase (ALT) levels and histology, HBV DNA sequences can be detected by PCR-based diagnostic tests. HBV dslDNA is likely the predominant integrating species, although the gap structure in the pdsDNA may facilitate integration of this form as well. Commonly, the core and polymerase genes are disrupted by integration, whereas the X and pre-S2/envelope ORFs remain intact. It has been demonstrated that the regulatory proteins HBx and the pre-S2 activators that can be encoded by the integrant can exert a tumor promoter-like effect and lead to a selection of cells that produce a functional regulatory protein. Integrated HBV DNA is found in the majority of HBsAg-positive hepatocellular carcinomas (HCCs). As with other viruses, these integrated viral genomes are characterized by rearrangements or partial deletions. HBV integration can induce deletions in the host chromosome at the integration site, as well as cause insertional mutagenesis, leading to activation of a proto-oncogene or inactivation of a tumor suppressor gene in cis. In woodchuck hepatitis virus, there is evidence of specific activation of the myc family of genes by this mechanism. In isolated cases of human HCC, HBV insertion has been observed near cyclin A, retinoic acid receptor , mevalonate kinase gene, sarco/endoplasmic reticulum calcium ATPase1 gene, and p53 loci. Integration in these genes can cause alterations in cellular signal transduction cascades, proliferation control, and cell viability. However, the HBV integration site is apparently random, and integration of full-length HBV genomes does not commonly lead to transformation of cultured cells.
2.9. X Protein and Hepatocarcinogenesis The oncogenic potential of HBV integration likely derives from the activation of host gene transcription in trans, rather than in cis (18). Truncated forms of the HBV pre-S/S envelope proteins may be formed as a result of integration. These exhibit potent transactivation in vitro and can stimulate the c-myc promoter, as seen in woodchuck hepatitis virus-related HCC. Integrated HBV DNA isolated from tumor nodules preferentially encompasses the X protein ORF. X is required for infection in vivo, but is dispensable for viral replication in transfection-based cell culture models. The X protein regulates transcription from viral and host RNA polymerase I, II, and III promoters in vitro (19). Although X has been shown to dimerize—a feature common to DNA-binding TFs—it likely acts as a coactivator. X associates with a myriad of host cell proteins, including transcriptional regulators such as NF-B,
10
Coash and Wu
AP-1, AP-2, c-EBP, ATF/CREB, and the calcium-activated factor NF-AT (20). It influences other TFs without binding them directly and so is thought to act by more global mechanisms, such as interaction with general transcription factors (TFIIB, RNA polymerase subunit 5). Among the multitude of cis-acting genetic elements responsive to X activity is HBV enhancer I: thus X may regulate its own synthesis. Enh I is responsive to many extracellular signals including 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid, IL-6, and genotoxic stimuli that are important in an acute inflammatory response and cell proliferation in the liver. X-responsive host genes include many involved in acute inflammatory and immune responses [e.g., major histocompatibility complex (MHC), tumor necrosis factor (TNF)-␣1, interleukin (IL)-6, signal transduction, cell proliferation, and apoptosis]. HBxAg sensitizes cells to TNF-␣ and is suspected to influence other apoptotic pathways. Overall, the transcriptional regulatory effects of X may contribute to viral persistence, increased cell turnover, and HBV-related hepatocarcinogenesis. Distinct from its transactivation function, HBxAg may disrupt DNA repair and normal cell-growth regulation by direct interaction with host regulatory proteins. X associates with a cellular factor called UVdamaged DNA-binding protein and downregulates nucleotide excision repair pathways. Sequestration by X protein also inhibits p53 nuclear translocation and tumor suppressor activities, disrupting transcriptioncoupled repair mechanisms. Consequently, X may sensitize cells to genotoxic stimuli and promote integration events and overall genetic instability common in HCC. Interestingly, HBxAg has been reported to exhibit endogenous adenosine monophosphate (AMP) kinase/ATPase activities and to colocalize with proteasome subunits, which may be mechanistically relevant to its observed effects on growth regulators. Stimulation of the Ras-Raf-mitogen-activated protein kinase pathway and activation of protein kinase C, c-Src, and c-Fyn have been reported in cell culture models of X expression. The retinoblastoma (Rb) tumor suppressor is inactivated by hyperphosphorylation in the presence of HBxAg. In vitro and transgenic studies indicate that X promotes cell transformation and carcinogenesis, but only upon overexpression to levels well beyond those typical of infected cells. Integration of X may lead to such overexpression, as subcellular localization studies indicate that expression of X from integrated templates leads to its accumulation and redistribution. Notably, an X-responsive bZip-family TF was found to be overexpressed in HCCs. However, cell transformation has been observed with the expression of the X gene product N-terminal domain, which lacks the transactivation function altogether. Indeed, most of the
Molecular Virology of Hepatitis B and C: Clinical Implications
11
proposed actions of X have not been demonstrated in the context of HCC-derived cells; it is possible that HBV-associated carcinogenesis is solely due to the induction of chronic hepatocellular necrosis and regeneration. Given that HBV-related HCC is closely associated with cirrhosis and that the peak incidence occurs 30–50 years after HBV infection, it is likely that the contribution of X expression alone is limited, relative to other factors, such as the extent of immune-mediated pathogenesis.
2.10. Virion Production Newly synthesized pdsDNA may be imported into the nucleus, resulting in the replenishment of the cccDNA pool, or secreted from the cells in virions. Completion of pdsDNA synthesis in some way facilitates nucleocapsid translocation into the endoplasmic reticulum (ER) and entry into the secretory pathway. The mechanism of this coupled maturation process is unknown, but may involve a conformational shift in the nucleocapsid exterior. Other factors, such as a core protein phosphorylation state or regulation by HBeAg, may influence the relative rate of cccDNA accumulation and virion production. HBeAg has been shown to slow HBV DNA replication in vitro by reducing HBcAg dimerization, thereby reducing encapsidation of pregenomic RNA and may induce immunological tolerance. Secretion is also dependent on the concentration of L envelope protein as the pre-S1 domain mediates association of the envelope with core particles. Through budding, the nucleocapsid acquires a coating of the S, M, and L transmembrane proteins. Transport of virions through the Golgi apparatus results in the maturation of envelope proteins into N-glycosylated disulfide-linked multimers. HBV is continuously released into the bloodstream, with a daily production of up to 1011 enveloped virions. HBV surface proteins are not only incorporated into virion envelopes, but they also bud very efficiently from intracellular post-ER pre-Golgi membranes. These envelopes lacking enclosed nucleocapsids can be secreted at more than a 100-fold excess over virions, resulting in very high serum concentrations of “surface antigen particles” or subviral particles. Subviral particles and virions have identical surface antigens (HBsAg), but their protein composition is not identical. Presumably the overproduction of HBsAg can influence the host immune response such that it is advantageous for the virus acting as immunological decoys (17–20). Extrahepatic symptoms may result from deposition of antigen–antibody complexes formed when these particles are neutralized by anti-HBsAg antibodies.
12
Coash and Wu
2.11. Immune System Evasion Infection of a high percentage of hepatocytes is observed even in acute, resolved cases, suggesting a delayed immune response to HBV antigens. Patients recovering from acute HBV infection exhibit humoral response to pre-S and S antigens, as well as vigorous, polyclonal cytotoxic T lymphocyte (CTL) activity against multiple epitopes of HBV envelope, core, and polymerase proteins. This response involves human leukocyte antigen class II-restricted CD4+ helper T lymphocytes and CD8+ cytotoxic T lymphocytes However, given the large quantity of hepatocytes infected and the rapid rate of clearance following transient infection, it has been proposed that HBV nucleic acids can be eliminated from infected hepatocytes by means other than direct CTL killing and replacement by noninfected cells. cccDNA may be lost from cell nuclei during mitosis. Additionally, the activation of an intracellular antiviral response by cytokines, such as TNF-␣, interleukin-12, and interferons (IFNs) alpha and gamma, is known to induce noncytocidal loss of viral RNA and proteins. At high doses, TNF and interferons downregulate the core promoter. Immunotolerance of HBV antigens may play a central role in viral persistence. Most infections in immunocompromised adults, and 90% of perinatal infections, progress to chronicity. These patients exhibit generally less severe liver disease than immunocompetent adults, despite higher viral load. The CTL and CD4+ T cell response in chronically infected patients is weak and restricted to relatively few epitopes. Hepatitis B e-antigen is not essential for infection in vivo, but appears to play an immunosuppressive role contributing to the maintenance of high-level viremia. HBeAg bears an N-terminal signal peptide and is actively secreted. It has been proposed to cross-react with antibodies to core or antagonize the inflammatory Th1 response, thereby suppressing the host’s ability to generate a sufficient CTL attack on infected hepatocytes. HBeAg may cross the placenta to establish T-cell tolerance to HBV e- and core antigens setting the stage for perinatally acquired chronic infection. Consistent with these proposed interactions, clearance of HBeAg during primary and chronic infections is frequently associated with ALT flare-ups. HBV mutant strains defective for e-antigen expression generally induce more severe immunemediated liver injury than wild-type and are more likely to be cleared during the acute phase of infection.
2.12. Viral Mutation The genetic stability of HBV is evidenced by the fact that each of the major genotypes exhibits only a few of the possible HBsAg sub-
Molecular Virology of Hepatitis B and C: Clinical Implications
13
types. The development of effective anti-HBV vaccines has been greatly facilitated by the high degree of sequence conservation in neutralization epitopes (e.g., the “a” determinant, amino acids 99–169) of the HBV envelope proteins. Even the most divergent genotype, F, retains approximately 85% genomic sequence identity with other genotypes. Despite this, viral reverse transcriptases lack a proofreading function and are inherently error prone, leading to frequency of HBV mutations estimated to be 1.4–3.2 ×10–5 nt substitutions per site per year. The remarkably low tolerance for mutations is most likely a consequence of the overlapping nature of the HBV genome, which dictates that a single-point mutation can affect multiple coding sequences and/or regulatory elements. HBV quasispecies variability is prone to stronger conservatory constraints than RNA viruses that do not have nonoverlapping reading frames such as HCV and poliovirus. Nonetheless, mutations in each of the four HBV genes have been clinically isolated, and these variants frequently arise in response to immune system selection and antiviral therapy (21, 22). In several cases, the emergence of a particular mutant is known to be contingent upon nearby wildtype sequences; therefore, HBV genotyping is valuable for the prediction and assessment of the clinical implications of viral mutation. This quasispecies distribution implies that if a newly generated mutation leads to a selective advantage for the virus, this will allow the corresponding viral population to overtake the other variants in a Darwinian manner.
2.13. Immune-Escape Mutants The emergence of HBV mutants has been implicated in vaccine failure and immune system evasion. Two major groups of mutations that lead to a reduction or a blockade of HBeAg expression have been identified. The common G-to-A transition at nucleotide 1896 results in a stop-codon mutation causing premature translation termination of the precore ORF, thereby preventing synthesis of HBeAg. Notably, this mutation is found in association with T1858, a sequence characteristic of HBV genotypes B–E, possibly because this pairing maintains stability of the pregenomic RNA encapsidation signal. This mutation is rarely found in genotypes A or F or in certain strains of HBV genotype C. The relative rarity of this mutation in genotype A may contribute to the observed low perinatal transmissibility of HBV from healthy HBsAg carrier mothers in Northwestern Europe where genotype A predominates. Precore mutants may replicate more efficiently than wildtype, but are most likely selected due to their ability to escape antiHBe surveillance. Their pathogenic significance is unclear, as mixed
14
Coash and Wu
viremia brings about a complex set of dynamic interactions with the host immune response (22). The second group of mutations resulting in alteration of HBeAg expression involves mutations affecting the basal core promoter occurring at nt 1762 and nt 1764. This results in reduced binding of liver-specific transcription factors, transcribing fewer precore and core mRNA transcripts and, therefore, less precore protein (HBeAg). These mutations, however, do not affect the transcription of pregenomic RNA or the translation of the core or polymerase. Genotype A-infected individuals often express this pattern of mutation and, therefore, have enhanced viral replication by suppression of precore and core mRNA relative to pregenomic RNA (23). Mutations in the X region lead to alteration in the regulatory elements that control replication and can include mutations in the basal core promoter and enhancer II. The basal core promoter spans nt 1742– 1802 and overlaps the reading frame of the X gene. The nt 1762 and the nt 1764 mentioned above are core promoter mutations that can cause changes in the X gene leading to production of truncated X proteins, which lack the amino acid domains required for transactivation activity of the HBxAg. Most hepatitis B vaccines contain the major HBsAg protein and induce an immune response to the major hydrophilic region at residues 99–170. The anti-HBsAg response produces protective immunity. Mutations within this epitope have been selected during vaccination. Envelope gene mutations are detected in roughly half of all individuals who develop postvaccination HBV infection and are particularly prevalent in infants born to carrier mothers. The most common of these so-called “vaccine-escape” mutants is G145R in the “a” determinant of HBsAg. Mutations here can lead to conformational alterations affecting the binding of neutralizing antibodies. These HBV mutants have been shown to escape vaccine-induced or passively transferred neutralizing responses allowing the propagation of a true HBsAg-positive HBV infection despite the high titer of anti-HBsAb (23, 14). Mutations within this locus have also been found in orthotopic liver transplant recipients who developed reinfection despite human immunoglobulin prophylaxis. The presence of escape variants correlated with a high incidence of graft failure, nearly double the percentage observed for patients lacking variants. The S140 residue, unique to HBV E and F genotypes, may predispose patients to a vaccine escape mutation at an adjacent locus, as K141E has been observed only in West Africa, where genotype E predominates. Pre-S1/S2 deletions and start codon mutants have been detected in patients with chronic and fulminant hepatitis, perhaps arising in
Molecular Virology of Hepatitis B and C: Clinical Implications
15
response to strong humoral and T-cell activity against this highly immunogenic region. Selection of emergent mutations in CTL epitopes of the envelope and core genes has been observed, though escape is incomplete due to the multispecific nature of the CTL response. Some of these mutant-derived core sequences act as antagonists of CTL response against the wild-type epitope and may contribute to viral persistence.
2.14. Polymerase Mutants HBV integration typically yields replication-deficient integrated genomes. Therefore, inhibition of reverse transcriptase for a sufficiently long duration should permit eventual immune-mediated clearance of the preexisting cccDNA pool. The advent of treatment with nucleoside and nucleotide analogues has resulted in the production of minor quasispecies containing mutations in the HBV Pol gene (23). Studies have shown that long-term monotherapy with lamivudine or other polymerase inhibitors is often unsuccessful due to breakthrough infection by drug-resistant polymerase gene mutants after approximately 1 year of therapy (21, 25). Polymerase mutants are absent from untreated patients and exhibit generally lower virulence than wild-type, due to lower catalytic activity or possible missense disruption of the overlapping S gene. Clinical manifestations of breakthrough infection are variable: most patients sustain lower-than-pretreatment serum DNA and ALT levels; but, in rare occasions, emergence is accompanied by ALT flares and hepatic decompensation. Upon therapy withdrawal, the reemergence of wild-type HBV typically yields further bouts of hepatitis. Lamivudine resistance increases progressively during treatment to 14–32% annually and can reach 70% after 48 months of treatment. Several mutations which confer resistance to lamivudine have been shown to cause substitutions within or adjacent to the “YMDD” motif at the catalytic site of the polymerase. A protein structure-based model by which these mutated residues block drug action has been proposed (24, 26). Famciclovir-associated polymerase gene mutations, commonly affecting upstream domains of the protein, have been identified in immunocompromised patients. Upstream mutations are more likely to affect immune epitopes on HBsAg, although the effect on antigenicity has yet to be determined. Unfortunately, the two most common famciclovir-resistant mutations, L528M and V521L, are also observed with lamivudine treatment, suggesting that patients who develop lamivudine-resistant mutants may not respond favorably to famciclovir treatment and vice versa. HBV resistance to adefovir occurs less
16
Coash and Wu
frequently—around 20% after 2 years—than lamivudine resistance. Adefovir resistance is conferred primarily by a mutation at codon 236 in the D motif of HBV Pol gene as well as a B motif mutation at 181. Entecavir resistance has been observed in two patients who were resistant to lamivudine with mutations mapped to the B motif at 184, the C motif at 202, and the D motif at 250 (23). Recent in vitro and in vivo studies indicate that YMDD gene variants resistant to lamivudine remain sensitive to adefovir, suggesting that the antiviral effects of these drugs will be additive. However, mutations that confer resistance to lamivudine have been shown to give partial resistance to entecavir in vitro. The identification of such mutually exclusive resistance profiles may be useful in the design of effective sequential or combination therapy regimens.
3. HEPATITIS C VIRUS One of the most remarkable features of hepatitis C virus is the frequency with which a chronic infection can be established, occurring in 55–85% of patients (27). In contrast to HBV, HCV exhibits extreme variability in nucleotide sequence. HCV, a member of the Flaviviridae family, has a single-stranded positive RNA genome with high genetic diversity. The diversity is due to defective repair activity of the RNAdependent RNA polymerase, which results in nucleotide substitution, as well as the absence of 5 to 3 exonuclease activity causing a lack of editing (28). At least six HCV genotypes and a large number of subtypes have been identified, some with different clinical outcomes. More recently, chimeric viruses generated by intergenotypic homologous recombination events in the NS2 gene have been described. For a genotype 1a strain, the complete ∼9600 nucleotide (nt) RNA genome has been verified by in vivo chimpanzee transfection, using transcripts derived from consensus cDNA clones. During the course of an infection, HCV mutations accrue at the rate of 1.4×103 to 1.9×103 substitutions per nucleotide per year. Variants reflecting slight modifications to the coding sequence, so-called “quasispecies”, are commonly found to coexist simultaneously within a patient, and any given serum-derived HCV inoculum contains a population of closely related viruses. The regions of the genome corresponding to essential viral functions such as those involved in translation or replication, as well as the noncoding 5 - and 3 -ends, are highly conserved. The most variable part of the genome is the region encoding the envelope glycoproteins E1 and E2, and certain strains have shown more than 50% variability (28). The observed “hypervariability” in HCV-envelope proteins is one explanation for the exceptional ability of HCV inocula to reinfect the same host following seroconversion and resolution of acute infection.
Molecular Virology of Hepatitis B and C: Clinical Implications
17
The absence of protective immunity against HCV continues to thwart vaccine development, and the emergence of drug-resistant strains will likely pose a future obstacle to long-term efficacy of inhibitors designed to target the enzymes responsible for viral replication.
3.1. Replication Cycle and Experimental Systems Chimpanzee infection studies revealed the principal etiologic agent of HCV hepatitis to be an enveloped, 9.6-kb linear single-stranded positive-sense RNA virus and has been characterized extensively in vitro (29, 30). The genome serves as a template for translation as well as for replication and is composed of a 5 -noncoding region (NCR), which includes an internal ribosome entry site (IRES), a single openreading frame that encodes structural and nonstructural proteins, and a 3 -NCR (31). The 5 -untranslated region (UTR) of virion RNA directs the cap-independent translation of a polyprotein, which is cleaved into structural (C,E1,E2,p7) and nonstructural (NS2,3,4A,4B,5A,5B) viral proteins (32). Replication of the viral RNA is carried out by an HCV-encoded RNA-dependent RNA polymerase, through a full-length negative-strand RNA intermediate without evidence of DNA formation (33) (Fig. 3). Nascent positive-strand RNAs can be utilized for translation, subsequent rounds of RNA replication, or packaging into virions. Although development of hepatitis in immunocompromised individuals suggests that HCV proteins may be directly cytopathic, the replication process is generally noncytolytic. In most cases, chronic infection continues for many years without evidence of hepatocyte injury. Since the discovery of the HCV in 1989, the difficulty in the development of a cell culture model has been a major obstacle for HCV research. Previous attempts using primary hepatocyte culture systems derived from resected liver tissue and inoculated with HCV-positive sera were only able to sustain low levels of viral RNA. One of the important milestones for HCV research was the development of replicon systems which supported HCV replication inside permissive cultured cells. Replicon systems have been used for screening antiviral compounds, studying host–viral interactions, RNA replication, and cellular innate immune responses. A shortcoming of this system is the lack of viral packaging and infectious viral release as would occur in infection. In 2005, several groups were able to establish complete viral cell culture systems. A genotype 1b HCV DNA was transfected into Huh7 cells, a cell line derived from a man with hepatocellular cancer. Another system developed included the JFH1 genotype 2a clone-based infectious cell culture system, which was cloned from a Japanese patient who had fulminant hepatitis caused by HCV. The viral replicons derived
18
Coash and Wu
Fig. 3. HCV life cycle. After HCV entry into the cell, the nucleocapsids are delivered to the cytoplasm, where the viral RNA acts as an mRNA for translation of a long polyprotein. RNA-dependent RNA replication converts the (+) into (−), which serves as a template for further (+) synthesis. Cytoplasmic replication occurs via membrane-associated replication complexes in a perinuclear membranous web. Genomic RNA-containing plasmids bud into cytoplasmic vesicles through intracellular membranes, which fuse with the plasma membrane. Adapted from Rehermann et al. (45).
from the JFH1 clone replicated much more efficiently without the need for adaptive mutation. It was later shown that infectious viral particles could be released from Huh7 cells when JFH1 full-length RNA was transfected into the cells and that these viral particles could reinfect other na¨ıve cells (33). Humans and chimpanzees are the only hosts able to support the complete viral life cycle, and the chimpanzee is still the only proven infection animal model. However, studies on chimpanzees are limited due to constraints on availability and cost. The development of other small animal models for HCV infection has been a priority. Tree shrews (T. belangeri) have been shown to be susceptible to infection with HCV. However, they must first be irradiated to reduce the immune response. Several lines of HCV transgenic mice have been established. These animals do produce circulating virus, but the lack of host immune tolerance to viral proteins does not simulate the normal immune response that
Molecular Virology of Hepatitis B and C: Clinical Implications
19
results in liver damage. A mouse model in which mouse hepatocytes were repopulated by human liver cells has also recently been demonstrated, and an even more successful model using a uPA-SCID transgenic mouse has shown potential applications in a model for HCV research (33). A rat model for HCV has recently been established through induction of tolerance of human hepatoma cell line Huh7. Rat livers transplanted with Huh7 cells were shown to develop HCV replication, gene expression, and biochemical as well as histological evidence of hepatitis. However, levels of virus were low, much lower than in average patients with HCV infection (34).
3.2. Viral Entry Recent studies have identified viral and host cell components involved in HCV cell entry. Hepatocytes are the main target cells for HCV infection. However, HCV has also been found in B cells, dendritic cells, and other cell types. The HCV envelope integral membrane proteins are glycosylated noncovalent heterodimers of two polypeptides, E1 and E2. The latter of these is apparently responsible for viral attachment, as E2-specific antisera can prevent HCV binding to cultured cells. Circulating HCV virions have been shown to associate with -lipoproteins. The capsid protein, core, colocalizes with apolipoprotein AII and intracellular lipid droplets; this interaction may contribute to hepatic steatosis observed in core transgenic mice. Notably, the expression of LDL receptor in some cell types was shown to induce HCV binding, which does not otherwise occur. The endocytosis of HCV particles appears to be mediated by LDL receptor, but may be assisted by other interactions. E2 was shown to bind a human cell surface membrane protein, CD81. This interaction may contribute to entry of HCV virions into hepatocytes, although expression of CD81 is a protein that has been found on the surface of many cell types. Other proposed HCV receptors in addition to LDL and CD81 include scavenger receptor class B type I (SR-BI), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN), and more recently, claudin-1 which has been found to be essential for HCV entry into hepatic cells and has been termed a coreceptor (31). HCV replication has been reported to occur in extrahepatic sites, most notably peripheral blood mononuclear cells (PBMCs) from chronically infected patients. High HCV RNA titers are observed in lymph nodes and approx. 50% of patients develop circulating HCV-associated cryoglobulins. An association with lymphoproliferative disorders such as
20
Coash and Wu
non-Hodgkin’s lymphoma has been reported. Lymphotropic variants of HCV have been isolated from passage in cell culture and chimpanzee PBMCs. Comparison of HCV RNA sequences isolated from viruses propagated in lymphocytes vs. hepatocyte cell lines revealed that the majority of amino acid positions which putatively influence cell tropism are located in E2. Events following HCV cell attachment remain to be elucidated. It is known that HCV enters by clathrin-mediated endocytosis via transit through an endosomal low pH compartment and presumably by endosomal membrane fusion. The actual mechanisms involved in activating the low pH-induced fusion as well as the fusion peptides still remain unknown (31). The E2 glycoprotein is insufficient for membrane fusion, and a hydrophobic region of the E1 glycoprotein has been proposed to mediate fusion of the viral envelope to the cell membrane. Upon cell entry, core associates with 60S ribosomal subunits, which may contribute to uncoating of RNA and initiation of IRES-mediated HCV translation and RNA replication (31).
3.3. Translation There is no evidence that HCV positive-strand RNA bears the 5 -methylguanidine cap and 3 -polyadenylate tail typical of eukaryotic messenger RNAs; but, it is nonetheless sufficient to direct translation of the ∼3000 amino acid-long HCV open-reading frame. The 5 -UTR sequence folds into a complex secondary and tertiary RNA structure. Notably, it is one of the few regions of the genome exhibiting little sequence variation among all HCV genotypes. The ∼300-nt region upstream of the initiator codon functions as an internal ribosome entry site (IRES). It directly recruits 40s ribosomal subunits to the start codon and can do so even in the absence of any canonical eukaryotic initiation factors. The IRES–40S ribosome complex then recruits eukaryotic initiation factor eIF-3 followed by Met-tRNA-eIF2-GTP to produce a 48S rRNA complex at the AUG initiation codon, which is then converted into an 80S complex in a rate-limiting step involving GTPdependent association of the 60S subunit (31). The formation of this complex is accelerated by the host NS1-associated protein-1 (NSAP-1), which binds to an adenosine-rich region within the HCV RNA (35). The unique internal entry and factor independence of HCV ribosome binding stand in marked contrast to cap-dependent translation initiation of host cell genes, making IRES a potential target for specific inhibition. Sequences adjacent to the minimal IRES element are thought to influence its activity either by preventing disruption of RNA secondary structure or possibly by recruiting host cell factors. Various host
Molecular Virology of Hepatitis B and C: Clinical Implications
21
RNA-binding proteins have been isolated via their direct interaction with the HCV UTRs, although in many cases their identity and contribution to translation initiation remain obscure. Disruption of these interactions might destabilize the IRES structure or diminish ribosome entry and could be explored as a treatment strategy. Indeed, the inhibition of translation and/or the direct cleavage of positive-strand RNA may be essential components of an effective antiviral therapeutic regime. Because HCV translation does not require the preexistence of virally encoded factors, any remaining RNA is sufficient to initiate new rounds of replication, even if all HCV enzymes are simultaneously inhibited.
3.4. Protein Processing Translation results in the production of a fusion protein which needs to be processed into each of its 10 proteins. Additionally an 11th protein is also produced by ribosomal frame-shifting within the core gene and is called alternative reading frame protein (ARFP) (35). Proteolytic processing of the HCV polyprotein is co- and posttranslational and mediated by both host and viral proteases (Fig. 4). The host signal peptidase, resident in the ER lumen, is responsible for cleavage between
Fig. 4. Structure of the HCV gene. A long single open-reading frame encodes a polyprotein of ∼3010 amino acids. The structural proteins are core, E1, and E2, the envelope proteins. The rest of the genome contains nonstructural proteins. Another protein known as ARFP (alternative reading frame protein) may be expressed from the core region of the genome as a result of translational frameshift.
22
Coash and Wu
the HCV structural proteins and separation at the p7/NS2 junction. The E1 and E2 proteins are translocated into the lumen of the ER, with the C-terminal domains remaining embedded in the membrane. Nonstructural proteins are cleaved by the activity of two virally encoded proteases, NS2 and NS3-4A serine protease (35). Enzymatically active viral proteases are essential for productive infection in the chimpanzee model (36). Autocatalytic cleavage at the NS2/3 site is carried out by the flanking protein domains, initially believed to function as a metalloprotease, but whose structural motifs are more indicative of a zinc-stabilized cysteine protease. All other principal cleavage sites within the HCV nonstructural region are hydrolyzed by a serine protease embodied in the N-terminal domain of the NS3 protein. (There is some evidence for further processing within the NS3 region by a cellular protease, which may contribute to proposed nonenzymatic functions of various NS3 domains discussed below.) Importantly, the stability and full activity of the NS3 protease requires association with the NS4A polypeptide, and the enzyme-active site may be subject to steric inhibition by the C-terminus of the NS3 protein. These properties, in addition to the known substrate specificity and crystal structure of the NS3/4A complex, will be important considerations for the design of HCV protease inhibitors. The structural proteins include core, E1, E2, and p7. Core is the highly conserved viral capsid protein, which has been shown to play a role in the regulation of gene transcription, apoptosis, alteration of IFN signaling, cell transformation, and interference of lipid metabolism, all of which may give a survival advantage to the virus. The E1/E2 proteins are glycoproteins present on the viral surface and are potential targets for vaccine development. However, mutations in the hypervariable E2 region have posed problems for the development of effective neutralizing antibodies. It has also been shown that E1/E2 proteins can form pseudoviral particles capable of eliciting antibody responses. The p7 protein has been identified as an ion channel which appears to be essential in the viral life cycle as chimpanzee studies have shown that viruses with p7 mutations were unable to establish infections in these animals (33). The remainder of the proteins are nonstructural proteins. NS2 is a cysteine protease which cleaves NS2/3 and has been shown to be involved in cell apoptosis and transcription modulation (33). NS3 is a bifunctional protein and has serine protease as well as RNA helicase activities. Fused NS3/4A is responsible for most of the nonstructural protein processing as stated above; it has also been shown to interfere with host innate immune response. NS4A has additional activity in that it targets NS3 to the ER via its N-terminal hydrophobic
Molecular Virology of Hepatitis B and C: Clinical Implications
23
amino acid stretch. NS4B is an integral membrane protein localized to the endoplasmic reticulum and plays a pivotal role in HCV replication (35). NS5A is a membrane-associated protein which interacts with other proteins and viral RNAs and has a role in cell transformation, transcription regulation, and apoptosis, as well has the suppression of IFN-induced antiviral efficacy. It has been found in association with p53, and its expression perturbs the Ras-ERK mitogenic signaling pathway as well as interferes with the function of the activator protein-1 (AP-1), a transcription factor involved in the activation of immediate-early genes (35). NS5B is an RNA-dependent RNA polymerase responsible for viral replication. It has been shown to associate with cyclophilin B resulting in enhanced RNA binding activity, and interestingly cyclosporine can inhibit HCV through this mechanism (33).
3.5. Immune System Evasion Once synthesized, the various HCV proteins are subject to hostmediated proteolytic degradation and presentation on the cell surface as foreign antigens. Epitopes from all HCV proteins can be presented by multiple MHC Class I and II haplotypes and are susceptible to recognition by immunoglobulins and T-cell receptors (37). In acute and IFN-resolved cases, humoral, CD4+ T cell, and CD8+ CTL responses are directed against all viral antigens and are especially vigorous against epitopes on core and NS3. In comparison to HBV, viral antigen expression is relatively low in hepatitis C; but, unlike some other viruses, HCV does not appear to actively subvert antigen processing and/or presentation. To the contrary, the expression of molecules which mediate antigen recognition, such as MHC, intracellular adhesion molecules, TNF-␣, and Fas antigen, is upregulated in HCV-infected cells. In chronic infection, the HCV-specific CTL response is effective enough to maintain some control over viral load; but, the majority of patients develop only a modest humoral response and are unable to establish a robust CTL activity sufficient to achieve clearance. How HCV is able to persist in the face of an active, concerted immune response is unclear. The lack of a virus-associated reverse transcriptase activity precludes integration into the host genome. Given the quasispecies nature of HCV infection, it is likely that “escape mutation” arises from nucleotide misincorporation by NS5B RNA-dependent RNA polymerase activity. It has long been presumed that sequence heterogeneity in immunodominant epitopes allows immune-mediated selection of resistant quasispecies. There is some evidence that selection of humoral escape variants can occur during the course of HCV
24
Coash and Wu
infection in humans and chimpanzees. The principal neutralization epitope, hypervariable region-1 (HVR1, a 27–30-residue amino acid sequence located in the E2 N-terminus), exhibits extreme variation among known isolates. Quasispecies with mutated HVR1 have been shown to arise in response to antibody selection against the parent sequence. It is also possible that mutations modify a dominant CTL epitope, as has been observed in chimpanzee acute infection. Mutation may convert viral polypeptides to potent antagonists of CTL directed against the wild-type sequence. This scenario has been observed with an NS3 epitope as well as an NS5B epitope, resulting in persistent infection (38, 39). The failure to clear HCV infection could conceivably result from a quantitative overwhelming of the T-cell response. The kinetics of viral replication may yield an insurmountably high ratio of infected hepatocytes to effector T cells. High viral load may also induce peripheral tolerance or T-cell “anergy,” wherein HCV-specific CTLs, activated in secondary lymphoid organs, are subsequently inactivated in the liver, because the viral antigen is presented in the absence of requisite costimulatory signals. HCV may exacerbate this scenario from within the host cell by debilitating the host cell response to cytotoxic mediators or other cytokines.
3.6. Inhibition of the Intracellular Antiviral Response HCV is recognized by innate virus-sensing mechanisms and induces a rapid interferon (IFN) response. Several lines of evidence suggest that HCV-infected cells are deficient in various aspects of IFN induction or response. This may allow the virus to persist in the face of IFN-based antiviral therapy. Several HCV-encoded proteins actively subvert the intracellular antiviral response. NS3-4A protease acts on cellular sensors of viral RNA to block the initial induction of IFN- (38). NS5A and E2 are known to inhibit the double-stranded RNA-activated protein kinase (PKR), an effector of the IFN-␣ pathway. Activation of PKR by double-stranded RNA substrates, such as viral RNA replication intermediates, causes phosphorylation of eukaryotic initiation factor 2, thereby shutting down translation of any host genes which might aid in viral replication. Binding by NS5A is thought to block dimerization of PKR, preventing its activation. The sequence of a relatively conserved 40 amino acid region within the putative PKR-binding domain of NS5A (the “interferon sensitivity-determining region,” ISDR) was previously shown to correlate with resistance to interferon treatment for Japanese patients infected with certain HCV genotypes. However, the correlation is weak or nonexistent when the analysis is extended to
Molecular Virology of Hepatitis B and C: Clinical Implications
25
other geographic regions or genotypes, and the selection of resistant ISDR sequences during the course of interferon treatment does not appear to be common. The NS5A protein may disrupt the interferon response in other ways, as the C-terminal region exhibits transcriptional activation properties and bears a nuclear localization signal. Although these functions are not evident in the full-length protein, liberation of the C-terminus by proteolytic processing raises the possibility that NS5A might influence the expression of other host genes involved in the antiviral immune response. HCV core protein is known to inhibit apoptosis in various cell types. Although results from some experimental systems suggest that core actually sensitizes cells to TNF or Fas-mediated apoptosis, it is possible that this viral protein modulates intracellular signal transduction pathways so as to abrogate cell death signals. The interaction of core protein with the lymphotoxin- receptor and TNF receptor-1 and concomitant effects on intracellular signaling have been demonstrated in vitro. It has been proposed that in this way, HCV disrupts host nuclear factor-B-mediated signaling, so as to confer a survival advantage to infected hepatocytes or to prevent activation of B cells. The NS3 protein may disrupt signal transduction pathways governing cell death and proliferation. The helicase domain includes a short amino acid sequence similar to autophosphorylation and inhibitor regulatory sites of cyclic AMP-dependent protein kinase (PKA). Polypeptides bearing this NS3 sequence bind to the PKA catalytic subunit, inhibiting its nuclear translocation and phosphorylation of host cell substrates. The NS3 protease domain suppresses actinomycin D-induced apoptosis in some cell types, apparently by sequestering or decreasing the expression of p53.
3.7. HCV Proteins and Hepatocarcinogenesis In recent years, the effects of hepatitis C viral proteins on hepatocarcinogenesis have undergone intense investigation (40). The antiapoptotic effects of viral proteins, in addition to increased cellular turnover resulting from chronic inflammation, may contribute to the development of HCV-associated HCC (41). The prevalent HCC incidence in HCV carriers, estimated at 20%, suggests an important role for the virus in hepatocarcinogenesis. HCV proteins are almost invariably expressed in these tumors, and some chronically infected patients develop HCC even in the absence of cirrhosis. The potentially oncogenic proteins implicated in HCC development in HCV-infected patients include core protein, NS3, and NS5A. Researchers have found relationships between subcellular localization,
26
Coash and Wu
concentration, specific molecular forms of the proteins, the presence of specific domains, and their effects on pathways leading to oncogenesis. Each of the proteins has been associated with control of the cell cycle via interaction with p53, p21, cyclins, and proliferating cell nuclear antigen. Interactions with transcription factors, protooncogenes, growth factors/cytokines and their receptors, and proteins related to apoptotic processes have also been described (40). The involvement of the core protein in hepatocarcinogenesis is probably the most recognized. Although the C-terminal hydrophobic region of full-length HCV core renders the polypeptide membraneassociated and localized to cytoplasmic membranes, the N-terminus bears a nuclear localization signal. Some in vitro expression studies suggest that core, and particularly its C-terminally truncated forms, can be phosphorylated by protein kinases A and C and translocated to the nucleus. Core may exhibit transcriptional regulatory activity on cellular promoters, so as to induce host cell proliferation. Accordingly, core has been shown to activate the c-myc promoter and to suppress transcription of c-fos, p53, Rb, and -IFN. Additionally, it may interact with heterogeneous nuclear ribonucleoprotein K, so as to depress the human thymidine kinase gene promoter. In coexpression studies with H-ras oncogene, core contributed to the tumorigenic transformation of primary rodent fibroblast cells. HCC development reportedly occurs in transgenic mice expressing core, and C-terminal mutations in the core coding sequence have been observed in HCV RNA isolated from human HCC tissue. The serine protease domain of NS3 has also been reported to transform murine cells and to induce HCC in transgenics. In HCV RNA replicon-harboring cells, physical interaction between NS3 and p53 was observed and p53-mediated transcriptional activation was suppressed compared with HCV RNA-negative control cells (42). Overexpression of HCV NS5A protein in cultured liver cells was found to promote chromosome instability and aneuploidy. It was also found to be associated with aberrant mitotic regulations such as a delay in mitotic exit and other mitotic impairments (43). In addition to the possible direct oncogenic effects of these proteins, neoplastic transformation likely arises as an inevitable consequence of chronic liver cell proliferation, a condition which may be deliberately induced by HCV in order to maximize viral replication.
3.8. RNA Replication The RNA polymerase activity responsible for HCV RNA synthesis is encoded in the NS5B region. This viral protein is sufficient for the
Molecular Virology of Hepatitis B and C: Clinical Implications
27
synthesis of full-length HCV RNA in vitro, although many host proteins are known to bind HCV 3 -terminal sequences and may influence template specificity in vivo. The HCV 3 -UTR contains a polypyrimidine (U/UC) sequence of variable length and terminates in a highly conserved 98-nt sequence, the “X region.” X is nearly identical in every isolate analyzed thus far, consistent with its essential role in replication. Deletion of X, or of the polypyrimidine sequence immediately upstream, renders RNA noninfectious in the chimpanzee model. Although the negative-strand 3 -terminus lacks a large polypyrimidine tract, the terminal 239 nt has been shown to function in vitro as a template for NS5B RDRP activity. In vitro NS5B assays indicate that HCV RNA synthesis is initiated by a primer-independent de novo mechanism. Notably the 3 -terminal 45 nt of the positive strand fold into a thermodynamically stable stem-loop structure, which may require unwinding by an RNA helicase in order for the polymerase to gain access. Accordingly, NS3, found to colocalize with NS5B, bears an NTPase/helicase activity in its C-terminal domain. NS3 helicase binds HCV UTR sequences, unwinds RNA duplexes in a 3 to 5 direction and is essential for infection in the chimpanzee model (36). The helicase is thought to dissociate nascent complementary strands from the HCV RNA template, although NS3 activity has not yet been demonstrated in the context of viral RNA synthesis. The C-terminal hydrophobic sequence of NS5B is necessary for its localization into membrane-associated complexes in the perinuclear region, the proposed site of HCV replication. A specific membrane alteration termed the membranous web was identified as the site of RNA replication. It is hypothesized that this web is derived from ER membranes (31). These complexes are thought to form by noncovalent protein–protein linkage of all HCV NS proteins with the exception of NS2, in association with one or more host-encoded factors. These protein aggregates are tethered to ER membranes by the NS4A peptide. Dissociation of replication complexes, or disruption of their anchorage to membranes, presents possible means to inhibit RNA replication. Also, the recently solved crystal structures of NS5B and the NS3 helicase domain will facilitate the rational design of inhibitors. HCV RNA replication appears to be influenced in subtle ways by the NS5A protein. Two forms of NS5A, differing in the extent of serine phosphorylation, are generally present within infected cells. This phosphorylation may serve to regulate NS5A subcellular localization and putative transcriptional regulatory activity. However, the utility of NS5A hyperphosphorylation and the identity of the kinase responsible for it remain to be determined. Interestingly, mutation of serine
28
Coash and Wu
phosphorylation sites, or deletion of the ISDR, greatly enhances replication of subgenomic HCV replicons in cell culture (44). Like the HBV polymerase, HCV NS5B lacks proofreading activity and exhibits a high rate of nucleotide misincorporation. To some degree, HCV may avoid replicating lethally mutated genomes by utilizing only the genomic RNA template from which NS5B is translated. Still, it is thought that the majority of serum HCV RNA is replication-defective, bearing one of more mutations prohibitive of viral replication. Because its coding sequence is nonoverlapping, HCV presumably exhibits a higher tolerance for mutation than HBV. Therefore, HCV escape variants may present an even greater obstacle for therapy than the HBV mutants. The oral nucleoside analogue, ribavirin, has shown promise as an inhibitor of HCV replication; but, its effects on HCV RNA levels are generally transient.
3.9. Assembly and Secretion The details of HCV virion assembly are very poorly understood at present. But, the recent development of cell culture-based systems for the production of virus-like particles may soon shed light on the relevant mechanisms. Although core protein oligomerization and specific interaction with E1 have been demonstrated, core exhibits only nonspecific RNA binding. Core may preferentially bind positive-strand RNA; but, no discrete encapsidation signal is apparent. By analogy to HBV pregenomic RNA, which binds to both of its gene products to facilitate packaging and replication, the HCV-positive strand may bind core and NS5B cotranslationally. Binding to core might suppress IRES activity, leading to a transition from replication to assembly. Another event which may contribute to virion formation is the C-terminal proteolytic processing of the core and E2 proteins. At the time of translation, the cleavage between E2 proper and p7 is incomplete, giving rise to two forms of the envelope protein. An as yet unidentified protease, possibly signal peptide peptidase, is believed to trim the E1 signal sequence from the core C-terminus posttranslationally. The E2 C-terminal domain acts as an ER retention signal; the glycoproteins are not translocated through the Golgi apparatus to the cell surface unless incorporated into virion envelopes. Therefore, cytoplasmic HCV core-encapsidated RNA particles are thought to bud through the ER membrane, rather than the cell membrane. In so doing, they acquire a coating of E1–E2 heterodimers. The complete virions progress through the Golgi apparatus and are released into the extracellular space by exocytosis. Interestingly, transgenic mice expressing HCV E1 and E2 exhibit salivary and lachrymal exocrinopathy resembling Sjogren’s syndrome, suggesting that these proteins may
Molecular Virology of Hepatitis B and C: Clinical Implications
29
disrupt cellular exocytosis and contribute to the pathogenesis of this disorder in chronically infected patients. It is estimated that a typical infected liver releases ∼1012 HCV virions per day. Assuming 10% of hepatocytes are infected, this amounts to 50 particles per cell per day. Hepatocytes generally maintain a low level of intracellular RNA; approx. 3×1011 RNA molecules are produced daily. Thus, as with HBV, there is evidence that a substantial portion of released particles are replication-defective virions, or naked core structures. With a virion half-life of just 4–7 h, most patients have an understandably low serum titer.
4. CONCLUSION: FUTURE TREATMENT STRATEGIES It is apparent from the above discussion that, given the compactness of HBV and HCV genomes, conserved sites exhibiting multiple essential functions can be readily identified. It may be possible to design single inhibitors, or therapeutic regimes, which target these important viral functions simultaneously. Our expanding knowledge of hepatitis virus molecular biology has provided a wealth of novel strategies to achieve maximal genomic coding capacity, persistence of infection, and immune system evasion. Application of these concepts may be useful for the design of gene therapy constructs, perhaps even hepatotropic vectors based on HBV-or HCV-derived replicons.
ACKNOWLEDGMENTS The support of the grant NIDDK-42182 from NIH, the Herman Lopata Chair in Hepatitis Research, is gratefully acknowledged.
REFERENCES 1. Seeger C, Mason WC. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000; 64: 51–68. 2. Echevarria J, Avellon A. Hepatitis B virus genetic diversity. J Med Virol 2006; 78: S36–S42. 3. Glebe D. Recent advances in hepatitis B virus research: A German point of view. World J Gastroenterol 2007; 13(1): 8–13. 4. Magnius LO, Norder H. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene. Intervirology 1995; 38: 24–34. 5. Glebe D, Urban S. Viral and cellular determinants involved in hepadnaviral entry. World J Gastroenterol 2007; 13(1): 22–38. 6. Mercer DF, Schuller DE, Elliott JF, Dpigas DM, Jap C, Romfret A, Addison WR, Fischer KP, Churchil TA, Lakey JRT, Tyrrell DLJ, Kneteman NM. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 2001; 7: 927–933.
30
Coash and Wu
7. Ouyang EC, Wu CH, Walton CM, Promrat K, Wu GY. Transplantation of human hepatocytes into tolerized genetically immunocompetent rats. Wld J Gastro 2001; 7: 324–330. 8. Wu CH, Ouyang EC, Walton CM, Promrat K, Forouhar F, Wu GY. Hepatitis B virus infection of transplanted human hepatocytes causes a biochemical and histological hepatitis in immunocompetent rats. Wld J Gastro 2003; 9: 978–983. 9. Roberts E. Hepatitis B: The next generation. Pediatr Res 2004; 56(3): 318–320. 10. Yokosuka O, Arai M. Molecular biology of hepatitis B virus: Effect of nucleotide substitutions on the clinical features of chronic hepatitis B. Med Mol Morphol 2006; 39: 113–120. 11. Oropeza C, McLachlan A. Complementarity between epsilon and phi sequences in pregenomic RNA influences hepatitis B virus replication efficiency. Virology 2007; 359(2): 371–381. 12. Lok AS. Hepatitis B infection: Pathogenesis and management. J Hepatol 2000; 32 (1 Suppl): 89–97. 13. Deng Q, Zhai J, Michel M, Zhang J, Qin J, Kong Y, Zhang X, Budkowska A, Tiollais P, Wang Y, Xie Y. Identification and characterization of peptides that interact with hepatitis B virus via the putative receptor binding site. J Virol 2007; 81(8): 4244–4254. 14. Pawlotsky J. The concept of hepatitis B virus mutant escape. J Clin Virol 2005; 34(1): S125–S129. 15. Kramvis A, Kew MC. The core promoter of hepatitis B virus. J Viral Hepat 1999; 6: 415–427. 16. Nassal M. Hepatitis B virus replication: Novel roles for virus–host interactions. Intervirology 1999; 42: 100–116. 17. Melegari M, Wolf S, Schneider R. Hepatitis B virus DNA replication is coordinated by core protein serine phosphorylation and HBx expression. J Virol 2005; 79(15): 9810–9820. 18. Feitelson MA. Hepatitis B virus in hepatocarcinogenesis. J Cell Physiol 1999; 181: 188–202. 19. Murakami S. Hepatitis B virus X protein: Structure, function and biology. Intervirology 1999; 42: 81–99. 20. Bouchard M, Schneider R. The enigmatic X gene of hepatitis B virus. J Virol 2004; 78(23): 12,725–12,734. 21. Bruss V. Hepatitis B virus morphogenesis. World J Gastoenterol 2007; 13(1): 65–73. 22. Brunetto MR, Rodriguez UA, Bonino F. Hepatitis B virus mutants. Intervirology 1999; 42:69–80. 23. Watanabe T, Sorenson E, Naito A, Schott M, Kim S, Ahlquist P. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. PNAS 2007; 104(24): 10,205–10,210. 24. Locarini S. Molecular virology of hepatitis B virus. Semin Liver Dis 2004; 24: 3–10. 25. Hussain M, Lok ASF. Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B. J Viral Hepat 1999; 6: 183–194. 26. Doo E, Liang TJ. Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection. Gastroenterology 2001; 120: 1000–1008. 27. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Int Med 2000; 132: 296–305.
Molecular Virology of Hepatitis B and C: Clinical Implications
31
28. Guillou-Guillemette H, Vallet S, Gaudy-Graffin C, Payan C, Pivert A, Goudeau, Lunel-Fabiani F. Genetic diversity of the hepatitis C virus: Impact and issues in the antiviral therapy. World J Gastroenterol 2007; 13(17): 2416–2426. 29. Hagedorn CH, Rice CM, editors. The hepatitis C viruses (Current Topics Microbiol Immunol, Vol 242). Springer-Verlag, New York, NY. 30. Bartenschlager R, Lohmann V. Replication of hepatitis C virus. J Gen Virol 2000; 81: 1631–1648. 31. Mardapour D, Penin F, Rice C. Replication of hepatitis C virus. Nat Rev 2007; 5: 453–463. 32. Suzuki R, Suzuki T, Ishii K, Matsuura Y, Miyamura T. Processing and functions of hepatitis C virus proteins. Intervirology 1999; 42: 145–152. 33. Liu C. Hepatitis C virus: Virology and experimental systems. Clin Liver Dis 2006; 10: 773–791. 34. Wu GY, Konishi M, Walton CM et al. A novel immunocompetent rat model of HCV infection and hepatitis. Gastroenterology 2005; 128: 1416–1423. 35. Qureshi S. Hepatitis C virus-biology, host evasion strategies, and promising new therapies on the horizon. Med Res Rev 2007; 27: 353–373. 36. Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3’ nontranslated region are essential for virus replication in vivo. J Virol 2000; 74: 2046–2051. 37. Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C: Immunological features of hepatic injury and viral persistence. Hepatology 1999; 30: 595–601. 38. Dustin L, Rice C. Flying under the radar: The immunobiology of hepatitis C. Annu Rev Immunol 2007; 25: 71–99. 39. Forns X, Thimme R, Govindarajan S, Emerson SU, Purcell RH, Chisari FV, Bukh J. Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees. Proc Natl Acad Sci USA 2000; 97: 13,318–13,323. 40. Kasprzak A, Adamek A. Role of hepatitis C virus proteins (C, NS3, NS5A) in hepatic oncogenesis. Hepatol Res 2007; 1789–1820. 41. Colombo M. Hepatitis C virus and hepatocellular carcinoma. Semin Liver Dis 1999; 19: 263–267. 42. Deng L, Nagano-Fujii M, Tanaka M, Nomura-Takigawa Y, Ikeda M, Kato N, Sada K, Hotta H. NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. J Gen Virol 2006; 87: 1703–1713. 43. Baek KH, Park HY, Kang CM, Kim SJ, Jeong SJ, Hong EK, Park JW, Sung YC, Suzuki T, Kim CM, Lee CW. Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation. J Mol Biol 2006; 359(1): 22–34. 44. Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290: 1972–1975. 45. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5: 215–228.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C Nalini K. Sharma, MD and Averell H. Sherker, MD FRCP (C) CONTENTS E PIDEMIOLOGY R ISK FACTORS NATURAL H ISTORY O F HCV C ONCLUSIONS R EFERENCES
Key Principles
• Approximately 3% of the world’s population is infected with the hepatitis C virus (HCV) with the highest prevalence rates noted in Africa and Asia. • In the United States, the incidence of HCV infection is declining secondary to effective blood donor screening adopted in the early 1990s and changing practices of intravenous drug users due to an increased awareness of HIV and hepatitis. • Hepatitis C can be categorized into six genotypes and 50+ subtypes. Genotypes 1a and 1b are the most common, accounting for about 60% of global infections.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 2, C Humana Press, a part of Springer Science+Business Media, LLC 2009
33
34
Sharma and Sherker
• Hepatitis C is transmitted primarily via parenteral routes. Mucosal exposures to blood or serum-derived fluids and environmental sources also play a role in HCV transmission. • Controversy exists regarding the natural history of hepatitis C. While many experts view hepatitis C as a progressive disease with a high likelihood of advancing to cirrhosis, hepatocellular carcinoma, and death, others consider this virus to be more variable in nature, with the majority of patients “dying with the disease, not of the disease.” The CDC estimates that up to 20% of chronic HCV infections lead to cirrhosis over a period of 20–30 years. • Several factors influence the rate of progression of hepatitis C. Progression is hastened when acquired via blood transfusion; at an older age; in males; in non-African-Americans; in the setting of excessive alcohol (and possibly tobacco) use; and, in persons with HIV and/or HBV coinfection or features of metabolic syndrome. It is controversial if HCV viral load and genotype affect the evolution of disease.
1. EPIDEMIOLOGY 1.1. Global Prevalence and Incidence The World Health Organization (WHO) reports that approximately 3% of the world population, or 170 million persons, is infected with the hepatitis C virus (HCV) with between 3 and 4 millions new infections each year (1). Limitations of global HCV epidemiological data include lack of data submission from numerous countries, variations in the population groups studied, and differing methods of data collection and interpretation. The majority of studies extrapolate data from blood donors alone, which is not representative of the entire population and is likely an underestimate. Figure 1 illustrates the global prevalence of HCV. Africa and Asia have the highest reported prevalence rates, in contrast to the low rates of HCV in North America, Western Europe, and Australia. Egypt has an unusually high prevalence of hepatitis C even by the standards of other developing nations with 20% of Egyptian blood donors positive for HCV antibody. Previous parenteral therapy for Schistosomiasis with inadequate sterilization techniques has been implicated as the cause for this high prevalence rate (2). Similar epidemiological events explain other countries’ spike in infection rates. For example, Italy’s HCV prevalence rate of 12.6% is attributed to the improper use of glass
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
Prevalence of infection ≥10% 2.5– 9.9% 1– 2.4% 0–0.9%
35
Source: WHO, 2003.
Fig. 1. Global prevalence of hepatitis C. Source: WHO, 2003.
syringes for administration of the Salk vaccine to prevent polio in the 1960s (3). Japan’s prevalence rate of 2.6% is thought to be secondary to the use of injection methamphetamines in the 1950s (WHO).
1.2. United States Prevalence and Incidence HCV is the most common bloodborne infection in the United States. The estimated prevalence of HCV seropositivity in the United States general population is 1.6% or 4.1 million persons. Of those who are anti-HCV positive, 79.7%, or 3.2 million persons, have chronic infection. The prevalence is highest among non-Hispanic black males between 40 and 49 years of age. This data is derived from the most recent National Center for Health Statistics (NHANES) survey (1999– 2002) of 15,079 random participants whose serum samples were tested for HCV antibody and HCV RNA (4). This information is consistent with results from NHANES III (1988–1994), except that peak prevalence data have shifted from ages 30–49 to 40–49 (representing similar birth-year cohorts) (5). Figure 2 illustrates this data. A drawback to analyzing the NHANES population is the exclusion of incarcerated, institutionalized, and homeless persons. The Centers for Disease Control (CDC) estimates that if the incarcerated population is included, 3.5 million persons have chronic HCV infection (6). Cheung et al. (7) performed a retrospective analysis of homeless veterans admitted to a domiciliary facility at the VA Palo Alto Health Care
36
Sharma and Sherker
Prevalence of Anti-HCV, United States, 1999–2002 (NHANES) Overall prevalence: 1.6% (4.1 million) Born~1945–1965
7%
Men Women
6% 5% 4% 3% 2%
Ams tong etal AASLD 2004.
55+
50–54
45–49
40–44
35–39
20–34
0%
6–19
1% ALL
Prevelence of anti-HCV
8%
Age Group (years)
Fig. 2. Prevalence of anti-HCV in the United States, 1999–2002.
System and found a 41.7% prevalence of HCV seropositivity, suggesting that homeless persons represent a significant pool of chronic HCV infection. Studies focusing on specific populations have shown varying prevalence rates. For example, Dominitz et al. (8) reported a prevalence rate of 4.0% among a Department of Veteran Affairs (VA) patient population randomly selected from 20 VA centers. This is lower than prior estimates that have ranged from 6.6 to 35% (9–11). Among 10,000 active duty military personnel, Hyams et al. (12) found an overall HCV seropositivity prevalence rate of 0.48%; this rate was lower (0.1%) in persons aged lesser than 30 as compared to those aged greater than 40 (3.0%). The lower prevalence among active duty members compared to the general VA population can be attributed to mandatory illicit drug testing throughout military service since 1971. Recently, Tabibian et al. (13) reported a seropositivity prevalence of 38% among 129 veterans in a psychiatric ward. Among health-care workers at Johns Hopkins Hospital, a prevalence of 0.7% was reported, comparable to that observed in local blood donors (14). In the United States, the incidence of HCV infection is declining secondary to effective blood donor screening adopted in the early 1990s and changing practices of intravenous drug users due to an increased
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
37
2.5
Incidence
2.0
1.5
1.0
0.5
0 1993
1995
1997
1999
2001
2003
2005
Year
Fig. 3. Incidence of acute hepatitis C. Source: Wasley A. Morbidity and Mortality Weekly Report 2007.
awareness of HIV and hepatitis. This decline is illustrated in Fig. 3 (15). The CDC estimates that while there were 180,000 new cases per year in the 1980s, this declined to 20,000 new cases in 2005 (15). This data is based on cases reported voluntarily to the CDC by state and territorial health departments via the National Electronic Telecommunications System for Surveillance (NETSS). Figure 3 illustrates the declining incidence of acute hepatitis C.
1.3. Genotype Hepatitis C can be categorized into six genotypes and 50+ subtypes. It is important to note an infected person’s specific genotype as it affects treatment dose, duration, and response. NHANES III reported that 73.7% of the US population is infected with genotype 1 (5). Genotypes 1–3 have a worldwide distribution. Genotypes 1a and 1b are the most common, accounting for about 60% of global infections. They predominate in Northern, Southern, and Eastern Europe; North America; and Japan. Genotype 2 is less frequently represented than genotype 1 and is often associated with the risk factor of prior blood transfusion (16). Type 3 is common in Southeast Asia and is variably distributed in different countries. In Western countries, it is often associated with a history of illicit drug use (16, 17). Genotype 4 is principally
38
Sharma and Sherker Table 1 Common global genotypes Country
Predominant genotype
United States (5) Egypt (2) England (171, 172) Chile (37, 173) Japan (174, 175) China (176) Thailand (177) India (178, 179) Saudi Arabia (180)
1a, 1b 4 3 1b 1b 2 3a 3 4
found in the Middle East, Egypt, North and Central Africa. Type 5 is found almost exclusively in South Africa, and genotype 6 is distributed throughout Asia (39, 58, 94, 103) (Table 1).
2. RISK FACTORS Hepatitis C is transmitted primarily via parenteral routes. Mucosal exposures to blood or serum-derived fluids and environmental sources also play a role in HCV transmission. Currently the predominant risk factor for HCV in the United States is intravenous drug use. Prior to 1990, blood transfusions contributed the majority of cases; however, with the adoption of effective blood donor screening programs and eventually universal serological screening, this method of transmission has been virtually eliminated. According to a large case–control study of US blood donors, injection drug use, history of blood transfusion, and sex with an injection drug user are the three commonest risk factors for HCV, whereas drug inhalation and high-risk sexual activity are not independently associated with hepatitis C (18). NHANES III reported an association between HCV and marijuana and/or cocaine use, in addition to high-risk sexual behavior (5). Dominitz et al. conducted a study involving veterans with hepatitis C at 20 Veteran Affairs medical centers and found that 78% reported intravenous drug use or blood transfusion as a risk factor. Among patients with HCV infection, 20–40% of patients do not have an identified risk factor for transmission. Karmochkine et al. surveyed 450 HCV patients without a history
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
39
of intravenous drug use or blood transfusion and 757 anti-HCV-negative controls. Multivariate analysis illustrated 15 independent risk factors for transmission including gastrointestinal endoscopy, intravenous or intramuscular injections, varicose vein sclerotherapy, acupuncture, contact sports, beauty treatments, and intranasal cocaine use (19). Kamili et al. conducted an experimental study that showed that HCV in blood is infectious even after exposure to drying and storage at room temperature (20). This study supports the notion that environmental sources are a potential route for HCV transmission. In 1998, the CDC recommended routine screening in persons at high risk for HCV infection (21). This recommendation was also endorsed by the National Institutes of Health (22) and Veterans Administration (VA) (23). In 2004, the US Preventive Services Task Force (USPSTF) recommended against screening for HCV in the general population and found insufficient evidence to advocate HCV screening of highrisk patients (24). Drs. Alter, Seeff and colleagues responded to the USPSTF recommendations by stating that HCV screening for high-risk patients is necessary to provide infected persons with counseling and potential treatment (25). Mallette et al. studied the clinical characteristics and outcomes of HCV patients diagnosed via a screening program based on risk factors. Results showed that 7.3% of patients who underwent screening were anti-HCV positive and 4.3% were viremic. Of the patients who tested positive for anti-HCV, 47% were considered treatment candidates. This study supports a policy of HCV screening for persons with identified risk factors to provide appropriate counseling and identify candidates for hepatitis A and B vaccination as well as antiviral therapy (Table 2 and Fig. 4).
Injecting drug use 60% Sexual 15%
Transfusion 10% (before screening)
Other* 5% Unknown 10%
Fig. 4. Risk factors for HCV. Source: CDC. Source: Finelli et al., Morbidity and Mortality Weekly Report, 2002.
40
Sharma and Sherker Table 2 CDC Recommendations for HCV screening
Testing recommended
Uncertain need for testing
Testing not mended
recom-
Current and former injection drug users Recipients of clotting factors before 1987 Hemodialysis patients Recipients of blood and/or solid organs before 1992 Persons with undiagnosed liver test abnormalities Infants born to infected mothers after 12–18 months
Recipients of transplanted tissue Intranasal cocaine users Persons with tattoos Persons with body piercings
Health care workers Pregnant women Household contacts General population
Persons with multiple sexual partners/STDs Long-term monogamous relationship with person infected with HCV
Health care/public safety workers with a known exposure
2.1. Intravenous Drug Use Currently, the majority of cases of HCV transmission can be attributed to intravenous drug use through the sharing of needles, syringes, and other paraphernalia (26–28). The CDC estimates that intravenous drug use accounts for up to 60% of new cases of HCV. The annual incidence of HCV transmission among intravenous drug users ranges from 15 to over 30% (29). Furthermore, the CDC reports that 60–80% of persons who have used intravenous drugs for 5 or more years are infected. Villano et al. conducted a prospective study of active intravenous drug users from Baltimore, MD and found that 30.3% participants became anti-HCV positive, mostly within the first 2 years of surveillance (30). Similarly, the Hepatitis C European Network for
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
41
Cooperative Research (HENCORE) group reported an 80% prevalence rate among intravenous drug users (31).
2.2. Blood Products The CDC reports that prior to 1989, blood transfusions were associated with a 7–10% risk of HCV transmission. As a result of the routine implementation of sensitive anti-HCV serological testing in 1992, the risk of hepatitis C acquisition via blood transfusion is currently 0.001% per unit transfused (32) as compared to 0.02% per unit transfused prior to effective blood donor screening (33). This minimal risk is attributed to the potential for transmission during the window period of infection, which occurs after transmission, but prior to detectable HCV antibody. The introduction of nucleic acid testing will further reduce this risk (34, 35). There have been no transfusion-associated HCV cases in the United States since 1992 among an NIH blood recipient population (28, 36). Although transfusion-associated HCV has declined in the United States, the incidence still remains high in certain parts of the world. In a recent study, 147 Chilean patients with chronic HCV were interviewed and blood transfusion was found to be the most common risk factor associated with infection : 54% of HCV-infected persons gave a history of blood transfusion, while only 5% had a history of intravenous drug users (37). Prior to the implementation of procedures to inactivate viruses from pooled plasma in 1987, persons who received clotting factor concentrates were at high risk of HCV transmission. In fact, prevalence rates in the setting of hemophilia were as high as 90% (38, 39). An outbreak of HCV occurred among recipients of intravenous immune globulin that was not inactivated for viruses in 1993 (40, 41). Although administration of intramuscular immune globulin has not been implicated as a risk factor for HCV transmission, inactivation of viruses is now required for both intravenous and intramuscular immune globulin in the United States (21). Two large outbreaks of HCV were linked to contaminated anti-rhesus D preparations given to female recipients during childbirth (42, 43).
2.3. High-Risk Sexual Activity Several case reports and studies have provided evidence that sexual activity is independently associated with transmission of HCV (44–47). Rates of transmission of hepatitis C are lower than those of hepatitis B and HIV (48, 49). CDC surveillance data in 2005 indicated that 15–20% of persons with acute HCV infection reported a history of sexual exposure as the only identifiable risk factor. Persons with a history
42
Sharma and Sherker
of sexually transmitted diseases, multiple sexual partners, vigorous sexual practices, and male homosexual activity are at greatest risk of HCV acquisition. Among heterosexuals, male to female transmission is more efficient than female to male transmission (50). On the contrary, several case–control studies did not find a link between acquisition of hepatitis C and either homosexual activity (44, 45, 51) or sexual promiscuity (51, 52). In the NHANES III study, the number of sexual partners and age of first sexual intercourse correlated with HCV seroconversion. Thomas et al. studied 1257 persons who denied intravenous drug use at an STD clinic in Baltimore, MD, and found that 9.7% were positive for anti-HCV (53). Alter postulated that HCV is more likely to be transmitted via sexual intercourse in the setting of acute infection, high viral load, and a lack of antibody to complex with antigen (26). Several studies have found an increased risk of HCV transmission among heterosexual partners in the setting of coinfection with HIV (49, 54). Terrault reports that among high-risk individuals with hepatitis C, there is a 1% annual risk of HCV transmission (50) (Table 3).
2.4. Intrafamilial and Monogamous Sexual Transmission Intrafamilial transmission of hepatitis C has been reported (55). Oshita et al. performed a study of 219 family members including spouses, children, and others who lived with 99 HCV-infected individuals. These family members were tested for ALT, anti-HCV +/− HCV RNA PCR and compared to a control population with similar demographic characteristics. Results showed that 26 family members (12%) tested positive for anti-HCV, specifically 18/75 (24%) spouses, 5/110 (5%) children, and 3/34 (9%) others, compared to 6 (2%) persons in the control group. These rates were similar to previous studies (56, 57). Of the family members with HCV seropositivity, 81% were HCV RNA positive. The higher rate of HCV seropositivity among spouses could have been secondary to sexual transmission. The rate of anti-HCV positivity increased with age and decades of marriage (55). More recently, a systematic review was performed to examine the risk of HCV transmission between infected patients and household contacts and stable heterosexual partners. The prevalence of HCV seropositivity among 4250 stable sexual contacts of patients with hepatitis C was 13.48%. Of 580 sexual contacts of patients who had acquired HCV via blood transfusions, the rate of HCV seropositivity was lower at 2.41%. Among household contacts, there was a 4.0% risk of transmission compared to 0% in contacts of anti-HCV-negative controls (58). Diago et al. reported an overall 4.5% prevalence of anti-HCV among household contacts with 30/394 (7.6%) of heterosexual stable partners and 35/1057 (3.3%)
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
43
Table 3 Reported Rates of Chronicity of HCV Infection Study
Patient population
Mode of transmission
% Chronic infection
Thomas et al., 2000 (93)
919 persons with a history of intravenous drug use 248 asymptomatic blood donors
Intravenous drug use
90
Alter HJ, 1997 (28)
Villano et al., 1999 (94) Seeff et al., 2001 (96) Seeff et al., 2000 (95)
43 persons with acute HCV 90 blood recipients 17 military recruits with stored blood samples from 1948–1954
Blood 86 transfusion, intranasal drug use, intravenous drug use (50%), sexual contact, male ear piercing Intravenous drug 86 use Blood transfusion 77 Unknown
65
62 55 55 54
of nonsexual contacts affected. Although the prevalence of anti-HCV among children of HCV-infected individuals was lower than other household contacts, the risk was higher when the mother was the index case (3%) as compared to the father (0.6%). Again, an increased prevalence was seen with increasing age (59). Saliva has also been cited as a possible route of HCV transmission (60, 61).
44
Sharma and Sherker
On the other hand, Caporaso et al. reported that after adjustment for confounders, sexual transmission does not play a role in intrafamilial spread of HCV infection (62). In addition, Stroffolini et al. found HCV transmission between spouses is likely secondary to parenteral exposures, and less likely sexual transmission (63). Kao et al. performed a prospective study of 112 anti-HCV-positive patients and their antiHCV-negative spouses. There was one seroconversion occurrence at 2 years over a follow-up period of 45.9 months. The annual interspousal transmission of HCV was 0.23%, with the possibility of a cumulative risk (64). Vandelli et al. reported the results of a prospective study in which 7879 HCV-infected persons and their anti-HCV-negative spouses were followed for 10 years. Three HCV seroconversions were observed for an incidence rate of 0.37 per 1000 person-years (65). Terrault reports a 0–0.6% annual risk of transmission and a 2.7% prevalence rate among monogamous partners of patients with hepatitis C (49). The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) reports an annual transmission rate of <1% per year and does not recommend a change in sexual practices among monogamous couples. Tahan et al. were the first to quantify HCV seroconversions in antiHCV-negative spouses of HCV-infected persons in terms of sexual encounters. Six hundred persons with spouses who were anti-HCV positive were tested for anti-HCV. Twelve (2%) persons were anti-HCV positive and 11 were HCV-RNA positive. Persons positive for antiHCV engaged in a greater number of sexual encounters (434 ± 295 vs. 307 ± 333). This population was followed prospectively for 3 years. There was no evidence of new seroconversion for 3 years and 257.9 ± 72.2 sexual occurrences (66). Collectively, this data suggests that both household contacts and sexual partners may be at increased risk – albeit small – of transmission of hepatitis C, with sexual contacts being at higher risk. Terrault advocates that family members should not share items that may be contaminated by blood (50).
2.5. Mother to Infant Transmission Vertical transmission is a known risk factor for HCV infection. Coinfection with HIV and increased viremia are thought to contribute to an even greater risk. Ferrero et al. prospectively studied 170 anti-HCVpositive women and their 188 newborn babies to determine the rate of vertical transmission. Babies were followed until clearance of antiHCV or diagnosis of HCV infection. Results revealed a 2.0% rate of HCV transmission among HIV-negative women, which increased to 5.4% with HIV coinfection. Increased maternal viremia was associ-
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
45
ated with an increased risk of transmission. With regard to clearance of anti-HCV among noninfected infants, babies born to viremic mothers have a slower rate of clearance of anti-HCV as compared to nonviremic mothers (67). Another prospective study of 86 infants born to anti-HCV-positive mothers showed similar results and also reported that HCV transmission is not affected by mother’s age, route of delivery, or genotype, but may be increased in the setting of active intravenous drug use and HCV/HIV coinfection (68). Hunt et al. reviewed studies from 1988 through 1996 and suggested that rates of vertical transmission may be higher among mothers with acute HCV infection as compared to chronic HCV infection (69). Although most studies do support an increased risk of mother to child transmission of HCV in the setting of HIV coinfection, Manzini et al. reported slower clearance of passively acquired anti-HCV among HIV-positive mothers, without an increase in vertical transmission of HCV (70). Airoldi has suggested that highly active antiretroviral therapy may significantly decrease the risk of vertical transmission of HCV (71).
2.6. Breastfeeding Several studies (69, 72, 73) and the CDC report no evidence linking HCV transmission to breastfeeding; therefore, HCV infection is not a contraindication to breastfeeding. However, if a mother’s nipples are cracked and bleeding, she should temporarily refrain from breastfeeding as a precautionary measure (72). Kumar performed a prospective study of 65 HCV-RNA-positive women and 42 anti-HCV-negative controls to assess breastfeeding as a mode of HCV transmission. All infants studied were breastfed. Five mothers with chronic HCV developed symptomatic liver disease and three of their infants were found to be HCV-RNA positive during a 12-month follow-up period. The authors concluded that women with symptomatic chronic HCV and high viral loads should not breastfeed (74). In the setting of HCV/HIV coinfection, breastfeeding is discouraged (71).
2.7. Hemodialysis Although hemodialysis is a well-known risk factor for HBV transmission, the CDC only recently cited it as a risk factor for HCV transmission. Recommendations for the prevention of hepatitis B in hemodialysis centers were initially published in 1977, with implementation of vaccination among patients and staff since 1982. These strategies led to a sharp decline in HBV transmission. With regard to HCV, limited data from US studies since 1990 have reported a 3% annual incidence of HCV transmission in the setting of
46
Sharma and Sherker
hemodialysis without a history of intravenous drug use or blood transfusions (75, 76). In 1999, the national prevalence rate of anti-HCV was 8.9%, with a greater than 40% rate among some hemodialysis centers (unpublished CDC data, 2001) (77). Higher rates of anti-HCV seroconversion were seen among persons on hemodialysis for 5 years or more, with rates increasing from 12% among persons on hemodialysis for less than 5 years to 37% among persons on hemodialysis for 5 or more years (75, 78, 79). During 1999–2000, the CDC studied three HCV outbreaks in hemodialysis centers and found that transmission occurred because of inadequate infection control practices. Seroconversion was associated with patients receiving hemodialysis immediately following a patient with chronic HCV, use of equipment and supplies that were not disinfected between patient use, shared utilization of medication carts and medication vials, and blood spills that were not promptly cleaned. In 2001, the CDC recommended the implementation of infection control practices specific to hemodialysis units, infection control training and education, and routine surveillance of hepatitis C for hemodialysis patients. Monthly ALT assessment and biannual anti-HCV antibody testing were suggested as initial testing modalities, with HCV PCR reserved for those with elevated transaminases of unknown etiology. Anti-HCV testing was not recommended for hemodialysis staff members. In addition, isolation of patients with hepatitis C was not considered necessary (77). The above recommendations resulted in an increase in the number of hemodialysis centers testing for HCV from 56 in 1999 to 64% in 2002. The prevalence rate of HCV decreased from 8.9 in 1999 to 7.8% in 2002. This decline in prevalence was attributed to a decline in new infections due to an increased awareness of HCV transmission in hemodialysis settings. In April 2008, the Kidney Diseases Improving Global Outcomes Foundation developed the first international clinical practice guidelines to address the prevention of hepatitis C in patients undergoing hemodialysis. Although several nephrology organizations recommend mandatory semiannual testing of anti-HCV in hemodialysis patients, the Centers for Medicare and Medicaid Services (CMS) do not reimburse providers for the cost of this testing unless there is a suspicion that the patient has been exposed to HCV-infected blood (80).
2.8. Intranasal Drug Use Although several studies have reported that intranasal drug use is not independently associated with an increased risk of HCV transmission (81, 82), others have noted an association (28). The CDC has described it as a potential risk factor, primarily through sharing of pipes and
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
47
straws. The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) states that intranasal cocaine use is associated with a slightly increased risk of hepatitis C. McMahon et al. reviewed the epidemiological evidence of HCV transmission in the setting of oral and intranasal drug use and found that although current studies do not dismiss these modes of transmission, further research is needed (83).
2.9. Tattoos The concept of tattooing as an independent risk factor for HCV transmission is controversial with various studies relaying discordant results. Ko et al. studied 213 healthy young men who denied participation in intravenous drug use or high-risk sexual activity. Results revealed that 11/187 (12.6%) men with tattoos as opposed to 3/126 (2.4%) tattoo-free men were positive for anti-HCV. The risk of HCV seropositivity was higher with an increased number of tattoos and non-professional status of the tattooer (84). Hellard et al. conducted a survey and found tattooing during incarceration to be an independent risk factor for HCV transmission among a group of prisoners in Australian correctional facilities (85). Neumeister et al. studied the risk factors and prevalence of HCV among native Americans and found tattoos > 5 years old to be a strong risk factor for transmission (86). Haley et al. reported a higher risk of HCV acquisition with commercial tattooing as compared to intravenous drug use (87). Haley also postulated that tattooing may be associated with subclinical HCV infection, while intravenous drug use may lead to an acute infection (88). The CDC acknowledges that although several studies have found an association between tattooing and HCV transmission in select populations, they may not pertain to the general population. As less than 1% of persons with hepatitis C reported a history of tattooing in the CDC’s surveillance system, the CDC believes that further studies are needed to determine if tattooing is a risk factor for HCV transmission.
2.10. Health Care Setting Hauri et al. reported that up to 40% of worldwide HCV infections can be attributed to contaminated health care injections in developing countries (89). Contaminated glass syringes for Schistosomiasis treatment have been implicated as a mode of HCV transmission in Egypt (2), while multiple injections for kala-azar treatment have been associated with HCV seropositivity in India (90). The World Health Organization has found the highest rates of therapeutic needle reuse in Southeast Asia, Middle East, and the Western Pacific. In order to combat unsafe therapeutic injection practices, the WHO implemented the
48
Sharma and Sherker
Safe Injection Global Network (SIGN), a partnership of various governments, international health agencies, and corporations that advocate safer worldwide injection practices (27). Regarding occupational transmission of HCV, health-care workers exposed to hollow-bore or deep tissue needle stick injuries from an HCV-positive source have a 1.8% risk of transmission, which is lower than that of HBV and HIV (26, 91). The prevalence of HCV infection among health-care workers is similar to the general population (26).
3. NATURAL HISTORY OF HCV Effective investigation of the natural history of a disease requires specific information including the identification of disease onset, method of differentiating between acute and chronic disease, and the ability to track disease morbidity and mortality without the influence of comorbid conditions and/or treatment (92). With regard to hepatitis C, the onset of disease is rarely known and patients often have comorbid conditions and available treatment options that can alter the natural course of the infection. Controversy exists regarding the natural history of hepatitis C. While many experts view hepatitis C as a progressive disease with a high likelihood of advancing to cirrhosis, hepatocellular carcinoma, and death; others consider this virus to be more variable in nature, with the majority of patients “dying with the disease, not of the disease.” These discordant opinions arise from the presence of variable types of studies that have been reported, including retrospective, prospective, and retrospective–prospective studies. Additionally, diverse patient populations with regard to host-related factors (age, gender, race, route of transmission, comorbidities) and virus-related factors (genotype, viral load, quasispecies) have been studied – often with discordant results.
3.1. Chronic Hepatitis C Acute hepatitis C is rarely symptomatic, thus most patients are unaware of the fact that they even contracted the illness, unless they can identify a recognized exposure. Chronic hepatitis C is defined as the persistence of HCV RNA viremia for at least 6 months. Potential clinical outcomes for persons with chronic hepatitis C include cirrhosis, hepatocellular carcinoma, and death. Progression from acute to chronic HCV occurs in 54–90% patients (28, 93–99). This variability is likely due to diverse study designs and patient populations. Thomas et al. reported that viral clearance was significantly more common in persons of non-black race and negative
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
49
HIV status. An association (although not statistically significant) was noted between viral clearance, female gender, age under 45 years, and coinfection with hepatitis B. There was no association between persistent viremia and weekly alcohol use or the frequency of intravenous drug use (93). In an analysis of 43 acute HCV infections, Villano and colleagues also reported that viral clearance was more common among non-black individuals, in addition to persons with jaundice and a lower peak viral load. Persons with undetectable viral load had no evidence of biochemical disease after clearance of infection. It should be noted, however, that persons with chronic hepatitis C often had normal transaminases at some point during the course of chronic infection (94). Rodger et al. compared HCV-RNA-positive persons with HCVRNA-negative persons to determine factors linked to chronic infection. They found that a longer duration and increased frequency of intravenous drug use, as well as an increased average lifetime consumption of alcohol were inversely associated with clearance of infection (99). Vogt et al. found that younger age at time of infection may be related to viral clearance (98). This factor may have contributed to the relatively low rate of chronic HCV in the population studied by Rodger, as the mean age of the study subjects at the time of infection was less than 22 years (99).
3.2. Cirrhosis, Hepatocellular Cancer, and Liver-Related Death While some studies show frequent progression of chronic HCV to cirrhosis, hepatocellular carcinoma, and death (95, 100–106), others report these outcomes as less common occurrences (28, 93, 98, 99, 107, 108). The CDC estimates that up to 20% of chronic HCV infections lead to cirrhosis over a period of 20–30 years. Poynard et al. performed a study using serial biopsies or a single biopsy with a presumed date of infection based on identified risk factors and reported that persons infected with HCV can be differentiated into three categories with regard to fibrosis progression without treatment: rapid fibrosers (33% of persons) who progress to cirrhosis in <20 years; intermediate fibrosers (36% of persons) who develop cirrhosis over 30 years; and slow fibrosers (31% of persons) who may progress to cirrhosis after >50 years of infection (109). Numerous studies have been performed to evaluate risks of HCVrelated morbidity and mortality. These evaluations are dependent on the type of study performed, host-related factors, and virus-related factors. This point is illustrated in a review by Freeman and colleagues, which analyzed 33 liver clinic series; 5 posttransfusion cohorts; 10 blood
50
Sharma and Sherker
donor cohorts; and 9 community-based cohorts. Development of cirrhosis after 20 years of infection was 22% for the liver clinic series; 24% for posttransfusion studies; 4% for blood donor studies; and 7% for community-based studies. Older age at the time of HCV infection, male gender, and heavy alcohol intake also correlated with a more rapid progression to cirrhosis (110). Limitations of studies on fibrosis progression include sample variability of liver biopsies, referral bias with inclusion of patients with severe liver disease, and inaccurate estimates of duration of infection. 3.2.1. S TUDY D ESIGN Retrospective Studies Initial studies of chronic hepatitis C natural history involved retrospective analysis of patients referred to academic centers. The advantage of these studies is that a long duration of infection can be studied and the roles of various factors can be evaluated. Disadvantages of these studies include an estimated date of exposure and a strong selection bias as this patient population is more likely to have clinically evident liver disease, resulting in referral to an academic liver center. Several retrospective studies have included patients with a presumed 20–30 years of infection and have shown that 20–51% of patients with chronic HCV progress to cirrhosis, 2–11% develop hepatocellular carcinoma, and 4–15% die of liver-related causes (100, 102–104). Bjoro and colleagues studied 17 Norwegian patients with primary hypogammaglobulinemia who contracted HCV infection as a result of transfusion with contaminated immune globulin from 1982 to 1986. Six patients had histological evidence of cirrhosis, and two went on to die of liver failure. The authors suggest that chronic HCV in the setting of primary hypogammaglobinemia was associated with a greater morbidity and mortality when compared to a “healthy population” with chronic HCV (103). • Tong and colleagues followed 131 patients who acquired HCV via blood transfusion, an average of 22 years prior to referral to a tertiary care center. Based on liver biopsy or abnormal coagulation parameters, 67 patients (51%) were cirrhotic. Upon entry into the study, seven patients (5.3%) had hepatocellular carcinoma, while an additional seven patients (5.3%) developed hepatocellular carcinoma during an average 4-year follow-up. Nineteen patients (14.5%) died of liver-related causes, including eight from cirrhosis complications and 11 from hepatocellular carcinoma. Persons who contracted HCV before age 50 developed cirrhosis and hepatocellular cancer at a slower rate as compared to persons who received blood transfusions after age 50 (100).
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
51
• Yano and colleagues from Japan studied liver biopsies of 70 patients with chronic HCV, acquired either sporadically or via blood transfusion. During follow-up, 35 patients (50%) developed histological evidence of cirrhosis. • Niederau and colleagues followed 838 patients with a history of chronic HCV referred to an academic hepatology clinic for potential antiviral treatment. Of 580 patients who had undergone liver biopsy, 130 had histological evidence of cirrhosis at entry, while an additional 11 unbiopsied patients had clinical evidence of cirrhosis. During a follow-up of approximately 4 years, an additional 26 patients developed manifestations of cirrhosis, while 17 patients developed hepatocellular carcinoma and 31 patients died of liver-related disease (13 of whom had hepatocellular carcinoma). The authors noted an increased mortality in patients with chronic HCV who had cirrhosis, or greater than 15 years of infection. Long disease duration, excessive alcohol use, history of intravenous drug use, and old age also contributed to a decreased complication-free survival. A drawback to the study was the inclusion of patients who had been treated with interferon, thus making it difficult to study the natural history without confounding factors (104).
Prospective Studies Prospective studies involve patients with recognized acute hepatitis who are followed to assess for the development of liver-related morbidity and mortality. Advantages include a known time of exposure and probable mode of infection, whereas disadvantages include a shorter duration of follow-up. Among patients followed in several prospective studies, 5–25% progressed to cirrhosis, 0–1.2% developed hepatocellular cancer, and 1.2–6% died of liver-related disease over a follow-up of 13–24 years (28, 101, 105, 106). • Di Bisceglie and colleagues prospectively studied 33 non-A, non-B hepatitis patients who received blood transfusions perioperatively at the time of cardiac surgery between 1972 and 1983 at the National Institutes of Health (NIH), as well as six additional NIH patients who contracted acute hepatitis from blood transfusions. Ninety percent of these patients had chronic hepatitis C. Eight patients (20.5%) had histological evidence of cirrhosis with an average of 4.2 years after blood transfusion. • Mattsson and colleagues studied stored blood samples from 39 of 61 patients who had acute non-A, non-B hepatitis in Sweden in 1978. Sixteen patients had chronic hepatitis C. Liver biopsies were performed in eight patients within 13 years of the acute episode, and two patients had histological findings of cirrhosis. One patient died of liver-related disease but was not included in the analysis. Drawbacks to the study
52
Sharma and Sherker
included a short duration of follow-up and the possibility of underestimation of patients with cirrhosis, as not all were biopsied (106). • Koretz and colleagues prospectively studied 80 patients with non-A, non-B hepatitis secondary to blood transfusions in the 1970s. Sixty-four of these patients were diagnosed with hepatitis C, 50 of whom were chronic. This study suggested that, based on life-table analysis, 20% of patients with chronic HCV could develop hepatic failure, defined by variceal bleeding, ascites, hepatic encephalopathy, coagulopathy, hypersplenism, or hypoalbuminemia. Liver biopsies were not performed in these patients. Drawbacks of this study were the variable duration of follow-up and the possibility of underestimation, based on exclusion of patients without clinically evident cirrhosis (101). • Alter and colleagues prospectively studied 248 asymptomatic blood donors positive for anti-HCV. Liver biospies were done in 81 HCV RNA-positive persons and 5% demonstrated cirrhosis. Three of these cirrhotic patients were discovered 27 years after their presumed exposure and one patient was found to have hepatocellular carcinoma 53 years after a blood transfusion. More severe disease was seen in patients with ALT elevations greater than twice the upper limit of normal (28).
Retrospective–Prospective Studies Retrospective–prospective studies involve the identification of patients who previously developed a known acute hepatitis. These patients were studied retrospectively, enrolled, and followed prospectively for the development of liver-related morbidity and mortality. Over a follow-up of 15–45 years, these studies have generally shown lower rates of progression to cirrhosis (0.4–18.1%), hepatocellular carcinoma (0%), and death from liver-related causes (0.2–9.1%) in comparison to purely retrospective studies (93, 95, 98, 99, 107, 108). • Vogt et al. compared 458 children under the age of 3, who underwent cardiac surgery in Germany prior to 1991, with 458 controls. When stored blood samples were tested, 67 patients (14.6%) who underwent cardiac surgery and three (0.7%) controls were anti-HCV positive. Thirty antibody-positive children (45%) had undetectable HCV RNA at a mean of 19.8 years after their first operation. Seventeen patients had liver biopsies, of which one, who had also been coinfected with HBV, was found to be cirrhotic. The authors concluded that clearance of HCV viremia was more common among children and progression of chronic HCV-related liver disease acquired at a young age was slower than older adults (98). • Kenny-Walsh and colleagues evaluated 376 women with chronic HCV is likely secondary to transfusion of contaminated anti-D immunoglobulin. Three hundred and sixty-three infected women underwent liver
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
53
biopsies. Cirrhosis was found in 7 women, or 2% of biopsies, an average of 17 years after the initial transfusion. Three of these cirrhotic participants reported excessive alcohol consumption (108). • Seeff et al. studied 8568 stored blood samples taken from healthy military recruits between 1948 and 1954 for evaluation of group A streptococcal infection and acute rheumatic fever. Seventeen persons were antiHCV positive and 11 were HCV RNA positive. Of these 11 patients, one person had been diagnosed with cirrhosis and another had died of liver-related disease, 42 years after the blood sample was taken. Liverrelated morbidity and all-cause mortality were slightly higher in the anti-HCV-positive group. There were no deaths attributed to hepatocellular carcinoma. Lower rates of cirrhosis, HCC, and liver-related death may have related to the fact that this was a young and healthy study population. Advantages of this study were an extended observation period in a healthy population, without comorbidities that could alter the course of HCV-related liver disease. Disadvantages included the possibility of false-negative anti-HCV results secondary to an extended period of serum specimen storage and a small cohort of patients with hepatitis C (95). • Rodger and colleagues compared long-term outcomes of 98 persons with acute hepatitis C to 202 persons with acute hepatitis unrelated to HCV. Anti-HCV testing was performed on stored sera from 1971 to 1975 in Australia. The presumed route of HCV transmission was intravenous drug use, as opposed to other studies that focused on transfusionassociated HCV. Fifty-one patients with anti-HCV positivity were found to have chronic HCV based on HCV RNA testing. Normal liver tests were associated with a lower risk of long-term complications, a finding which has been observed in other studies as well (28, 111, 112). The authors concluded that outcomes of cirrhosis, hepatocellular cancer, and liver-associated death in the setting of chronic HCV after a followup of 25 years were less common than previously perceived. Although patients with anti-HCV positivity had a higher rate of mortality compared to the anti-HCV-negative group, these deaths were not related to HCV complications. A drawback to this study was that only 14% of antiHCV-positive persons underwent liver biopsy, although hyaluronate levels were measured as a surrogate for fibrosis to reduce an underestimation of cirrhosis (99). • Thomas and others studied 1667 patients with a history of intravenous drug use within 10 years of recruitment and anti-HCV positivity. Forty patients were categorized as having end-stage liver disease (ESLD), defined by clinical documentation of varices, ascites, or hepatic encephalopathy. Of these patients, 35 had died while one had received a liver transplant. Of patients without documented ESLD, 374 had died of non-liver-related causes. Liver biopsies were performed on
54
Sharma and Sherker
210 participants without clinical evidence of ESLD and cirrhosis was found in two persons. In addition, five patients who died without previously identified ESLD had evidence of cirrhosis on autopsy. ESLD was associated with age greater than 38, male sex, and heavy alcohol use. It did not correlate with HIV status, HBV status, moderate alcohol use, race, viral load, or viral genotype. The low incidence of ESLD in this cohort may be attributed to the restrictive definition of ESLD, without considering laboratory results suggestive of cirrhosis, as well as a relatively short duration of follow-up (93). • An endemic outbreak of hepatitis C in Germany in 1979 secondary to administration of contaminated anti-D immunoglobulin provided a patient population of 1016 women who were prospectively studied for 20 years by Weisse and colleagues. Of these women, 55% had evidence of chronic HCV infection (7% had not responded to interferon), while 42% had spontaneous clearance of virus and 3% responded to interferon. Four participants had clinical evidence of cirrhosis; it was not seen in any of the 220 biopsy specimens obtained. Two patients died of liver disease; one patient had fulminant hepatitis B and the other was a chronic alcohol abuser. There were no cases of hepatocellular carcinoma (107).
3.2.2. H OST-R ELATED FACTORS Age Several studies have suggested that younger age at the time of infection may protect against progression to cirrhosis, HCC, and liver-related mortality (93, 95, 98, 100, 109, 110, 113). As discussed previously, Vogt et al. evaluated young children who underwent cardiac surgery during their first 3 years of life and found that only 5.4% of children had histological evidence of cirrhosis after a follow-up of 17 years (98). Furthermore, two studies of young women who received contaminated immunoglobulin at median ages of 24 and 28 years showed that a relatively low number ( 0.4–2.0% ) had cirrhosis after a follow-up of 17–20 years (107, 108). Even among Seeff’s study of young (age < 25) military recruits with chronic hepatitis C, two of 11 patients were cirrhotic after a 45-year follow-up (95). Ryder and colleagues performed serial liver biopsies in 214 patients with chronic hepatitis C to assess progression of fibrosis. Results showed that older age of patients and presence of fibrosis on the initial biopsy were associated with progression of fibrosis (114). These results were similar to Svirltlih et al., who performed liver biopsies in 144 patients with chronic hepatitis C and found that age over 40 years at the time of liver biopsy was associated with an increased Ishak fibrosis score (115). What is not known is whether the rate of progression increases as these young persons age over time,
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
55
possibly explained by the inability of the immune system to contain the virus as it ages (109). Gender HCV is more commonly eliminated by women (107–110, 116). Poynard and Freeman conducted separate studies and found that male gender, in addition to alcohol consumption and older age at infection, was associated with fibrosis progression (109, 110). Yamakawa and colleagues conducted a study to compare progression to chronic hepatitis C in men and women in a town in Japan. They found that although anti-HCV positivity did not differ between genders, the proportion of anti-HCV-positive participants who were also HCV-RNA positive was higher in men (78.2%) than in women (67.3%) (116). Several studies have postulated that this may relate to the anti-fibrotic effects of estrogen (117–119). Yasuda and colleagues induced hepatic fibrosis in male and female rats with administration of dimethylnitrosamine and found that estradiol inhibited fibrogenesis by preventing proliferation of hepatic stellate cells which are responsible for collagen synthesis, as well as contributing antioxidant activity (118). Race Relative to Caucasians, African-Americans are 2–3 times more likely to be anti-HCV positive and less likely to undergo spontaneous clearance of HCV viremia (5). In addition, African-Americans are more prone to develop complications of cirrhosis, including hepatocellular carcinoma, and have lower response rates to antiviral treatment (120–122). However, their rates of fibrosis progression are slower than Caucasians (120, 123, 124). Bonacini and colleagues studied the histological progression of 291 chronic HCV patients (53 AfricanAmerican, 116 Caucasian) with regard to duration of infection and race. The estimated rate of fibrosis among African-Americans was 0.055 stages per year compared to 0.096 stages per year among Caucasians (120). This disparity may be explained by variable immune responses between both groups (123). HIV Coinfection In the United States, 30% of HIV-positive patients are also infected with HCV (125). In the setting of HIV infection, HCV fibrosis is accelerated (126, 127). Benhamou and colleagues compared the rates of fibrosis progression in 122 anti-HIV positive, anti-HCV-positive persons and 122 anti-HIV negative, anti-HCV-positive persons. They found a Metavir fibrosis score of 2–4 in 60% of coinfected patients as compared to 47% of HCV-monoinfected patients. The median fibrosis
56
Sharma and Sherker
progression rate (ratio between fibrosis stage and HCV duration) was 0.153 fibrosis units per year in the former and 0.106 fibrosis units per year in the latter. Multivariate analysis showed that HIV seropositivity, CD4 count <200, age >25 at the time of HCV infection, and alcohol >50 g/day were all associated with a faster rate of fibrosis progression (126). Fibrosis progression may be linked to a weaker CD8+ T-cell response to HCV antigens in the setting of HIV (128). HAART therapy slows the progression of fibrosis through immune reconstitution, and possibly, HIV viral load suppression (129, 130). HBV Coinfection Several studies have reported that HBV infection in the setting of chronic HCV leads to a worsening of liver disease and increased risk for hepatocellular carcinoma (131–133). However, Senturk et al. evaluated 51 patients with HCV and HBV coinfection and found that clinical or histological findings did not differ between the group with HBV/HCV coinfection as compared to the groups with single infections. The authors did find that HCV was the dominant infection (134). Other studies have shown that hepatitis C tends to reduce HBV virus replication (131, 135, 136). The AASLD recommends that non-HBV immune patients with chronic HCV should be vaccinated against hepatitis B (137). Metabolic Syndrome The metabolic syndrome is defined as a constellation of factors including hypertension, abdominal obesity, diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). NAFLD comprises a histological spectrum of disease ranging from steatosis alone to steatohepatitis to fibrosis, and in some cases, cirrhosis. Extensive research has been conducted to examine correlations between the metabolic syndrome and hepatitis C. The metabolic syndrome can promote progession of hepatic fibrosis and a decreased response to antiviral therapy (138). The prime mechanism responsible for the metabolic syndrome is insulin resistance (139). Insulin resistance leads to hepatic steatosis and stimulates inflammation, resulting in steatohepatitis and possibly fibrosis (138). Other theories describe oxidative stress as a necessary “second-hit” in the development of steatohepatitis. Oxidative stress initiates lipid peroxidation, resulting in stellate cell activation and synthesis of type I collagen (138, 140). Leptin, a peptide primarily produced by adipose tissue, may also play a role in fibrinogenesis (139). Of note, hepatic steatosis itself may cause activation of stellate cells (139). The AASLD Practice Guidelines state that patients with a BMI
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
57
>25 kg/m2 in the setting of chronic HCV should make an effort to lose weight (137).
Alcohol Consumption Heavy alcohol intake hastens progression to cirrhosis (93, 109, 110, 124, 141–144). Harris and colleagues found a fourfold increased risk for cirrhosis in the setting of increased alcohol consumption in a population of patients with transfusion-associated HCV (124). Ostapowicz et al. studied 234 patients in Australia with chronic hepatitis C and found that greater alcohol use during HCV infection and an increased cumulative consumption of alcohol were associated with progression of liver disease (142). Pessione et al. found a dose–response relationship between self-reported past and present alcohol consumption and HCV viremia (143). They also reported a link between fibrosis and prior alcohol use (143). Corrao noted a synergistic effect of alcohol on chronic HCV at doses of 75–100 g/day and suggested that patients without signs of liver disease could consume <50 g alcohol daily (141). Poynard and colleagues found that daily consumption of alcohol >50 g is a risk factor for advanced liver disease (109), while Hezode reported that even 21–50 g/day can have a negative impact on women with chronic HCV (145). The physiological basis for the detrimental effects of alcohol include immune dysregulation, proinflammatory and profibrotic cytokine stimulation, oxidative stress, and steatosis (146). Seeff advises against “alcoholism” in the setting of chronic HCV (147). AASLD guidelines recommend that patients with chronic HCV should minimize alcohol consumption, and not exceed 50 g/day (137). Tobacco Use Tobacco use is suspected to promote fibrosis in the setting of chronic HCV (148, 149). Pessione and colleagues identified smoking as an independent risk factor for fibrosis in a study of 310 patients with chronic HCV who underwent a liver biopsy. In addition, smoking has been linked to hepatocellular carcinoma in the setting of chronic hepatitis (150, 151). Hepatotoxic compounds in cigarettes may account for this progression (152). 3.2.3. V IRUS -R ELATED FACTORS Mode of Transmission Several studies have suggested that the mode of transmission of HCV may affect progression to complications, with blood transfusions associated with increased risk of cirrhosis possibly related to a higher initial inoculum (99–101, 105, 106, 153). Transfusion studies have shown a 20% rate of progression to cirrhosis at 20 years (100, 147, 154), while
58
Sharma and Sherker
studies of intravenous drug users show lower rates of serious sequelae (99). Gordon and colleagues evaluated 463 patients at an nonurban medical center with chronic hepatitis C and available liver histology, of which 215 (45%) were transfusion recipients, 195 (42%) acquired HCV mainly through intravenous drug use, and 53 (13%) were without identified risks. With a median follow-up duration of 21 years, 173 (37%) patients were cirrhotic and 118 (68%) of them were transfusion recipients. The Kaplan–Meier cumulative risk for cirrhosis 25 years after HCV acquisition was 52.5% among transfusion recipients and 35% among intravenous drug users (155). Viral Load While some studies have suggested that an increased viral load is indicative of more advanced liver disease (156, 157), others have not revealed similar findings (142, 158–161). Adinolfi et al. studied liver biopsies of 298 patients with chronic hepatitis C and found that viral load was linked to grade of inflammation and stage of fibrosis in noncirrhotic patients. However, once patients advanced to cirrhosis, their viral loads declined (157). Fanning and colleagues examined liver biopsies of 77 young, healthy women with chronic HCV genotype 1b of 17 years duration with contaminated anti-D immunoglobulin as a source for infection. The authors discovered a weak but statistically significant correlation between viral load and hepatic inflammation. However, viral load was not associated with the degree of liver fibrosis (161). Virus Genotype There are conflicting data regarding the effect of virus genotype on fibrosis progression. While some studies have suggested that specific genotypes are associated with progression of fibrosis (162–164), others have not found such a correlation (109, 165, 166). Kobayashi and colleagues evaluated 136 patients with chronic hepatitis C who had two liver biopsies performed 5 years apart. Ninety-six patients were infected with genotype 1 virus, while 40 patients had genotype 2 virus. Genotype 1 infected patients had a higher initial viral load and repeat liver biopsy showed worsening of liver histology in terms of grade and stage of disease. The authors suggested that genotype 1b disease was more “pathogenic” than genotype 2 disease (167). In contrast, Mahaney and colleagues reported more severe liver disease in patient infected with genotype 2 virus (168). Mihm et al. examined 90 liver biopsies of patients with chronic HCV genotypes 1a, 1b, or 3a and found that fibrosis was more common in genotype 1b infection, while steatosis was seen more frequently with genotype 3a infection. The authors
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
59
Table 4 Factors that influence the progression of chronic HCV Factor
Effect on progression
Age at infection Sex Race HIV or HBV coinfection Metabolic syndrome Alcohol consumption Tobacco use Mode of transmission Virus concentration Virus genotype
Younger age, slower rate of progression Female, slower rate of progression AA, slower rate of progression More rapid progression
Virus quasispecies
More rapid progression More rapid progression More rapid progression suggested Transfusion: higher inoculum, more rapid rate of progression Inconclusive evidence Inconclusive evidence, 1b may be associated with more severe disease No evidence
speculated that the increase in fibrosis seen in genotype 1b disease could be attributed to an older age population and a longer duration of disease (169). Virus Quasispecies The presence of HCV quasispecies has been compared in patients with resolution of acute hepatitis and the development of chronic hepatitis. Human studies suggest that the development of heterogeneous quasispecies is linked to progression to chronic hepatitis (170). There is no evidence that quasispecies affect advancement of liver disease in the setting of chronic hepatitis C (92) (Table 4).
4. CONCLUSIONS Chronic hepatitis C is associated with progression to cirrhosis, hepatocellular carcinoma, and liver-related death. It is difficult to clearly define morbidity and mortality risk as variable study types and patient populations yield conflicting results. It is therefore important to takes these factors into consideration when analyzing studies appropriately.
60
Sharma and Sherker
Retrospective studies show the highest rates of morbidity and mortality, followed by prospective studies and retrospective–prospective studies. The actual rates likely lie somewhere in between the extremes of these three categories of study. Progression of HCV is hastened when acquired via blood transfusion; at an older age; in males; in nonAfrican-Americans; in the setting of excessive alcohol (and possibly tobacco) use; and, in persons with HIV and/or HBV coinfection or features of metabolic syndrome. It is controversial if HCV viral load and genotype affect the evolution of disease.
REFERENCES 1. Hepatitis C – global prevalence (update). Wkly Epidemiol Rec 1999; 74:425–7. 2. Frank C, Mohamed MK, Strickland GT et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000; 355:887–91. 3. Montella M, Crispo A, Grimaldi M, Tridente V, Fusco M. Assessment of iatrogenic transmission of HCV in Southern Italy: was the cause the Salk polio vaccination? J Med Virol 2003; 70:49–50. 4. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144:705–14. 5. Alter MJ, Kruszon-Moran D, Nainan OV et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999; 341:556–62. 6. Weinbaum C, Lyerla R, Margolis HS. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention. MMWR Recomm Rep 2003; 52:1–36; quiz CE1–4. 7. Cheung RC, Hanson AK, Maganti K, Keeffe EB, Matsui SM. Viral hepatitis and other infectious diseases in a homeless population. J Clin Gastroenterol 2002; 34:476–80. 8. Dominitz JA, Boyko EJ, Koepsell TD et al. Elevated prevalence of hepatitis C infection in users of United States veterans medical centers. Hepatology 2005; 41:88–96. 9. Roselle GA, Danko LH, Kralovic SM, Simbartl LA, Kizer KW. National Hepatitis C Surveillance Day in the Veterans Health Administration of the Department of Veterans Affairs. Mil Med 2002; 167:756–9. 10. Briggs ME, Baker C, Hall R et al. Prevalence and risk factors for hepatitis C virus infection at an urban Veterans Administration Medical Center. Hepatology 2001; 34:1200–5. 11. Cheung RC. Epidemiology of hepatitis C virus infection in American veterans. Am J Gastroenterol 2000; 95:740–7. 12. Hyams KC, Riddle J, Rubertone M et al. Prevalence and incidence of hepatitis C virus infection in the US military: A seroepidemiologic survey of 21,000 troops. Am J Epidemiol 2001; 153:764–70. 13. Tabibian JH, Wirshing DA, Pierre JM et al. Hepatitis B and C among veterans on a psychiatric ward. Dig Dis Sci 2008; 53(6):1693–8.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
61
14. Thomas DL, Factor SH, Kelen GD, Washington AS, Taylor E, Jr., Quinn TC. Viral hepatitis in health care personnel at The Johns Hopkins Hospital. The seroprevalence of and risk factors for hepatitis B virus and hepatitis C virus infection. Arch Intern Med 1993; 153:1705–12. 15. Wasley A, Miller JT, Finelli L. Surveillance for acute viral hepatitis – United States, 2005. MMWR Surveill Summ 2007; 56:1–24. 16. Shev S, Widell A, Foberg U et al. HCV genotypes in Swedish blood donors as correlated to epidemiology, liver disease and hepatitis C virus antibody profile. Infection 1995; 23:253–7. 17. Chlabicz S, Flisiak R, Kowalczuk O et al. Changing HCV genotypes distribution in Poland-Relation to source and time of infection. J Clin Virol 2008. 18. Murphy EL, Bryzman SM, Glynn SA et al. Risk factors for hepatitis C virus infection in United States blood donors. NHLBI Retrovirus Epidemiology Donor Study (REDS). Hepatology 2000; 31:756–62. 19. Karmochkine M, Carrat F, Dos Santos O, Cacoub P, Raguin G. A case-control study of risk factors for hepatitis C infection in patients with unexplained routes of infection. J Viral Hepat 2006; 13:775–82. 20. Kamili S, Krawczynski K, McCaustland K, Li X, Alter MJ. Infectivity of hepatitis C virus in plasma after drying and storing at room temperature. Infect Control Hosp Epidemiol 2007; 28:519–24. 21. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998; 47:1–39. 22. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002 – June 10–12, 2002. Hepatology 2002; 36:S3–20. 23. Mallette C, Flynn MA, Promrat K. Outcome of screening for hepatitis C virus infection based on risk factors. Am J Gastroenterol 2008; 103:131–7. 24. Chou R, Clark EC, Helfand M. Screening for hepatitis C virus infection: A review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004; 140:465–79. 25. Alter MJ, Seeff LB, Bacon BR, Thomas DL, Rigsby MO, Di Bisceglie AM. Testing for hepatitis C virus infection should be routine for persons at increased risk for infection. Ann Intern Med 2004; 141:715–7. 26. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13:2436–41. 27. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5:558–67. 28. Alter HJ, Conry-Cantilena C, Melpolder J et al. Hepatitis C in asymptomatic blood donors. Hepatology 1997; 26:29S–33S. 29. Des Jarlais DC, Diaz T, Perlis T et al. Variability in the incidence of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infection among young injecting drug users in New York City. Am J Epidemiol 2003; 157:467–71. 30. Villano SA, Vlahov D, Nelson KE, Lyles CM, Cohn S, Thomas DL. Incidence and risk factors for hepatitis C among injection drug users in Baltimore, Maryland. J Clin Microbiol 1997; 35:3274–7. 31. Touzet S, Kraemer L, Colin C et al. Epidemiology of hepatitis C virus infection in seven European Union countries: A critical analysis of the literature. HENCORE
62
32.
33. 34.
35.
36. 37. 38. 39. 40.
41.
42.
43.
44.
45.
46. 47.
48.
Sharma and Sherker Group. (Hepatitis C European Network for Co-operative Research. Eur J Gastroenterol Hepatol 2000; 12:667–78. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusiontransmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996; 334:1685–90. Donahue JG, Munoz A, Ness PM et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992; 327:369–73. Candido A, Chionne P, Milazzo L et al. Nucleic acid testing (NAT) for HCV RNA in Italian transfusion centres: An external quality assessment. J Clin Virol 2008; 41:277–82. Nationwide nucleic acid amplification testing of hepatitis B virus, hepatitis C virus and human immunodeficiency virus type 1 for blood transfusion and followup study of nucleic acid amplification positive donors. Japanese Red Cross NAT Screening Research Group. Jpn J Infect Dis 2000; 53:116–23. Alter H. Discovery of non-A, non-B hepatitis and identification of its etiology. Am J Med 1999; 107:16S–20S. Soza A, Arrese M, Gonzalez R et al. Clinical and epidemiological features of 147 Chilean patients with chronic hepatitis C. Ann Hepatol 2004; 3:146–51. Brettler DB, Alter HJ, Dienstag JL, Forsberg AD, Levine PH. Prevalence of hepatitis C virus antibody in a cohort of hemophilia patients. Blood 1990; 76:254–6. Troisi CL, Hollinger FB, Hoots WK et al. A multicenter study of viral hepatitis in a United States hemophilic population. Blood 1993; 81:412–8. Outbreak of hepatitis C associated with intravenous immunoglobulin administration – United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep 1994; 43:505–9. Bresee JS, Mast EE, Coleman PJ et al. Hepatitis C virus infection associated with administration of intravenous immune globulin. A cohort study. Jama 1996; 276:1563–7. Power JP, Lawlor E, Davidson F, Holmes EC, Yap PL, Simmonds P. Molecular epidemiology of an outbreak of infection with hepatitis C virus in recipients of anti-D immunoglobulin. Lancet 1995; 345:1211–3. Meisel H, Reip A, Faltus B et al. Transmission of hepatitis C virus to children and husbands by women infected with contaminated anti-D immunoglobulin. Lancet 1995; 345:1209–11. Alter MJ, Gerety RJ, Smallwood LA et al. Sporadic non-A, non-B hepatitis: frequency and epidemiology in an urban U.S. population. J Infect Dis 1982; 145:886–93. Alter MJ, Coleman PJ, Alexander WJ et al. Importance of heterosexual activity in the transmission of hepatitis B and non-A, non-B hepatitis. Jama 1989; 262:1201–5. Capelli C, Prati D, Bosoni P et al. Sexual transmission of hepatitis C virus to a repeat blood donor. Transfusion 1997; 37:436–40. Halfon P, Riflet H, Renou C, Quentin Y, Cacoub P. Molecular evidence of maleto-female sexual transmission of hepatitis C virus after vaginal and anal intercourse. J Clin Microbiol 2001; 39:1204–6. Feldman JG, Minkoff H, Landesman S, Dehovitz J. Heterosexual transmission of hepatitis C, hepatitis B, and HIV-1 in a sample of inner city women. Sex Transm Dis 2000; 27:338–42.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
63
49. Terrault NA. Sexual activity as a risk factor for hepatitis C. Hepatology 2002; 36:S99–105. 50. Thomas DL, Zenilman JM, Alter HJ et al. Sexual transmission of hepatitis C virus among patients attending sexually transmitted diseases clinics in Baltimore – an analysis of 309 sex partnerships. J Infect Dis 1995; 171:768–75. 51. Weinstock HS, Bolan G, Reingold AL, Polish LB. Hepatitis C virus infection among patients attending a clinic for sexually transmitted diseases. Jama 1993; 269:392–4. 52. Husa P, Kohoutkova M. [Hepatitis C virus infection in sex workers]. Klin Mikrobiol Infekc Lek 2007; 13:66–9. 53. Thomas DL, Cannon RO, Shapiro CN, Hook EW, 3rd, Alter MJ, Quinn TC. Hepatitis C, hepatitis B, and human immunodeficiency virus infections among non-intravenous drug-using patients attending clinics for sexually transmitted diseases. J Infect Dis 1994; 169:990–5. 54. Lissen E, Alter HJ, Abad MA et al. Hepatitis C virus infection among sexually promiscuous groups and the heterosexual partners of hepatitis C virus infected index cases. Eur J Clin Microbiol Infect Dis 1993; 12:827–31. 55. Oshita M, Hayashi N, Kasahara A et al. Prevalence of hepatitis C virus in family members of patients with hepatitis C. J Med Virol 1993; 41:251–5. 56. Kiyosawa K, Sodeyama T, Tanaka E et al. Intrafamilial transmission of hepatitis C virus in Japan. J Med Virol 1991; 33:114–6. 57. Transmission of hepatitis C virus. Ann Intern Med 1990; 113:411–2. 58. Ackerman Z, Ackerman E, Paltiel O. Intrafamilial transmission of hepatitis C virus: a systematic review. J Viral Hepat 2000; 7:93–103. 59. Diago M, Zapater R, Tuset C et al. Intrafamily transmission of hepatitis C virus: sexual and non-sexual contacts. J Hepatol 1996; 25:125–8. 60. Takamatsu K, Koyanagi Y, Okita K, Yamamoto N. Hepatitis C virus RNA in saliva. Lancet 1990; 336:1515. 61. Dusheiko GM, Smith M, Scheuer PJ. Hepatitis C virus transmitted by human bite. Lancet 1990; 336:503–4. 62. Caporaso N, Ascione A, Stroffolini T. Spread of hepatitis C virus infection within families. Investigators of an Italian Multicenter Group. J Viral Hepat 1998; 5:67–72. 63. Stroffolini T, Lorenzoni U, Menniti-Ippolito F, Infantolino D, Chiaramonte M. Hepatitis C virus infection in spouses: sexual transmission or common exposure to the same risk factors? Am J Gastroenterol 2001; 96:3138–41. 64. Kao JH, Liu CJ, Chen PJ, Chen W, Lai MY, Chen DS. Low incidence of hepatitis C virus transmission between spouses: A prospective study. J Gastroenterol Hepatol 2000; 15:391–5. 65. Vandelli C, Renzo F, Romano L et al. Lack of evidence of sexual transmission of hepatitis C among monogamous couples: Results of a 10-year prospective follow-up study. Am J Gastroenterol 2004; 99:855–9. 66. Tahan V, Karaca C, Yildirim B et al. Sexual transmission of HCV between spouses. Am J Gastroenterol 2005; 100:821–4. 67. Ferrero S, Lungaro P, Bruzzone BM, Gotta C, Bentivoglio G, Ragni N. Prospective study of mother-to-infant transmission of hepatitis C virus: a 10-year survey (1990–2000). Acta Obstet Gynecol Scand 2003; 82:229–34.
64
Sharma and Sherker
68. Syriopoulou V, Nikolopoulou G, Daikos GL et al. Mother to child transmission of hepatitis C virus: Rate of infection and risk factors. Scand J Infect Dis 2005; 37:350–3. 69. Hunt CM, Carson KL, Sharara AI. Hepatitis C in pregnancy. Obstet Gynecol 1997; 89:883–90. 70. Manzini P, Saracco G, Cerchier A et al. Human immunodeficiency virus infection as risk factor for mother-to-child hepatitis C virus transmission; persistence of anti-hepatitis C virus in children is associated with the mother s anti-hepatitis C virus immunoblotting pattern. Hepatology 1995; 21:328–32. 71. Airoldi J, Berghella V. Hepatitis C and pregnancy. Obstet Gynecol Surv 2006; 61:666–72. 72. Mast EE. Mother-to-infant hepatitis C virus transmission and breastfeeding. Adv Exp Med Biol 2004; 554:211–6. 73. Polywka S, Schroter M, Feucht HH, Zollner B, Laufs R. Low risk of vertical transmission of hepatitis C virus by breast milk. Clin Infect Dis 1999; 29:1327–9. 74. Kumar RM, Shahul S. Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol 1998; 29:191–7. 75. Niu MT, Coleman PJ, Alter MJ. Multicenter study of hepatitis C virus infection in chronic hemodialysis patients and hemodialysis center staff members. Am J Kidney Dis 1993; 22:568–73. 76. Fabrizi F, Martin P, Dixit V et al. Acquisition of hepatitis C virus in hemodialysis patients: A prospective study by branched DNA signal amplification assay. Am J Kidney Dis 1998; 31:647–54. 77. Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001; 50:1–43. 78. Selgas R, Martinez-Zapico R, Bajo MA et al. Prevalence of hepatitis C antibodies (HCV) in a dialysis population at one center. Perit Dial Int 1992; 12:28–30. 79. Hardy NM, Sandroni S, Danielson S, Wilson WJ. Antibody to hepatitis C virus increases with time on hemodialysis. Clin Nephrol 1992; 38:44–8. 80. Levy R. CMS proposed revisions to conditions to participation: Part 1-patient safety requirements. Dial Transplant 2006; 35:156–166. 81. Hwang LY, Kramer JR, Troisi C et al. Relationship of cosmetic procedures and drug use to hepatitis C and hepatitis B virus infections in a low-risk population. Hepatology 2006; 44:341–51. 82. Galperim B, Cheinquer H, Stein A, Fonseca A, Lunge V, Ikuta N. Intranasal cocaine use does not appear to be an independent risk factor for HCV infection. Addiction 2004; 99:973–7. 83. McMahon JM, Tortu S. A potential hidden source of hepatitis C infection among noninjecting drug users. J Psychoactive Drugs 2003; 35:455–60. 84. Ko YC, Ho MS, Chiang TA, Chang SJ, Chang PY. Tattooing as a risk of hepatitis C virus infection. J Med Virol 1992; 38:288–91. 85. Hellard ME, Hocking JS, Crofts N. The prevalence and the risk behaviours associated with the transmission of hepatitis C virus in Australian correctional facilities. Epidemiol Infect 2004; 132:409–15. 86. Neumeister AS, Pilcher LE, Erickson JM et al. Hepatitis-C prevalence in an urban native-American clinic: A prospective screening study. J Natl Med Assoc 2007; 99:389–92.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
65
87. Haley RW, Fischer RP. Commercial tattooing as a potentially important source of hepatitis C infection. Clinical epidemiology of 626 consecutive patients unaware of their hepatitis C serologic status. Medicine (Baltimore) 2001; 80:134–51. 88. Haley RW, Fischer RP. The tattooing paradox: Are studies of acute hepatitis adequate to identify routes of transmission of subclinical hepatitis C infection? Arch Intern Med 2003; 163:1095–8. 89. Hauri AM, Armstrong GL, Hutin YJ. The global burden of disease attributable to contaminated injections given in health care settings. Int J STD AIDS 2004; 15:7–16. 90. Singh S, Dwivedi SN, Sood R, Wali JP. Hepatitis B, C and human immunodeficiency virus infections in multiply-injected kala-azar patients in Delhi. Scand J Infect Dis 2000; 32:3–6. 91. Puro V, Petrosillo N, Ippolito G. Risk of hepatitis C seroconversion after occupational exposures in health care workers. Italian study group on occupational risk of HIV and other bloodborne infections. Am J Infect Control 1995; 23:273–7. 92. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36:S35–46. 93. Thomas DL, Astemborski J, Rai RM et al. The natural history of hepatitis C virus infection: Host, viral, and environmental factors. Jama 2000; 284:450–6. 94. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999; 29:908–14. 95. Seeff LB, Miller RN, Rabkin CS et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000; 132:105–11. 96. Seeff LB, Hollinger FB, Alter HJ et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33:455–63. 97. Alter MJ, Margolis HS, Krawczynski K et al. The natural history of communityacquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992; 327:1899–905. 98. Vogt M, Lang T, Frosner G et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341:866–70. 99. Rodger AJ, Roberts S, Lanigan A, Bowden S, Brown T, Crofts N. Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975. Hepatology 2000; 32:582–7. 100. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusionassociated hepatitis C. N Engl J Med 1995; 332:1463–6. 101. Koretz RL, Abbey H, Coleman E, Gitnick G. Non-A, non-B post-transfusion hepatitis. Looking back in the second decade. Ann Intern Med 1993; 119:110–5. 102. Yano M, Kumada H, Kage M et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996; 23:1334–40. 103. Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994; 331:1607–11. 104. Niederau C, Lange S, Heintges T et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998; 28:1687–95.
66
Sharma and Sherker
105. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology 1991; 14:969–74. 106. Mattsson L, Sonnerborg A, Weiland O. Outcome of acute symptomatic non-A, non-B hepatitis: a 13-year follow-up study of hepatitis C virus markers. Liver 1993; 13:274–8. 107. Wiese M, Berr F, Lafrenz M, Porst H, Oesen U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in germany: a 20-year multicenter study. Hepatology 2000; 32:91–6. 108. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999; 340:1228–33. 109. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349:825–32. 110. Freeman AJ, Dore GJ, Law MG et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001; 34:809–16. 111. Jamal MM, Soni A, Quinn PG, Wheeler DE, Arora S, Johnston DE. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States. Hepatology 1999; 30:1307–11. 112. Mathurin P, Moussalli J, Cadranel JF et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998; 27:868–72. 113. Costa LB, Ferraz ML, Perez RM et al. Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection. Braz J Infect Dis 2002; 6:219–24. 114. Ryder SD, Irving WL, Jones DA, Neal KR, Underwood JC. Progression of hepatic fibrosis in patients with hepatitis C: A prospective repeat liver biopsy study. Gut 2004; 53:451–5. 115. Svirtlih N, Jevtovic D, Simonovic J et al. Older age at the time of liver biopsy is the important risk factor for advanced fibrosis in patients with chronic hepatitis C. Hepatogastroenterology 2007; 54:2324–7. 116. Yamakawa Y, Sata M, Suzuki H, Noguchi S, Tanikawa K. Higher elimination rate of hepatitis C virus among women. J Viral Hepat 1996; 3:317–21. 117. Shimizu I, Mizobuchi Y, Yasuda M et al. Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut 1999; 44:127–36. 118. Yasuda M, Shimizu I, Shiba M, Ito S. Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 1999; 29:719–27. 119. Lu G, Shimizu I, Cui X et al. Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats. Life Sci 2004; 74:897–907. 120. Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans: summary of a workshop. Gastroenterology 2000; 119:1385–96. 121. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745–50. 122. Reddy KR, Hoofnagle JH, Tong MJ et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology 1999; 30:787–93.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
67
123. Wiley TE, Brown J, Chan J. Hepatitis C infection in African Americans: Its natural history and histological progression. Am J Gastroenterol 2002; 97:700–6. 124. Harris DR, Gonin R, Alter HJ et al. The relationship of acute transfusionassociated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001; 134:120–4. 125. Staples CT, Jr., Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): The effect of coinfection on survival. Clin Infect Dis 1999; 29:150–4. 126. Benhamou Y, Bochet M, Di Martino V et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999; 30:1054–8. 127. Thomas DL. Hepatitis C and human immunodeficiency virus infection. Hepatology 2002; 36:S201–9. 128. Kim AY, Lauer GM, Ouchi K et al. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1. Blood 2005; 105:1170–8. 129. Shuhart MC, Sullivan DG, Bekele K et al. HIV infection and antiretroviral therapy: effect on hepatitis C virus quasispecies variability. J Infect Dis 2006; 193:1211–8. 130. Brau N, Salvatore M, Rios-Bedoya CF et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol 2006; 44:47–55. 131. Fong TL, Di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology 1991; 14:64–7. 132. Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin Liver Dis 2004; 24 Suppl 2:61–8. 133. Tsai JF, Jeng JE, Ho MS, Chang WY, Lin ZY, Tsai JH. Independent and additive effect modification of hepatitis C and B viruses infection on the development of chronic hepatitis. J Hepatol 1996; 24:271–6. 134. Senturk H, Tahan V, Canbakan B et al. Clinicopathologic features of dual chronic hepatitis B and C infection: A comparison with single hepatitis B, C and Delta infections. Ann Hepatol 2008; 7:52–8. 135. Pontisso P, Ruvoletto MG, Fattovich G et al. Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 1993; 105:1529–33. 136. Cheruvu S, Marks K, Talal AH. Understanding the pathogenesis and management of hepatitis B/HIV and hepatitis B/hepatitis C virus coinfection. Clin Liver Dis 2007; 11:917–43, ix–x. 137. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39:1147–71. 138. Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis 2004; 24:399–413. 139. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006; 40:S17–29. 140. Kowdley KV, Caldwell S. Nonalcoholic steatohepatitis: A twenty-first century epidemic? J Clin Gastroenterol 2006; 40:S2–4.
68
Sharma and Sherker
141. Corrao G, Arico S. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology 1998; 27:914–9. 142. Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998; 27:1730–5. 143. Pessione F, Degos F, Marcellin P et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology 1998; 27:1717–22. 144. Alter HJ. To C or not to C: These are the questions. Blood 1995; 85:1681–95. 145. Hezode C, Lonjon I, Roudot-Thoraval F, Pawlotsky JM, Zafrani ES, Dhumeaux D. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: A prospective study. Aliment Pharmacol Ther 2003; 17:1031–7. 146. Safdar K, Schiff ER. Alcohol and hepatitis C. Semin Liver Dis 2004; 24:305–15. 147. Seeff LB. Natural history of hepatitis C. Hepatology 1997; 26:21S–28S. 148. Chiba T, Matsuzaki Y, Abei M et al. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996; 91:1195–203. 149. Tzonou A, Trichopoulos D, Kaklamani E, Zavitsanos X, Koumantaki Y, Hsieh CC. Epidemiologic assessment of interactions of hepatitis-C virus with seromarkers of hepatitis-B and -D viruses, cirrhosis and tobacco smoking in hepatocellular carcinoma. Int J Cancer 1991; 49:377–80. 150. Mori M, Hara M, Wada I et al. Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan. Am J Epidemiol 2000; 151:131–9. 151. Mukaiya M, Nishi M, Miyake H, Hirata K. Chronic liver diseases for the risk of hepatocellular carcinoma: a case-control study in Japan. Etiologic association of alcohol consumption, cigarette smoking and the development of chronic liver diseases. Hepatogastroenterology 1998; 45:2328–32. 152. Pessione F, Ramond MJ, Njapoum C et al. Cigarette smoking and hepatic lesions in patients with chronic hepatitis C. Hepatology 2001; 34:121–5. 153. Kiyosawa K, Sodeyama T, Tanaka E et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990; 12:671–5. 154. Seeff LB. Natural history of viral hepatitis, type C. Semin Gastrointest Dis 1995; 6:20–7. 155. Gordon SC, Bayati N, Silverman AL. Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology 1998; 28:562–7. 156. Kato N, Yokosuka O, Hosoda K, Ito Y, Ohto M, Omata M. Quantification of hepatitis C virus by competitive reverse transcription-polymerase chain reaction: increase of the virus in advanced liver disease. Hepatology 1993; 18:16–20. 157. Adinolfi LE, Utili R, Andreana A et al. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci 2001; 46:1677–83. 158. Romeo R, Colombo M, Rumi M et al. Lack of association between type of hepatitis C virus, serum load and severity of liver disease. J Viral Hepat 1996; 3:183–90.
Epidemiology, Risk Factors, and Natural History of Chronic Hepatitis C
69
159. Hollingsworth RC, Sillekens P, van Deursen P, Neal KR, Irving WL. Serum HCV RNA levels assessed by quantitative NASBA: Stability of viral load over time, and lack of correlation with liver disease. The Trent HCV Study Group. J Hepatol 1996; 25:301–6. 160. Lau JY, Davis GL, Kniffen J et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 1993; 341:1501–4. 161. Fanning L, Kenny E, Sheehan M et al. Viral load and clinicopathological features of chronic hepatitis C (1b) in a homogeneous patient population. Hepatology 1999; 29:904–7. 162. Dusheiko G, Schmilovitz-Weiss H, Brown D et al. Hepatitis C virus genotypes: an investigation of type-specific differences in geographic origin and disease. Hepatology 1994; 19:13–8. 163. Ichimura H, Tamura I, Kurimura O et al. Hepatitis C virus genotypes, reactivity to recombinant immunoblot assay 2 antigens and liver disease. J Med Virol 1994; 43:212–5. 164. Pozzato G, Moretti M, Franzin F et al. Severity of liver disease with different hepatitis C viral clones. Lancet 1991; 338:509. 165. Yoshioka K, Kakumu S, Wakita T et al. Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: Relationship to genotypes of hepatitis C virus. Hepatology 1992; 16:293–9. 166. Tsubota A, Chayama K, Ikeda K et al. Factors predictive of response to interferon-alpha therapy in hepatitis C virus infection. Hepatology 1994; 19:1088–94. 167. Kobayashi M, Tanaka E, Sodeyama T, Urushihara A, Matsumoto A, Kiyosawa K. The natural course of chronic hepatitis C: a comparison between patients with genotypes 1 and 2 hepatitis C viruses. Hepatology 1996; 23:695–9. 168. Mahaney K, Tedeschi V, Maertens G et al. Genotypic analysis of hepatitis C virus in American patients. Hepatology 1994; 20:1405–11. 169. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997; 25:735–9. 170. Farci P, Shimoda A, Coiana A et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000; 288:339–44. 171. Thomson BJ, Finch RG. Hepatitis C virus infection. Clin Microbiol Infect 2005; 11:86–94. 172. Mohsen AH. The epidemiology of hepatitis C in a UK health regional population of 5.12 million. Gut 2001; 48:707–13. 173. Munoz G, Velasco M, Thiers V et al. [Prevalence and genotypes of hepatitis C virus in blood donors and in patients with chronic liver disease and hepatocarcinoma in a Chilean population]. Rev Med Chil 1998; 126:1035–42. 174. Yamada G, Tanaka E, Miura T et al. Epidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver diseases: A multi-institution analysis. J Gastroenterol Hepatol 1995; 10:538–45. 175. Ohno O, Mizokami M, Wu RR et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol 1997; 35:201–7. 176. Wang Y, Tao QM, Zhao HY et al. Hepatitis C virus RNA and antibodies among blood donors in Beijing. J Hepatol 1994; 21:634–40.
70
Sharma and Sherker
177. Apichartpiyakul C, Apichartpiyakul N, Urwijitaroon Y et al. Seroprevalence and subtype distribution of hepatitis C virus among blood donors and intravenous drug users in northern/northeastern Thailand. Jpn J Infect Dis 1999; 52:121–3. 178. Das BR, Kundu B, Khandapkar R, Sahni S. Geographical distribution of hepatitis C virus genotypes in India. Indian J Pathol Microbiol 2002; 45:323–8. 179. Valliammai T, Thyagarajan SP, Zuckerman AJ, Harrison TJ. Diversity of genotypes of hepatitis C virus in southern India. J Gen Virol 1995; 76 (Pt 3):711–6. 180. Osoba AO. Hepatitis C virus genotypes in Saudi Arabia. Saudi Med J 2002; 23:7–12.
Current and Future Therapy of Chronic Hepatitis C Mohammad Ashfaq, MD and Gary Davis, MD CONTENTS I NTRODUCTION C URRENT S TANDARD OF C ARE T REATMENT OF S PECIFIC PATIENT G ROUPS T HERAPEUTICS AGENT IN D EVELOPMENT R EFERENCES
Key Principles
• The current standard of care for treatment of chronic hepatitis C is once weekly pegylated interferon and daily oral ribavirin. The optimal treatment regimen is determined by viral genotype, patient weight, and the initial virus response to therapy, termed early virologic response (EVR). Non-responders can be identified after the first 12 weeks of treatment so that therapy can be stopped. • Treatment of chronic hepatitis C with antiviral therapy requires close monitoring since about 30% of patients require dose modifications for cytopenia or side effects. • Approximately half of treated patients are cured of their infection. Treatment response, termed sustained viral response (SVR), is associated with resolution of inflammation and fibrosis regression. Patients with cirrhosis who achieve an SVR have no further risk of liver failure and the risk of liver cancer is markedly reduced, though not eliminated. From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 3, C Humana Press, a part of Springer Science+Business Media, LLC 2009
71
72
Ashfaq and Davis
• Some groups of patients have a lower chance of response to treatment than others. Recent studies suggest that higher doses of antiviral drugs might be of benefit in these cases. Patients with advanced cirrhosis or extrahepatic manifestations of hepatitis C infection are best treated by a physician, who has considerable experience with these drugs. • New virus-specific antiviral agents are in development but it appears that they will need to be given in conjunction with interferon and ribavirin. It is hoped that these new drugs will improve efficacy and perhaps shorten the required duration of treatment. These drugs, if approved, will probably not be available before 2010.
1. INTRODUCTION The global prevalence of hepatitis C virus (HCV) infection is estimated to be 130–170 million persons (1). The prevalence varies widely in different regions of the world (2). In the United States, it is estimated that between 3 and 5 million persons have chronic infection (3, 4). The identification of the virus responsible for the disease in 1989 led to increased attention to risk factors for transmission and screening of blood donors which caused a dramatic fall in new infections (5). Currently, the incidence of new HCV infections is only about 25,000 to 30,000 cases per year (6). Nonetheless, the prevalence of infection has remained quite stable since most (50–90%) acute infections result in chronic infection and hepatitis. Modeling studies have predicted that the prevalence will gradually decline over the next two decades as the infected population ages, but the likelihood of cirrhosis and disease complications such as decompensated cirrhosis and hepatocellular carcinoma (HCC) will increase (7,8). Thus, there is a great need for the medical community to address this problem with increased efforts to identify infected patients and deliver effective therapy.
2. CURRENT STANDARD OF CARE The current standard of care for treatment of chronic hepatitis C is the combination of pegylated interferon and ribavirin. This is a regimen that has evolved over the last 18 years. Recombinant interferon was first approved by the FDA for the treatment of non-A, non-B hepatitis in 1991 as monotherapy, but it was effective in a relatively small proportion of patients (9, 10). Ribavirin was added to the regimen after it was noted that it reduced the chance of relapse when treatment was stopped (11). Pegylated interferons replaced the standard formulation
Current and Future Therapy of Chronic Hepatitis C
73
in 2001 and offered the convenience of once a week dosing (12, 13). Improved outcomes have accompanied these changes (Fig. 1).
Fig. 1. Outcomes of treatment regimens for chronic hepatitis C.
2.1. Current Agents Interferons are naturally occurring glycoproteins that are produced in vivo by cells, particularly leukocytes, in response to viral infection. Pharmacologic doses of interferons were first produced by stimulation of cultures of buffy coat lymphocytes collected from blood donors, but commercially available interferons today are recombinantly produced. Interferons inhibit the replication of many viruses, including hepatitis viruses, through a variety of mechanisms, including direct antiviral (inhibition of virus attachment and uncoating, induction of intracellular proteins and ribonucleases) and by amplification of specific (cytotoxic T-lymphocyte) and nonspecific (natural killer cell) immune responses (14). In the late 1980 s, interferons were among the first agents studied for treatment of what was then called chronic non-A, non-B hepatitis (9). Although IFN suppresses the level of HCV replication, the exact mechanisms of action in HCV infection are not known. Nonetheless, it is generally believed that clearance of the HCV is at least in part mediated by IFN-related enhancement of the host immune response to the virus. Initially, standard recombinant interferons were used for treatment of chronic HCV infection. These had a limited half-life that required dosing three times per week. Long-acting pegylated interferons replaced standard interferons after their approval by FDA in 2001. Pegylation involves the attachment of a large inactive molecule (polyethylene gly-
74
Ashfaq and Davis
col; PEG) to the interferon molecule in order to reduce its renal clearance. This process results in some variable loss of activity of the native protein that is dependent on the size and site of attachment of the PEG molecule but is also associated with a tenfold increase in drug half-life and a corresponding decrease in clearance (15–17). The PEG molecule is cleaved after binding of the complex to the interferon receptor and cleared. The longer half-life allows large doses of the drug to be administered less frequently (once weekly instead of three times per week), increases host exposure to interferon, and doubles the response seen with standard interferon preparations (18–20). Pegylated interferons are more effective than standard interferon and there is a clear dose response with increasing doses of the PEG-interferons (9, 12, 13, 21). Ribavirin (1--D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is a synthetic nucleoside analogue which structurally resembles guanosine and has in vitro activity against many viruses, including flaviviridae which closely resemble HCV (22, 23). The mechanism of action in HCV infection is not clear, but the predominant current opinion is that ribavirin induces lethal mutations in the viral genome, a mechanism known as viral error catastrophe (22–24). Early studies of ribavirin alone found that serum ALT levels fell to within the normal range in 40% of treated patients, but virus levels did not significantly change (25–27). However, when combined with interferon, the combination both improves response during treatment and reduces subsequent relapse. Thus, there is a dramatic improvement in the sustained virologic response rate (11, 28–30). The results of two similarly designed large randomized controlled trials comparing combination therapy to interferon monotherapy showed sustained viral-negative responses in 41 and 33% of subjects treated with 12 or 6 months of combination therapy, respectively, compared to 16 and 6% in those treated with interferon alone for 12 or 6 months (31). Furthermore, the combination of pegylated interferon with ribavirin (the current standard of care) showed an even higher viral response rate (12, 13). PEG-interferon alfa2b 1.5 g/kg once weekly plus 800 mg daily ribavirin led to a sustained virologic response rate of 54%, even though the dose of ribavirin in this study was suboptimal (12). Sustained response was 42% in patients infected with genotype 1 and 82% in those with genotype 2 or 3. Similarly, PEG-interferon alfa-2a 180 g once weekly plus 1000–1200 mg of ribavirin per day resulted in a sustained virologic response rate of 56% (13). Sustained response was 46% in patients infected with genotype 1 and 76% in those with genotype 2 or 3.
Current and Future Therapy of Chronic Hepatitis C
75
2.2. Optimizing Treatment Regimens The sensitivity of different HCV genotypes to interferon-based therapies varies considerably and this determines both the drug doses and the treatment duration required (Table 1). Thus, the determination of the virus genotype before treatment remains the initial critical step in evaluating a patient with chronic hepatitis C. Patients infected with genotype 1 should receive 1 year of one of the two available pegylated interferons (PEG-IFN) plus ribavirin. The two pegylated interferons are, for all intents and purposes, bioequivalent. Although the approved dose of ribavirin is 1000–1200 mg/day for those with weight less than or greater than 75 kg, respectively (32), an extended weight-based dose ranging from 800 to 1400 mg/day is commonly used (Table 1) (33). It is not known whether such dosing improves response or is appropriate for other genotypes. Recently, some investigators have suggested that “rapid viral response” (RVR; undetectable HCV RNA after 4 weeks of treatment) in patients with genotype 1 identifies a small subgroup (about 20% of treated patients) who may be treated for only 24 weeks and still achieve an SVR rate of 73–91% (34). Others have found a lower SVR rate with 24 weeks of treatment, so this needs to be confirmed before becoming standard practice (35). Patients with genotype 2 or 3 respond as well with doses of 800 mg/day and just 6 months of treatment as they do with higher doses and a longer duration (32). Recently, studies have suggested that some patients with genotype 2 or 3 infection who respond rapidly to treatment (RVR) can be treated for as little as 12–16 weeks with excellent outcomes if weight-based dosing of ribavirin is utilized (36–38). Shortening the course of treatment is not recommended regardless of the early viral response if a standard dose (800 mg per day) of ribavirin has been used (39). Patients who are infected with genotype 4 have viral response rates similar to or perhaps slightly better than genotype 1 and, like genotype 1, some achieve good responses with only 24 weeks of therapy (40). Genotypes 5 and 6 have SVR rates approaching those achieved with genotypes 2 and 3, although they require a full year of therapy (41, 42).
2.3. Patient Selection, Drug Administration, and Monitoring Therapy All HCV-infected patients should be counseled about routes of virus transmission, the natural history of the infection, the detrimental effects of alcohol and cannabis use on the course of disease, treatment options,
Ribavirin Dose (mg/day) 800–1400 mg/daya weight-based 800 mg/dayb 800 mg/dayb 1000–1200 mg/daya
Interferon Dose (per week)
180 g PEG alfa-2a or 1.5 g/kg PEG alfa-2b 180 g PEG alfa-2a or 1.5 g/kg PEG alfa-2b 180 g PEG alfa-2a or 1.5 g/kg PEG alfa-2b 180 g PEG alfa-2a or 1.5 g/kg PEG alfa-2b
48 24 24 48
Duration (weeks)
41–42% 66–75% 66–75% 55–64%
SVR (%)
a Weight-based dosing of ribavirin is 800 mg daily in a divided dose for weight less than 65 kg, 1000 mg for weight 65–84 kg, 1200 mg for weight 85–104 kg, and 1400 mg for weight of 105 kg or more. b Ribavirin dose should be weight-based if shorter duration of therapy is anticipated in patients with rapid viral response.
1 2 3 4, 5, 6
Genotype
Table 1 Doses and Duration of Antiviral Drugs According to Viral Genotype
Current and Future Therapy of Chronic Hepatitis C
77
possible treatment risks especially including the risk of teratogenicity of ribavirin, and outcomes regardless of what intervention, if any, is ultimately decided upon. If treatment is not considered, the importance of long-term follow-up must be emphasized. Valuable patient resources are available on the websites for the Centers for Disease Control and Prevention (http://www.cdc.gov/ncidod/diseases/hepatitis/) and the American Liver Foundation (http://www.liverfoundation.org/ education/info/hepatitisc/). Up-to-date physician information on epidemiology and treatment is available from several different online resources including Clinical Care Options (http://www. clinicaloptions.com/Hepatitis.aspx) and subscription services such as Up-ToDate and WebMD. Rationale treatment management decisions are based on a clear understanding of the epidemiology and natural history of chronic hepatitis C, as well as the factors that influence the response to treatment. The potential benefits in terms of freedom from risk of progression, longevity, and quality of life must be weighed against the current effectiveness, cost, tolerability of therapy, other comorbid conditions that the patient might have, financial impact, and desire for therapy. The balance of these factors defines the treatment threshold for a particular patient. If the physician and patient agree to proceed with treatment, assessment of the status of the disease (as determined by liver biopsy) and infection (as determined by viral genotype and HCV RNA level) should be made. This allows a more accurate estimate of prognosis and chance of response to available treatment. It also allows the physician to use these patient characteristics that may independently influence treatment response to personalize the treatment strategy to achieve the optimal response (see above). Although most hepatologists use only viral genotype and histology to choose the best treatment duration, others have recommended a more complex “a la carte” method that also incorporates gender, age, and viral level into Equation (43). Retrospective analysis suggests that such algorithms might improve sustained viral response rates to 50–83%. However, the wisdom of complicated algorithms that would, in effect, treat a higher proportion of infected cases with a longer and more costly regimen is controversial and has not been confirmed prospectively. Baseline assessment of liver tests, complete blood counts, and HCV RNA level are important in order to later determine treatment response and drug-related toxicity. The patient should be instructed in injection techniques. Treatment tolerance is improved if the patient is educated about the potential side effects of therapy and what they might expect. Some easy measures such as evening dosing, exercise, adequate
78
Ashfaq and Davis
hydration, and use of acetaminophen at the time of each interferon dose will reduce anxiety, side effects, and non-compliance. Physician extenders such as nurses, pharmacists, and commercial pharmacy support services are extremely helpful in this respect. Reinstitution of antidepressants should be considered in patients with active depression or a significant past history of depression. Monitoring response and potential drug toxicity is essential (Fig. 2). Symptoms related to treatment rarely necessitate dose adjustments. However, hematologic alterations, particularly anemia, can be significant and clinically important during the first few weeks and may require dose adjustments (Table 2). Therefore, blood counts including hemoglobin, white count, differential, and platelet count should be repeated 2 and 4 weeks after starting therapy. Transient interferon dose reduction is indicated only for a neutrophil count less than 750 per mL or platelets to less than 50,000 per mL. Ribavirin should be reduced if the hemoglobin falls to less than 10 g/dL. The amount of dose reduction required to reverse cytopenia has not been established and this has led to differences in the recommendations for the two interferon preparations (Table 2). Although the labeling of the drugs calls for reducing doses by approximately half, this is usually not necessary. Temporary dose modifications are common in patients treated with combination therapy. In fact, in large controlled trials dose modifications were required at least transiently in 34 and 42%, respectively (12, 13). Ribavirin causes a hemolytic anemia that is accompanied by a vigorous reticulocytosis. Although this usually serves to maintain stable levels of hemoglobin after the first few weeks of treatment, about 8–13% of patients will require reduction of the ribavirin dose for anemia, usually during the first 4 weeks of treatment (44). Ribavirin-induced anemia is dosedependent and therefore anemia usually stabilizes or improves with dose reduction. Occasionally transfusion or support with erythropoietin is necessary, though it generally takes 4–8 weeks before the hemoglobin increases after erythropoietin is started (45). About 15–20% of patients treated with pegylated interferon require dose reductions for neutropenia (12, 13). Growth factor support is rarely required for neutropenia. Significant thrombocytopenia necessitating dose reduction is uncommon since the anemia caused by ribavirin induces a reactive thrombocytosis. Thus, platelet counts tend to remain relatively stable throughout combination therapy, even when the pre-treatment count is low. Interferon should be permanently stopped only if symptoms are incapacitating, the absolute neutrophil count is less than 500 per mL, or the platelet count is less than 25,000 per mL. Discontinuation of therapy for cytopenia is uncommon if patients have been monitored and dose adjusted appropriately. It is extremely important that treatment not be
Fig. 2. Monitoring of antiviral treatment for chronic hepatitis C (sample data sheet).
Platelet <80,000/mm3 Platelet <50,000/mm3 Platelet <25,000/mm3 Hemoglobin: <10 gm/dL if no cardiac disease >2 gm/dL fall if history of stable cardiac disease
ANC >750/mm3 ANC <750/mm3 ANC <500/mm3
Laboratory Values
No changea No changea
Reduce to 135 g Discontinue until ANC values return to more than 1000/mm3 . No change Reduce to 90 g Discontinue permanently
No change
Pegylated IFN alfa-2a
No changea No changea
Reduce by 50% Discontinue permanently
No change Reduce by 50% Discontinue permanently
Pegylated IFN alfa-2b
Dose Reductions
Table 2 Modification of Doses of Antiviral Drugs (from Product Labeling Except Where Noted)
b
b
No change No change
No change No change
No change
Ribavirin
Stop Decrease dose to 135 g (in some cases reduction to 90 g may be needed). Discontinue permanently
Pegylated IFN alfa-2a
Stop No recommendation Stop
Discontinue permanently
Ribavirin
Stop Decrease dose by 50%
Pegylated IFN alfa-2b
Dose Reductions
a Authors’ note: Interferon suppresses bone marrow function and modest dose reductions may allow the hemoglobin to stabilize and/or recover if ribavirin reduction alone is insufficient. Also consider iron deficiency of ribavirin reduction does not stabilize the hemoglobin level. b Recommendation with Copegus (Roche) is to reduce dose to 600 mg/day. Recommendation with Rebetol (Schering) is to reduce in 200 mg/day increments until hemoglobin is stable.
<8.5 gm Moderate side effects (symptoms) Severe side effects (symptoms)
Laboratory Values
Table 2 (Continued)
82
Ashfaq and Davis
stopped prematurely or for decreases in blood counts that do not meet the criteria stated above. Inappropriate dose reduction and discontinuation significantly reduces the likelihood of a treatment response. Early discontinuation of treatment can reduce the likelihood of a sustained treatment response by 80% (46). The safety and tolerability of combination therapy have been reviewed in detail elsewhere and will only be highlighted here. These reviews are highly recommended for physicians who have not used these drugs before. Overall, interferon-based therapies are reasonably well tolerated. Most patients experience flu-like side effects including fatigue, fever, headache, myalgia, and arthralgia (44, 47). These are most severe during the first few weeks of therapy and often abate to a large degree as treatment is continued. Gastrointestinal symptoms including nausea, vomiting, or diarrhea occur in about a third of patients but are rarely severe. Psychiatric symptoms such as depression, impaired concentration, irritability, and insomnia occur in about a third of cases, but are also common in untreated patients with chronic hepatitis C. Dermatologic signs and symptoms occur in about a quarter of patients. Injection site erythema is most common and occurs more frequently with pegylated interferons. A faint morbilliform rash can be seen from the ribavirin. As described above, ribavirin causes a predictable dose-related hemolysis. Thus, the drug should be used with great caution or avoided completely if there is pre-existing anemia, a hemolytic disorder, coronary artery disease, or hypoxia. Since ribavirin is renally excreted, it can cause profound hemolysis in patients with renal failure and should generally be avoided. Careful consideration should be given to the potential effects of an acute anemia in each patient in whom combination treatment is considered. The mean fall in hemoglobin is 2–3 gm/dL (11–13, 28). The decline occurs gradually during the first 4 weeks of treatment and the hemoglobin level usually remains relatively stable thereafter. Finally, ribavirin has embryotoxic and teratogenic effects in animals and should be avoided in patients of child-bearing potential unless adequate contraception is assured. Severe adverse events, including severe psychiatric symptoms, suicide attempts, and profound cytopenia are extremely uncommon being reported in fewer than 1 in 1000 treated cases (47). Development of immune-mediated disorders such as thyroid disease, diabetes, dermatologic conditions, neuropathy, and other autoimmune-like signs was seen in about 1% in a large retrospective series (47). Development of autoantibodies is not necessarily associated with autoimmune disease. Autoantibodies are common in patients with HCV infection and may be more common during interferon treatment (48, 49).
Current and Future Therapy of Chronic Hepatitis C
83
2.4. Assessing Treatment Response Treatment responses are defined by changes in the HCV RNA level during and after treatment (Table 3). HCV RNA should be measured with a sensitive quantitative assay such as real-time PCR, for example the Roche Taqman. Serum ALT is not part of the definition of response since its level does not always reflect on treatment response. Ribavirin may cause the ALT to normalize in the absence of a virologic response and ALT may occasionally be elevated despite a virologic response, especially in those receiving pegylated products (12, 13, 27). Early virologic response (EVR) is defined as a fall in the HCV RNA level by at least 2 logs (99%) within the first 12 weeks of treatment. EVR is based on the concept that the slope of the second phase decline in HCV RNA levels during treatment correlates with the likelihood of eventual virus clearance (50). Thus, EVR is used to assess responsiveness to treatment during the first weeks of therapy. Genotype 1-infected patients who fail to achieve an EVR have less than a 1% chance of reaching an SVR with continued therapy (51). This justifies discontinuation of therapy after 12 weeks in the 20% or so of patients without EVR. Patients with genotype 2 or 3 almost always reach an EVR, so it is not usually helpful to assess HCV RNA levels during treatment in them. Measurement of HCV RNA at the end of therapy is helpful in identifying those who have cleared virus (ETR) and require subsequent screening to confirm a durable response. About 15% of patients with ETR will relapse during the first few months after treatment is stopped. Sustained viral response (SVR) is confirmed by the absence of detectable HCV RNA by a sensitive molecular test 6 months after completing therapy. Occasionally studies will report “SVR-3 months” since almost all relapses occur within 12 weeks of stopping treatment. SVR is the major goal of treatment and is durable. It implies viral eradication and is associated with histologic improvement, regression of inflammation and fibrosis, and in patients with cirrhosis, a marked reduction in risk for hepatocellular carcinoma and elimination of the risk of decompensation (52–54). The implications of rapid viral response (RVR) are described above, but this is a new concept and requires confirmation before influencing treatment duration in most patients. RVR identifies those patients who are most sensitive to antiviral treatment and might tolerate dose reductions or early treatment discontinuation. Importantly, failure to reach an RVR does not connote treatment failure and it is not a reason to stop treatment.
End of treatment
End-of-treatment response (ETR) Sustained virologic response (SVR)
a
12
Early virologic response (EVR)
HCV RNA decreased by > 2 logs from baseline or HCV RNA undetectable HCV RNA undetectable by rtPCR or TMA HCV RNA undetectable by rtPCR or TMA
HCV RNA undetectable by rtPCR or TMA
Definitiona
Implication Higher chance of SVR may respond as well if treatment needs to be shortened Failure to achieve EVR associated with <1% chance of SVR and treatment can usually be stopped On treatment response. Observe for SVR or relapse Eradication of virus (cure)
rtPCR = real-time polymerase chain reaction such as TaqMan; TMA = transcription mediated amplification.
24 weeks after treatment
4
Week of Treatment
Rapid viral response (RVR)
Milestone
Table 3 Treatment Milestones and Endpoints
Current and Future Therapy of Chronic Hepatitis C
85
3. TREATMENT OF SPECIFIC PATIENT GROUPS Treatment of most patients with chronic hepatitis C is done by hepatologists, gastroenterologists, and infectious disease physicians. A physician’s experience and comfort with these patients and the medications required for their treatment determines one’s treatment threshold. Some patients are more complicated and require more experience with the complexities of treatment. Such cases should generally be referred to an experienced treater or managed in collaboration with one.
3.1. Fibrosis or Cirrhosis Bridging fibrosis or cirrhosis is present in 20–30% of patients with chronic hepatitis C. The rationale for treating patients with advanced fibrosis is clear since these patients have a greater risk of progressing to develop hepatocellular carcinoma or complications of cirrhosis. These complications are significantly reduced if the patient clears virus (see above). Although the presence of significant fibrosis negatively impacts treatment response to interferon-based regimens, it does not preclude response or necessarily increase the complexity of treatment. Patients with stage 3 (bridging fibrosis) or 4 (cirrhosis) fibrosis have about a 10% lower SVR rate than patients without fibrosis (41–44% compared to 54–55% in those with stage 0–2) (12, 13). Higher doses of interferon or ribavirin may improve the response to treatment in patients with fibrosis. In one trial using a dose of 3.0 g/kg of pegylated interferon alfa-2b (twice the normal dose), the SVR rate was identical in patients with and without advanced fibrosis (55). Continuous interferon, so-called maintenance therapy, has not been shown to be effective in preventing fibrosis progression or disease complications (56, 57). Treatment of patients with decompensated cirrhosis can be considered in hopes of eradicating infection prior to liver transplantation. SVR in this group usually prevents recurrence of HCV infection after transplant (58, 59). However, such treatment is extremely difficult. Most patients have pre-existing cytopenia that prevents them from receiving full doses of medications and severe complications, often related to the liver disease rather than the treatment, may require dose reductions or discontinuation of therapy. Cytopenia may be partially avoided by use of growth factors or by initiating treatment at low doses and escalating as tolerated (58). Despite the problems, SVR is possible in about 25% of patients. Treatment in this group of patients is best managed by experienced transplant hepatologists.
86
Ashfaq and Davis
3.2. African-Americans SVR rates have consistently been lower in African-Americans than in Caucasians in trials of interferon-based therapy. Recent studies with pegylated interferon and ribavirin in previously untreated patients with genotype 1 infection observed SVR rates of 19–26% in AfricanAmericans vs 39–52% in Caucasians (60, 61). Several factors including the higher proportion with genotype 1, higher body weight, and a slower decline in HCV RNA in viral kinetic studies might at least partially explain this observation. However, the apparent ability of higher doses of interferon or ribavirin to improve responses suggests that the explanation may lie in an impaired ability of intracellular antiviral mechanisms to turn on at standard doses of these medications (55).
3.3. HIV–HCV Coinfection HCV infection is common in HIV-infected individuals (62). Coinfected patients tend to have high HCV RNA levels and some studies suggest that they have more severe liver disease, more rapid disease progression, and a higher prevalence of hepatic fibrosis (63–65). Liver disease due to hepatitis B, hepatitis C, or alcohol is second only to AIDS as a cause of death in HIV patients (66). Several clinical trials of pegylated interferon and ribavirin have recently been reported (67–69). Treatment responses vary considerably in these studies due to differences in design and compliance. However, SVR in genotype 1 patients was low (14–29%) while it was reasonably intact in genotypes 2 and 3 subjects (62–73%). Overall, SVR rates appeared to be 10–15% below what would be expected in an HIV-negative population, but this may be in part related to the lower doses of ribavirin that were used in these studies because of concerns about potential drug interactions. Such interactions were not observed and full weight-based doses of ribavirin are now appropriate. It is important to educate HIV-coinfected patients about the endpoints of antiviral therapy for chronic hepatitis C since they differ from HIV. Viral eradication, not chronic suppression, is the goal. Thus, failure to achieve EVR reliably predicts lack of response and justifies stopping treatment. Patients receiving highly active anti-retroviral therapy (HAART) or with low CD4 counts appear to be more likely to experience adverse effects from treatment, including drug hepatotoxicity, and must be monitored for this. Severe hepatotoxicity, especially related to ritonovir and didanosine (ddI), is almost four times higher in HIV patients who are coinfected with HCV with a risk of about 12% (70).
Current and Future Therapy of Chronic Hepatitis C
87
3.4. Obesity and Fatty Liver Disease Obesity and hepatic steatosis are both associated with a reduced response of HCV-infected patients to interferon-based treatments (12, 13, 71). For genotypes 1 and 2, hepatic steatosis is associated with a fall in SVR from 57 to 25% and 96 to 86%, respectively (71). Genotype 3 infection induces steatosis in and of itself and this is not associated with reduced SVR. The mechanism(s) by which obesity or steatosis reduce SVR is(are) not known, but it has recently been suggested that it may be related to insulin resistance and hyperinsulinemia (72). Other mechanism may also be involved. It is not yet known if higher doses will overcome the lower response, but pilot studies suggest that this might be the case (73).
3.5. Extrahepatic Manifestations Mixed cryoglobulinemia is the most common extrahepatic manifestation in patients with chronic hepatitis C. It typically manifests as cutaneous vasculitis, glomerulonephritis, neuropathy, or systemic vasculitis (74, 75). Interferon alone, or in combination with ribavirin (if renal function is intact), is able to suppress cryocrits in the majority of patients with mixed essential cryoglobulinemia and treatment may be indicated based solely on the presence of clinical complications of cryoglobulinemia, regardless of the presence or severity of the liver disease. The fall in cryocrit observed during treatment usually correlates with a drop in serum HCV RNA levels, normalization of complement levels, and clinical improvement. However, polyneuropathy appears to be relatively resistant to treatment (76, 77). Although results in these small series vary considerably, sustained virologic response following discontinuation of interferon-based treatment appears to be lower than in patients without cryoglobulinemia (78). Glomerulonephritis (GN) has been associated with chronic HCV infection. Most of these cases present with cryoglobulinemia and proteinuria that may reach the nephrotic syndrome range (79). The histologic lesion is usually membranoproliferative GN, so-called cryoglobulinemic GN, although other histologic forms such as mesangial proliferative GN (usually IgA nephropathy) and membranous GN may also occur. In contrast to membranoproliferative GN, the latter two histologic lesions are typically not associated with cryoglobulinemia (79–81). Membranous GN responds poorly, if at all, to interferon (80). Furthermore, a recent report cautions that glomerulonephritis not caused by HCV may worsen under interferon treatment (82). Finally, ribavirin is renally excreted and should be used with great caution, if at
88
Ashfaq and Davis
all, in patients who have developed significant renal insufficiency as a consequence of their GN.
3.6. Post-transplantation Complications of chronic hepatitis C including hepatocellular carcinoma and decompensated cirrhosis are the most common indication for liver transplantation accounting for about 40% of transplants performed in the United States and Europe. If HCV RNA is detectable at the time of transplantation, infection will always recur in the graft. HCV RNA levels increase rapidly following transplant as a consequence of immunosuppression. These patients often have very high HCV RNA levels which may sometimes result in rapidly progressive chronic hepatitis or, less commonly, an aggressive cholestatic hepatitis which leads to liver failure (83). Treatment of such patients is predictably difficult since most patients have genotype 1 infection, high viral loads, have previously failed to respond or tolerate interferon-based therapy, often have pre-existing cytopenia and renal insufficiency, and have drug interactions that increase the risk of cytopenia or symptoms. While antiviral treatment is successful in some patients with recurrent hepatitis C, it is extremely difficult to administer and fraught with hazards that may threaten the patient or the graft. Thus, these patients should be managed by an experienced transplant hepatologist. Interferon-based antiviral therapy should generally be avoided in recipients of other (not liver) solid organ transplants because of the risk of rejection (84). However, treatment appears to be safe in autologous and most allogeneic bone marrow transplant recipients (85).
3.7. Viral Non-Responders Perhaps the most difficult group of patient to manage are those who have failed to respond to a previous course of antiviral therapy. These patients fall into several categories including those who were unable to tolerate therapy, those who had the dose of one or both drugs reduced (appropriately or not) or received less than the optimal duration of therapy, those who received an older treatment regimen (for example, standard interferon and ribavirin), and those who simply did not sufficiently inhibit viral replication. Thus, non-responders are a very heterogeneous group. The first step in managing these patients is to find out why they failed treatment and decide if that problem can be overcome with retreatment. If it cannot, retreatment is not an option with current regimens. Another issue to consider in deciding whether to restart antiviral therapy is if the patient needs therapy or can wait for regimens that might offer a greater chance of response.
Current and Future Therapy of Chronic Hepatitis C
89
The best strategy is to optimize therapy to have the best chance of an SVR during the initial course because responses to retreatment are not very good. Approximately 10–20% of viral non-responders to interferon monotherapy or standard combination therapy achieve a sustained response when retreated with pegylated combination therapy (Table 4) (86). Factors that predict a better response to retreatment include a genotype other than 1 (65% vs 14% for genotype 1), HCV RNA level less than 1.5 million IU/mL (27% vs 15%), absence of cirrhosis (23% vs 11%), Caucasian rather than African-American (20% vs 6%), age less than 60 years (19% vs 6%), and achievement of EVR during the previous course of treatment (34% vs 1%) (87). Table 4 Response to Retreatment with Pegylated Interferon and Ribavirin in Prior Relapsers and Non-responders Prior Therapy
Retreatment Regimen
SVR
Non-responders IFN monotherapy IFN + RBV
Peg-IFN + RBV Peg-IFN + RBV
16–28% 6–15%
Relapsers IFN + RBV
Peg-IFN + RBV
30–50%
Virologic relapse occurs in 45–80, 35–40, and 15% of those who lose detectable HCV RNA during interferon monotherapy, standard combination therapy, or pegylated combination therapy, respectively (9–13). There is little or no benefit in retreating patients with the same treatment regimen (88). However, treatment of relapsers to monotherapy with higher doses or a longer duration of interferon, or combination therapy may achieve a sustained response (Table 4). A recent study found that half of patients who relapsed after standard interferon and ribavirin achieved SVR when retreated with pegylated interferon and ribavirin (86).
4. THERAPEUTICS AGENT IN DEVELOPMENT The next decade should see the introduction of specifically targeted antiviral therapy for hepatitis C (STAT-C). These are agents that are specifically directed at HCV replication mechanisms including
90
Ashfaq and Davis
viral entry, genome attachment to intracellular structures such as the endoplasmic reticulum, viral polymerase, viral protease, and assembly of viral components required for virus export and function. The viral protease inhibitors are furthest along in clinical development (Table 5). Many of these drugs have now entered phase 2 or 3 human clinical trials. It is possible that some of these drugs may be approved for clinical use by 2010 or soon thereafter. However, it is clear from the studies to date that they will need to be given in combination with interferon and ribavirin. Thus, patients who are intolerant of interferon-based therapy will not be candidates for these new agents. It is not yet clear how these new agents will be combined with the current regimen of pegylated interferon and ribavirin to provide the best outcome, but it is hoped that such combinations will allow shorter courses of therapy with greater efficacy. This appears to be an achievable goal.
Table 5 New Agents in Development in Man as of January 2008 Mechanism of Action
Drug
Investigation Phase
Company
III III II I I I
Vertex Schering-Plough Merck Gilead InterMune Boeringer
RO 5024048 R7128 BILB1941 GSK625433 DEBIO-025
II II I I L
Roche Pharmasset Roche Boeringer Debiopharm
None in clinical studies Alinia (nitazoxanide)
I
Romark Laboratories
Protease inhibitor
VX-950 (Telaprevir) SCH 503034 MK-7009 GS3192/ACH806 ITMN B BILN 1931
Polymerase inhibitor
R1626(prodrug)/ R1479
Cyclophilin B inhibitors Helicase inhibitor UPR agonist (thiazolide)
Current and Future Therapy of Chronic Hepatitis C
91
REFERENCES 1. Hutin Y, Kitler ME, et al. Global burden of disease for hepatitis C. J Clin Pharmacol 2004; 44:20–9. 2. Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis c virus in Egypt. Lancet 2000; 355:887–91. 3. Gregory LA, Annemarie W, Edger PS, Geraldine MM, Wendi LK, Miriam JA. The prevalence of hepatitis C virus infection in the United States 1999 through 2002. Ann Int Med 2006; 144:705–14. 4. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994 N Eng J Med 1999; 341:556–62. 5. Alter MJ. The epidemiology of acute and chronic hepatitis C. Clin Liver Dis. 1997; 1:559–68. 6. Steele CB, Melendez-Morales L, Campoluci R, DeLuca N, Dean HD. Health disparities in HIV/AIDS, viral hepatitis, sexually transmitted disease, and tuberculosis: Issues, burden and response. A retrospective review, 2000–2004. Atlanta, GA: Department of Health and Human Services, Center for Disease Control and Prevention, November, 2007. Available at http://www.cdc.gov/nchhstp/ healthdisparities/. 7. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting the future healthcare burden from hepatitis C in the United States. Liver Transpl 2003; 9:331–8. 8. Armstrong GL, Alter MJ, McQuillen GM, Margolis HS. The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States. Hepatology 2000; 31:777–82. 9. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: A multicenter randomized controlled trial. New Engl J Med 1989; 321:1501–6. 10. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: Effects of dose and duration. Hepatology 1996; 24:778–89. 11. McHutchison JG, Gordon S, Schiff ER, et al. Interferon alfa-2b monotherapy versus interferon alfa-2b plus ribavirin as initial treatment for chronic hepatitis C: Results of a U.S. multicenter randomized controlled study. New Engl J Med 1998; 339:1485–92. 12. Manns MP, McHutchison JG, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: A randomized trial. Lancet. 2001; 358:958–65. 13. Fried MW, Shiffman ML, Reddy R, et al. Peg-interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–82. 14. Peters M, Davis GL, Dooley JS, et al. The interferon system in acute and chronic viral hepatitis. In Popper H, Schaffner F (eds): Progress in Liver Diseases, vol. 8. New York: Grune and Stratton, 1986, p 453–67. 15. Wang YS, Youngster S, Bausch J, Zhang R, McNemar C, Wyss DF. Identification of the major positional isomer of pegylated interferon alpha-2b. Biochemistry 2000; 39:10,634–40. 16. Glue P, Fang JW, Rouzier-Panis R, et al. Pegylated interferon-alpha2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther 2000; 68:556–67.
92
Ashfaq and Davis
17. Pedder SC. Pegylation of interferon alfa: Structural and pharmacokinetic properties. Semin Liver Dis 2003; 23(Suppl 1):19–22. 18. Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343:1673–80. 19. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343:1666–72. 20. Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001; 34:395–403. 21. Modi MW, Fulton JS, Buckmann DK, Wright TL, Moore DJ. Clearance of pegylated (40 kDa) interferon alfa-2a is primarily hepatic (abstract). Hepatology 2000; 32:371A. 22. Patterson JL, Fernandez-Larson R. Molecular action of ribavirin. Rev Infect Dis 1990; 12:1132–46. 23. Crumpacker CS. Overview of ribavirin treatment of infection caused by RNA viruses. In: RA Smith, V Knight, and Smith JAD, eds. Clinical Applications of Ribavirin. Orlando: Academic Press, 1984. pp. 33–8. 24. Vo NV, Young KC, Lai MM. Mutagenic and inhibitory effects of ribavirin on hepatitis C virus RNA polymerase. Biochemistry 2003; 42:10,462–71. 25. Reichard O, Andersson J, Schvarcz R, et al. Ribavirin treatment for chronic hepatitis C. Lancet 1991; 337:1058–61. 26. Di Bisceglie AM, Shindo M, Fong T-L, et al. Pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 1992; 16:649–54. 27. Bodenheimer HC, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: A multicenter trial. Hepatology 1997; 26:473–7. 28. Poynard T, Marcellin P, Lee S, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352:1426–32. 29. Reichard O, Norkrans G, Fryden A, et al. Alfa-interferon and ribavirin versus alfainterferon alone as therapy for chronic hepatitis C – a randomized, double-blind, placebo-controlled study. Lancet 1998; 351:83–7. 30. Zeuzem S, Schmidt JM, Lee JH, et al. Hepatitis C virus dynamics in vivo: Effect of ribavirin and interferon alfa on viral turnover. Hepatology 1998; 28:245–52. 31. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis 1999; 19: 57–65. 32. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346–55. 33. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weightbased or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007; 46:971–81. 34. Jensen D, Morgan T, Marcellin P, et al. Rapid virological response at week R ) plus ribavirin (RBV, 4 (RVR) of peginterferon alfa-2a (40KD) (PEGASYS R COPEGUS ) treatment predicts sustained virological response (SVR) after 24 weeks in genotype 1 patients (abstract). Hepatology 2005; 42:650A.
Current and Future Therapy of Chronic Hepatitis C
93
35. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44:97–103. 36. von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129:522–7. 37. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352:2609–17. 38. Dalgard O, Bjøro K, Hellum KB, Myrvang B, et al. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: A pilot study. Hepatology 2004; 40:1260–5. 39. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357:124–34. 40. El-Zayadi AR, Attia M, Barakat EM, et al. Response of hepatitis C genotype-4 naive patients to 24 weeks of Peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005; 100:2447–52. 41. Legrand-Abravanel F, Sandres-Saune K, Barange K, et al. Hepatitis C virus genotype 5: Epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin. J Infect Dis 2004; 189:1397–1400. 42. Yuen MF, Lai CL. Response to combined interferon and ribavirin is better in patients infected with hepatitis C virus genotype 6 than genotype 1 in Hong Kong. Intervirology 2006; 49:96–8. 43. Poynard T, McHutchison J, Goodman Z, Ling ML, Albrecht J. Is an “A la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? Hepatology 2000; 3:211–8. 44. Maddrey WC. Safety of combination interferon alfa-2b / ribavirin therapy in chronic hepatitis C: relapsed and treatment-na¨ıve patients. Semin Liver Dis 1999; 19:67–75. 45. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126:1302–11. 46. McHutchison M, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123:1061–9. 47. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24:38–47. 48. MacFarlane BM, Bridger C, Tibbs CJ, et al. Virus-induced autoimmunity in hepatitis C virus infections: A rare event. J Med Virol 1994; 42:66–72. 49. Rocco A, Gargano S, Provenzano A, et al. Incidence of autoimmune thyroiditis in interferon-alpha treated and untreated patients with chronic hepatiti c virus infection. Neuroendocrinol Lett 2001; 22:39–44. 50. Layden JE, Layden TJ. How can mathematics help us understand HCV? Gastroenterology 2001; 120:1546–9. 51. Davis GL, Wong JB, McHutchison JG, Manns MP, Albrecht J. Early virologic response to treatment with pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38:645–52.
94
Ashfaq and Davis
52. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV-RNA in patients with chronic hepatitis C and sustained response to interferon alpha therapy. Ann Intern Med 1997; 127:875–81. 53. Poynard T, McHutchison J, Davis GL, Esteban Mur R, Goodman Z, Bedossa P, Albrecht J. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology. 2000; 32:1131–7. 54. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007; 45:579–87. 55. Gross J, Johnson S, Kwo P, Afdhal N, Flamm S, Therneau T. Double-dose peginterferon alfa-2b with weight-based ribavirin improves response for interferon/ribavirin non-responders with hepatitis C: final results of “RENEW.” (abstract). Hepatology 2005; 42:219A. 56. Fartoux L, Degos F, Tr´epo C, et al. Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related cirrhosis: A randomized trial. Clin Gastro Hepatol 2007; 5:502–7. 57. DiBisceglie AM, Shiffman M, Everson GT, et al. Prolonged antiviral therapy with peginterferon to prevent complications of advanced liver disease associated with hepatitis C: Results of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial (abstract). Hepatology 2007; 46:290A. 58. Everson FT, Trotter J, Forman L, Kugelmas M, Halprin A, Fey B, Ray C. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005; 42:255–62. 59. Crippin JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl 2002; 8:350–5. 60. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 39:1702–8. 61. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350:2265–71. 62. Dieterich DT, Purow JM Rajapaksa R. Activity of combination therapy with interferon alfa-2b plus ribavirin in chronic hepatitis C patients co-infected with HIV. Semin Liver Dis 1999; 19:87–94. 63. Pol S, Lamorthe B, Thi NT, et al. Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users. J Hepatol. 1998; 28:945–50. 64. Thomas DL, Shih JW, Alter HJ, et al. Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 1996; 174: 690–5. 65. Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. Natural history of hepatitis C virus infection in multi-transfused hemophiliacs: Effect of co-infection with human immunodeficiency virus. J Acquir Immune Defic Syndr 1993; 6:602–10. 66. Salmon-Ceron D, Lewden C, Morlat, et al. Liver disease as a major cause of death among HIV infected patients: Role of hepatitis C and B viruses and alcohol. J Hepatol 2005; 42:799–805.
Current and Future Therapy of Chronic Hepatitis C
95
67. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:451–9. 68. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–50. 69. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA 2004; 292:2839–48. 70. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283:2526–7. 71. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003; 38:75–85. 72. Sanyal AJ, Chand N, Comar K, et al. Hyperinsulinemia blocks the inhibition of hepatitis C virus (HCV) replication by interferon: a potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic fatty liver disease (abstract). Hepatology 2004; 40:179A. 73. Bressler B, Wang K, Gries J-M, Heathcote J. Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of Peg-IFN alfa-2a (abstract). Hepatology 2005; 42(suppl 1):661A. 74. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: Role of hepatitis C virus and liver damage. Gastroenterology 1994; 106: 1291–1300. 75. Limaye AP, Schmidt RA, Glenny RW, Davis CL, Kowdley KV. Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient. Transplantation 1998; 65:998–1000. 76. Zuckerman E, Keren D, Slobodin G, et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferonalpha. J Rheumatol 2000; 27:2172–8. 77. Donada C, Crucitti A, Donadon V, et al. Interferon and ribavirin combination therapy in patients with chronic hepatitis C and mixed cryoglobulinemia (letter). Blood 1998; 92:2983–4. 78. Calleja JL, Albillos A, Moreno-Otero R, et al. Sustained response to interferonalpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinemia. Aliment Pharmaol Ther 1999; 13: 1179–86. 79. Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. New Engl J Med 1993; 328:465–70. 80. Jefferson JA, Johnson RJ. Treatment of hepatitis C-associated glomerular disease. Semin Nephrol. 2000; 20:286–92. 81. Komatsuda A, Imai H, Wakui H, et al. Clinicopathological analysis and therapy in hepatitis C virus-associated nephropathy. Intern Med 1996; 35:529–33. 82. Ohta S, Yokoyama H, Wada T, et al. Kobayashi K. Exacerbation of glomerulonephritis in subjects with chronic hepatitis C virus infection after interferon therapy. Am J Kidney Dis. 1999; 33:1040–8.
96
Ashfaq and Davis
83. Davis GL. Chronic hepatitis C and liver transplantation. Rev Gastroenterol Disord. 2004; 4:7–17. 84. Baid S, Tolkoff-Rubin N, Saidman S, et al. Acute humoral rejection in hepatitis C-infected renal transplant recipients receiving antiviral therapy. Am J Transplant 2003; 3:74–8. 85. de Latour RP, Asselah T, Levy V, et al. Treatment of chronic hepatitis C virus in allogeneic bone marrow transplant recipients. Bone Marrow Transplant 2005; 36:709–13. 86. Jacobson IM, Gonzalez SA, Ahmed F, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol 2005; 100:2453–62. 87. Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126:1015–23. 88. Camm`a C, Giunta M, Chemello L, et al. Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data. Hepatology 1999; 30:801–7.
Hepatitis C in Special Populations Douglas Dieterich, MD, Marie-Louise Vachon, MD and Damaris Carriero, MD CONTENTS I NTRODUCTION C O -I NFECTION WITH H UMAN I MMUNODEFICIENCY V IRUS (HIV) C O -I NFECTION WITH H EPATITIS B (HBV) E THNIC VARIATIONS IN HCV HCV AND I NSULIN R ESISTANCE /D IABETES HCV IN C HRONIC K IDNEY D ISEASES (CKD) C ONCLUSIONS R EFERENCES Key Principles
• “Special” HCV-infected populations are those in whom specific aspects relating to the clinical presentation, diagnosis, and/or treatment can be identified and targeted to improve the health of a patient and a population. • The populations described in this chapter include the following: those co-infected with the human immunodeficiency virus (HIV)/hepatitis B virus (HBV), specific ethnic groups (Latinos/African Americans), those with insulin resistance and those with chronic kidney disease.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 4, C Humana Press, a part of Springer Science+Business Media, LLC 2009
97
98
Dieterich et al.
• Approximately 30% of those infected with HIV have concomitant HCV. HIV appears to accelerate the progression of HCV. The standard of care in this population is pegylated interferon and ribavirin. All patients in whom the potential benefit of therapy outweighs its risk should be offered therapy. • HBV co-infection is unusual but may cause hastened disease progression in HCV. Treatment options would depend on which viral infection is believed to predominate. • Ethnic differences exist in the epidemiology, natural history, and treatment responses of HCV in Latinos and African Americans. • Latinos infected with hepatitis C are more likely to be males, coinfected with HIV, and have acquired HCV at a younger age compared to Caucasians. The Latino population has a lower chance of SVR compared to Caucasians. • Multiple studies show a slower progression of liver disease in African Americans, who also have a lower chance of response to peg-IFN + RBV therapy compared to Caucasians. • There is an increased prevalence of insulin resistance and diabetes in HCV. Patients with insulin resistance and diabetes in chronic HCV have more severe liver disease and decreased response to treatment compared to the general population. • There is a higher prevalence of HCV infection in patients with chronic kidney disease (CKD), especially in those on hemodialysis (HD), than in the general population. Interferon-based therapy does produce comparable response rates to those with preserved renal function, but there is lower tolerability to therapy and a high dropout rate. • When evaluating a member of a special population, efforts should be made to customize treatment both to the patient and to the virologic response in order to maximize chances of success.
1. INTRODUCTION What makes a population special? As medical care givers, what should prompt us to consider a population differently? In this chapter, we consider a population special when specific aspects relating to the clinical presentation, diagnosis, and/or treatment can be identified and targeted to improve the health of a patient and a population. Considering a population special is recognizing that diversity exists and needs to be addressed as individualized care. In the case of hepatitis C (HCV), populations can differ according to the prevalence of the infection, risk factors for acquisition, access to care and acceptance of treatment, presentation and evolution of disease, comorbidities, development of
Hepatitis C in Special Populations
99
complications, and safety and efficacy of treatment. In this chapter, we will review hepatitis C in six different populations: the co-infected with HIV, the co-infected with hepatitis B, Latinos, African Americans, the insulin resistant/diabetic, and the patient with chronic kidney disease.
2. CO-INFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) 2.1. Prevalence and Epidemiology HCV/HIV co-infection is prevalent. In the United States, it is estimated that 300,000 persons are co-infected with hepatitis C and HIV. The overall prevalence of HCV in HIV individuals is about 30% which is higher than the 1.8% reported in the general population (1–3). From the hepatitis C perspective, around 8% of this population is co-infected with HIV (1). The high rate of co-infection rests on the shared risk factors for transmission which, moreover, determine the prevalence of co-infection. Intravenous drug use (IVDU) is still the number one cause of HCV transmission (independent of the HIV status). Studies have reported co-infection rates of 75–90% in HIV seropositive IVDUs (4, 5); more recent data suggest that HCV prevalence is decreasing in this population (6). If we examine more closely patients with HCV who are IVDUs, their risk of co-infection with HIV climbs to 33% (7). Heterosexual transmission of HCV is a subject of discussion. We can conclude from multiple studies that HCV is not transmitted efficiently between men and women if at all (8). However an increasing number of HCV infections are observed in HIV+ men who have sex with men (MSM). This latter group have recently been identified as part of an outbreak of acute HCV. In those reports, acquisition of acute HCV is associated with high-risk sexual behavior, ulcerative sexually transmitted infections and use of recreational, non-IV drugs such as methamphetamine. This drug may enhance hepatitis C virus replication in human hepatocytes (9). It is also noteworthy that HCV RNA has been detected more frequently (38 vs 18%) in the semen of co-infected patients compared to HCV mono-infected (10). There are reports of needlestick exposure where HIV and HCV have been simultaneously transmitted (11, 12). Vertical transmission of HCV is also of particular matter in this special population. The perinatal transmission of HCV is estimated to be two- to fourfold higher among HIV-infected women (13, 14). In the mono-infected patients, the risk of transmission is increased at a higher HCV RNA level. One study compared HCV transmission in mono- and co-infection and found a similar risk at higher RNA levels (>6 log10 IU/ml). But, the risk was increased in
100
Dieterich et al.
the co-infected patients at lower RNA levels (15). Vertical transmission is not affected by the mode of delivery (16–18). Elective caesarean section is generally not indicated to avoid the transmission of hepatitis C; it is the HIV viral load that determines the mode of delivery (19). Breastfeeding is not an option in co-infected women because HIV infection contraindicates it in the developed world.
2.2. Natural History Co-infection exacerbates the natural history of HCV. HCV monoinfection may not be progressive in all patients. The same assumption may not be true in HIV-co-infected patients. This special population has a more aggressive form of disease characterized by rapid fibrosis progression, increased incidence of cirrhosis and end-stage liver disease (ESLD), and development of hepatocellular carcinoma (HCC) and death. This is more evident as the antiretroviral therapy (ART) era leads to a lower mortality from AIDS, permitting the concomitant viral hepatitis to evolve. Serum and hepatic HCV RNA levels are higher in coinfected individuals (20, 21). The correlation between higher viremia and more advanced liver disease, however, has been inconsistently reported (21–23). HCV RNA levels further increase after initiation of ART, especially in patients with low pre-treatment CD4 cell count (<350 cells/mm3 ) (24). Another distinctive feature of co-infection is the lower likelihood of patients to spontaneously clear HCV after the acute infection. The rate of spontaneous viral clearance is about 25–30% in HCV mono-infected patients following acute hepatitis C (25). In one study, HIV-negative patients cleared HCV two times more often than HIV-positive ones and in this latter group, clearance was less likely to occur at a lower CD4 cell count (<200/mm3 ) (7). The method of acquisition could also influence the rate of spontaneous clearance: it has been suggested that sexual transmission is more likely to lead to spontaneous clearance in co-infected individuals (26). Interestingly, hepatitis B virus co-infection also increases the likelihood of HCV clearance in co-infected individuals (7, 27). HIV infection accelerates the progression of liver fibrosis in coinfected individuals (23, 28). More advanced liver fibrosis is associated with lower CD4 cell count (<500 cells/mm3 ) and HIV viremia (29, 30). Those findings suggest that early intervention with ART may help to slow HCV progression in co-infected patients. This hypothesis is supported by some investigators (31), but rejected by others (32–34). While early findings suggested that higher CD4 cell counts predicted a more successful response to HCV treatment (35), results from large trials did not find any association. Besides the CD4 cell count, other factors that
Hepatitis C in Special Populations
101
have been associated with more rapid hepatic fibrosis progression rates in co-infected patients are high alcohol intake (>50 g/d), age at HCV infection (over 25 years), male gender and, recently, acute HCV infection (36, 37). In this last study, 11 HIV-positive patients without any pre-existing liver disease presented with acute hepatitis C, and underwent a liver biopsy. The histology showed moderately advanced fibrosis (Metavir score stage 2 fibrosis) in nine of them (82%). Fibrosis can lead to cirrhosis and once HIV-co-infected patients present with decompensated liver disease, the chance of survival at 3 years is about 30%, half what is expected for their mono-infected counterparts (38–40). The expected time after HCV exposure to develop cirrhosis in monoinfected patients is about 30 years. Studies looking at the rate of fibrosis progression have estimated that this period is reduced by half in coinfected individuals (41). HCC is also more likely to develop in this population, and do so at a younger age, and after a shorter interval of time from acquisition of HCV infection (42). Whether HCV has a deleterious effect on HIV is unclear (43–45). Co-infection with HCV does not seem to affect the risk of HIV disease progression (3, 43). The effect of antiretroviral therapy (ART) on the evolution of liver disease in co-infection is controversial. The concept that keeping HIV undetectable, there by improving cellular immunity, would stop or slow liver injury makes perfect sense. ART has been found to be related to lower liver-related mortality (39). However, ART can cause liver injury by different mechanisms and HCV, in fact, increases the risk of ART-related hepatotoxicity (46, 47). Investigators from the D:A:D study reported an increased risk of liver-related deaths with long-term ART-exposure. These data should be interpreted with caution. ART results in lower AIDS-related deaths (hence, increased rate of liverrelated mortality) which allows co-infected individuals to live longer and develop liver-related complications (48). On the other hand, one study reported that successful treatment of hepatitis C reduces the risk of ART toxicity (49). This suggests that in co-infected patients with stable untreated HIV infection, HCV therapy should be addressed first. In any case, when there is an indication to treat HIV, therapy should be instituted because benefit clearly outweighs risk. Every HIV-infected individual should be screened for the presence of HCV antibody (hepatitis A and B serologies are also indicated). The two infections share the same transmission risks. Hence, the prevalence of co-infection is high and justifies screening (50). A positive result may indicate past/resolved infection or current/chronic disease. This distinction is made by measurement of the quantitative serum viral load and viremia indicates chronic disease. A negative result
102
Dieterich et al.
can, however, represent a false-negative in this immunosuppressed population (mostly when CD4 cell count is <100 cells/mm3 ) or in the presence of chronic kidney disease and warrants confirmation with serum viral load. Viremia establishes the diagnosis of chronic HCV infection. A negative result can also reflect the window period during acute infection and testing should be repeated if clinically indicated. Apart from the first visit screening test, anti-HCV antibody testing should be performed when a patient presents with liver enzyme elevation, but should also be part of a periodical blood check-up in patients with high-risk sexual behavior (mostly MSM) or drug exposure. Some experts believe that yearly HCV testing is appropriate in HIV-infected individuals. Once the diagnosis is established, the standard test to stage the disease is the liver biopsy. It is also helpful to guide the decision to initiate treatment, inform patients and physicians of prognosis, and provide an accurate diagnosis when the etiology is multifactorial or diagnosis is uncertain. It is not an absolute prerequisite to treatment initiation. The invasive nature of this technique aroused interest among researchers in finding alternative non-invasive strategies to evaluate liver fibrosis. It is not in the scope of this chapter to focus on the different assays available. Serum biomarkers (HCV FibroSURETM , FIB4, APRI score, others) can help differentiate earlier stages of fibrosis from cirrhosis but are unprecise in the evaluation of intermediate stages of fibrosis (51, 52). Transient elastography (FibroScan) estimates the extent of hepatic fibrosis by measuring liver stiffness (53, 54). Until now, results from studies in co-infected individuals do not significantly differ from mono-infected ones and further research is underway to determine the role of those noninvasive tests in this population.
2.3. Treatment of Co-infection SVR rates are lower in co-infected patients. Multiple studies report a lower rate of hepatitis C treatment initiation among co-infected patients when compared to their mono-infected counterparts (55). This is explained by physician’s lack of trust in patient’s adherence, reluctance because of potential drug interactions or adverse events with ART, and perception of poor treatment outcomes. However, the accelerated course of liver disease prompts initiation of treatment in many cases. This famous sentence in the treatment of coronary artery disease: “time is muscle” can certainly be used here: “time is liver”. The decision to treat is based on the evaluation of benefits against risks associated with the treatment’s toxicity. Which baseline factors are associated with sustained virological response (SVR)? As in HCV-mono-infection, the two major ones
Hepatitis C in Special Populations
103
are the HCV genotype and the baseline viral load (HCV RNA). Findings from the APRICOT trial revealed that a baseline viral load < = 400,000 IU/ml has an odds ratio (OR) of 4.77 in predicting SVR, while the genotype has one of 2.87 (56, 57). Other factors can help to predict SVR and should be taken into account in an effort to increase response (Table 1). Patients who are more likely to respond to treatment are those with genotype 2 or 3, genotype 1 with low baseline viral load (<400,000 IU/ml), no, or minimal fibrosis. The likelihood of response does not represent an indication to treat or not. This is an independent decision. Table 1 Factors Associated with SVR in Chronic Co-Infected Patients Potentially Modifiable
Non-modifiable
Low BMI No polysubstance abuse
Low baseline viral load Genotypes 2–3 RVR and EVR Host genetic (Caucasian) Younger age No or minimal liver fibrosis stage No psychiatric comorbidity
Use of adjuvant growth factors during treatment if needed Optimal peg-IFN and RBV doses Length of treatment Adherence to treatment No ddI or AZT use Lack of IR∗ Lack of hepatic steatosis∗
SVR, sustained virologic response; BMI, body mass index; peg-IFN, pegylatedinterferon; RBV, ribavirin; ddI, didanosine; AZT, zidovudine; RVR, rapid virologic response; EVR, early virologic response; IR, insulin resistance. ∗ Potentially modifiable: No studies have shown yet that improving those factors lead to a higher SVR.
The ultimate goal of therapy is eradication of the virus in view of stopping or even reversing liver injury and its later complications (58). In practice, this is assessed by an undetectable level of plasma HCV RNA at the end of the treatment (end of treatment response, EOTR) followed by the sustained undetectability after 6 months off-treatment (sustained virologic response, SVR). SVR correlates with long-term “cure”, measured at 5 years, in co-infected as in mono-infected patients in 99% of cases (48, 59).
104
Dieterich et al.
When considering treatment for a patient, “First, do no harm” (see Table 2). Every co-infected patient who is not considered a candidate for treatment at one point should be followed closely as the dynamic interactions between the viruses, the host, and the environment can sooner or later favor the benefit over the risk of treatment. Experts consider a liver biopsy every 2–3 years in this population (60). Table 2 Contraindications to Combined HCV Therapy Absolute Contraindications Allergy to peg-IFN or RBV Active opportunistic infection Decompensated liver disease (Child-Pugh B or C) Severe cardio-pulmonary disease Sarcoidosis Uncontrolled autoimmune diseases Pregnancy or not willing to use birth control ∗
Relative Contraindications Active drug use HIV suboptimally controlled Renal insufficiency Depressive disorder Hematologic abnormalities∗
Correction of hematologic abnormalities may allow treatment.
Active drug use is changed from an absolute to a relative contraindication (61). The reduced chance of response in this population is in part due to poorer adherence and higher discontinuation rate. Efficacy of treatment is reduced by the loss of cellular immunity associated with chronic drug abuse. The decision to start treatment must be individualized, and is based on patient commitment, and a relation of trust between patient and caregiver. Is there a CD4 cell count threshold over which treatment is effective and safe? The answer is no. Over the past few years, different thresholds have been proposed. However, the AASLD guidelines do not specify any. Many experts agree that treatment should be individualized. CD4 cell count should not prevent treatment in a patient for whom benefit outweighs risk. Liver fibrosis progresses more rapidly in co-infected patients, and to a greater extent in those with lower CD4 cell counts. Treating patients offers the opportunity to stop liver injury and prevent progression to ESLD. In the major HCV treatment studies in HIV (where in some, patients could be enrolled with a CD4 cell count as low as 100
Hepatitis C in Special Populations
105
cells/mm3 ), SVR was not related to the CD4 cell count. HIV viremia, however, is an important factor particularly in patients with lower CD4 cell count. In clinical trials, the safety and efficacy of treatment could not be established at a count lower than 200. HCV therapy can exacerbate a pre-existing mental illness or lead to irritability, anxiety, and depression in people without any underlying psychiatric condition. Patients must be aware of this possibility so they can recognize early symptoms and seek help for proper management. Early intervention can improve the patient’s quality of life during treatment, prevent more severe psychiatric manifestations following interferon administration (e.g., suicidal attempt), and maintain adherence to treatment. We recommend a thorough psychiatric evaluation prior to treatment and a low threshold for prophylactic antidepressant use. A psychiatry referral and follow-up during therapy is sometimes needed (62). The standard of care for the treatment of co-infected patients is pegylated-interferon (peg-IFN) and weight-based ribavirin (RBV). The duration of treatment is 48 weeks independent of genotype. There are several different studies on which the recommendations are based (see Table 3). The reader is referred to the guidelines for HCV treatment: • Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents (63) • Diagnosis, management, and treatment of HCV (50) • Care of patients co-infected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel (60) • Short statement of the first European consensus conference panel of the treatment of chronic hepatitis B and C in HIV-co-infected patients (64).
APRICOT is the largest study (multicentered) with 868 patients enrolled. Co-infected patients (all genotypes) not previously treated were randomized to one of the three arms to receive either (1) pegIFN alpha-2a 180 g + RBV 800 mg, (2) peg-IFN alpha-2a 180 g + placebo, or (3) standard interferon (3 M IU 3X/wk) + RBV 800 mg. Treatment duration was 48 weeks. With an overall SVR of 40% (compared to 20% in the peg-IFN alone arm and 12% in the standard IFN arm), peg-IFN alpha-2a and RBV 800 mg was found as the combination of choice. For genotype 1 compared to genotypes 2 and 3, the SVR rate was 29 and 62%, respectively. This trial also found that (1) overall, and with genotype 1 infection, patients with higher baseline HCV RNA levels (>800,000 IU/ml) have lower rates of SVR compared to low pretreatment levels, (2) the CD4 cell count decreases during therapy, but the mean percentage of CD4+ lymphocytes increases, (3) the high negative predictive value of the absence of an EVR to predict virologic
48 61% 29% 62% 40% 12%
Duration (weeks) Genotype 1 SVR Genotype 1 SVR Genotypes 2–3 SVR All genotypes SVR Control arm
133 alpha-2a (180 g/wk) 600–800 to 1000 mg dose-esc. 48 77% 14% 73% 27% 12%
ACTG 5071 2004
48 59% 17% 44% 27% 20%
412 alpha-2b (1.5 g/kg/wk) 800 mg
RIBAVIC 2004 95 alpha-2b (100 vs 150 g/wk) 600–1200 mg (w-based) 48 55% 38% 53% 44% 21%
Laguno et al. 2004
389 alpha-2a (180 g/wk) 1000 vs 1200 mg (w-based) 48–72 49% 35% 72.4% 49.6% –
PRESCO 2007
APRICOT, AIDS Pegasys Ribavirin International Co-infection Trial; ACTG, AIDS Clinical Trials Group; PRESCO, Peginterferon Ribavirin ESpana Co-infection, w-based, weight-based; dose-esc., dose-escalation; SVR, sustained virological response.
RBV dosage
868 alpha-2a (180 g/wk) 800 mg
Patients (n) Peg-IFN (dosage)
APRICOT 2004
Table 3 Summary of the five Pivotal Studies of Peg-IFN + RBV in Co-Infected Patients
Hepatitis C in Special Populations
107
failure applies to co-infected as well as mono-infected patients, and (4) safety issues are mostly hematologic in this population and comparable to HCV mono-infected patients. The RIBAVIC study had a similar design to the APRICOT trial, but was meant to compare standard interferon (3 MU three times a week) with peg-IFN alpha-2b (1.5 g/kg/wk) (65); 412 patients were enrolled. SVR rates of 27% (17% for genotypes 1 and 4) in the peg-IFN compared to 20% in the regular interferon arm were reported. Compared to the APRICOT trial in which the SVR rate was 40%, the RIBAVIC population included a higher proportion of patients with bridging fibrosis and cirrhosis (40%), which is a negative prognostic factor for SVR. Many patients had adverse events not related to treatment, discontinued treatment and could not achieve SVR. However, SVR rates in the control arm were 20% in both studies. The number of serious adverse events, although similar in both groups, was higher than reported in the mono-infected population with 11 cases of pancreatitis/hyperlactatemia in patients taking didanosine (ddI) as part of their ART regimen. Another major study, ACTG 5071, randomized 133 subjects to receive either peg-IFN alpha-2a (180 g/wk) or standard interferon alpha-2a + RBV in a dose-escalation schedule: 600 mg for 4 weeks, then 800 mg for 4 weeks, then 1000 mg for 48 weeks (66). They again demonstrated the superiority of peg-IFN formulation over regular interferon with a SVR rate of 27% (14% in genotype 1 vs 73% in other genotypes) compared to 12% in the standard interferon arm. A liver biopsy was performed at week 24 of treatment in patients with no virologic response, and histologic improvement was present in 35% of those patients in both arms. This suggests that benefits from the therapy extend beyond virologic control. This study also pinpoints the importance of the cumulative dose of ribavirin early in the treatment of hepatitis C. The inadequate dosage of RBV may have explained the low SVR (high relapse) rates observed. The fourth important study published the same year was the one by Laguno et al. Standard interferon (3 MU 3 times a week) was compared to peg-IFN alpha-2b (100–150 g/wk), but with weight-based RBV 800–1200 mg for 48 weeks (67). Ninety-five patients, of whom 30% had bridging fibrosis or cirrhosis, were randomized. Forty-four percent achieved a SVR, 38% of those with genotype 1, and 53% of those with genotypes 2 and 3 (genotype 2 or 3 infections with HCV RNA <800,000 IU/ml were treated for 24 weeks only). Safety analyses also showed a higher rate of side effects compared to studies in monoinfected patients, particularly depressive symptoms in 43% patients. They also diagnosed nine cases of mitochondrial toxicity in patients receiving ddI/d4T.
108
Dieterich et al.
The most recent trial is PRESCO (2007) aimed at determining the role of weight-based RBV and extended duration of therapy in co-infected patients (68). It enrolled 389 patients who received pegIFN alpha-2a (180 g/wk) plus rabavirin (1000 or 1200 mg according to weight). Genotype 1-infected participants were treated for 48 vs 72 weeks while the length of therapy in genotype 2 or 3 was 24 vs 48 weeks. They achieved an overall SVR rate of 49.6%; 35% for genotype 1 and 72.4% for genotype 2 or 3. SVR rates were significantly greater in the 72 weeks arm, but 36/45 (80%) patients in the genotype 1 group withdrew from treatment. Therefore those results must be interpreted cautiously. High-dose ribavirin was well tolerated. These studies underlie guideline’s recommendations for HCV treatment in HIV-co-infected patients. Every patient for whom the benefit outweighs the risk should be offered treatment. The standard of care is peg-IFN alpha (2a or 2b) + weight-based RBV in genotype 1-infected patients, and fixed-dose of 800 mg in genotypes 2 and 3 infections, all for 48 weeks. It is reasonable to use weight-based RBV in overweight genotypes 2- and 3-infected individuals. The expected SVR rates are 14–38% with genotype 1 infection and 44–73% with genotype 2 or 3. Traditionally, response is assessed at week 12 (EVR); this measure correlates with SVR in mono- as in co-infected patients (57, 68, 69). In patients with less than a 2 log10 IU/ml drop from baseline HCV RNA load, treatment should be discontinued since SVR can be achieved in only 2% of patients without EVR. More recently, a substudy from RIBAVIC found that when the viral load cannot be suppressed below 460,000 IU/ml at week 4, the chance of achieving SVR is null (negative predictive value of 100%) (70). Following this report, another substudy, this time from APRICOT, demonstrated that RVR is the best predictor for SVR while the absence of an EVR is the best predictor of the lack of SVR (71) (Table 4). Table 4 Major Differences in Treatment of HCV in Co-Infection vs Mono-Infection Higher Pre-treatment HCV RNA levels Lower kinetic of RNA decrease Lower rate of SVR More side effects More treatment discontinuation
Hepatitis C in Special Populations
109
Once treatment is initiated in co-infected patients, be alert for adverse events. This population may experience more side effects from treatment. Hematologic abnormalities are frequent and growth factors can correct anemia (recombinant human erythropoietin) and neutropenia (filgrastim) and should be used in order to avoid dose reduction which compromises chances of response. There is no FDA-approved treatment to increase platelets although some new agents are under study. Other more common side effects in these patients are psychiatric (see previous section) and gastrointestinal such as nausea and diarrhea. Higher rate of side effects translates into decreased adherence to therapy and discontinuation of treatment. Second, there is a risk for drug–drug interactions with the use of antiretroviral agents. The use of didanosine (ddI) and stavudine (d4T) is now contraindicated with RBV therapy because of the cumulative mitochondrial toxicity that causes hyperlactatemia, pancreatitis, hepatic failure, and even death in some patients (65, 72). When it comes to HCV treatment, ddI means “don’t do it.” The newer nucleoside reverse transcriptase inhibitors (NRTIs) are much less prone to cause such side effects, but the risk exists and physicians have to be aware of the clinical presentation of hyperlactatemia: nausea and vomiting, extreme fatigue, abdominal and muscle pain. The use of zidovudine (AZT) should also be avoided because of the risk of worsening anemia (73). Finally, the choice of ART may be related not only to safety issues, but also to efficacy. Co-infected patients on ART including tenofovir (TDF) have a better response to peg-IFN + RBV compared to abacavir (ABC)-based regimens. SVR rates of 45 vs 29% have been reported in one study and 36.4 vs 7.1% in another one (74–76). Consider early treatment of acute hepatitis C. The recent outbreaks of acute hepatitis C in MSM have increased our knowledge of the natural history of hepatitis C and its treatment in HIV individuals. We know that the likelihood of spontaneous clearance is lower than in mono-infected patients. Treatment of HCV in the acute stage is associated with a lower rate of SVR compared to mono-infected patients (77, 78). However, when compared to chronic disease, treatment of acute HCV infection in HIV-positive patients leads to a higher SVR if treatment is initiated early (78–80). To improve the chance of response to treatment, initiation should be considered before infection becomes chronic, but after 12 weeks from acquisition to give the patient the chance to spontaneous clear (81). We have found it helpful to closely monitor the serum viral load during the first months (every 1–2 weeks) to determine if spontaneous clearance is occurring. Treatment recommendation is peg-IFN plus weight-based RBV for 24 weeks, independently of genotype. Factors associated with SVR in the acute infection differ from the chronic stage (Table 5) (60).
110
Dieterich et al. Table 5 Factors Associated or Not with SVR in Acute HCV in HIV Predictors of SVR
Factors not Associated with SVR
Genotypes 2 and 3 Elevated ALT RVR
Age CD4 cell count Baseline HCV viral load HIV viremia Symptomatic infection
3. CO-INFECTION WITH HEPATITIS B (HBV) The population of patients dually infected with HBV and HCV warrants special consideration. Both viruses are transmitted parenterally. The prevalence of co-infection varies, with an estimated 7–30% HCV antibody in HBsAg-positive patients (82, 83). In HCV seropositive individuals, HBsAg is found in 2–10% (83, 84). In a study of hepatitis B core antibody (HBcAb)-positive patients, up to 50% had HCV antibody (85). The prevalence of co-infection varies, depending on endemicity of both viruses and risk factors for transmission. Populations at risk for co-infection are IVDUs, patients who received blood transfusions, dialysis patients, renal transplant patients, and others (86, 87). HBV and HCV influence each other. Usually, their interaction is characterized by the dominance of one or the other, frequently, HCV (88, 89). The dominance may reverse over time (89). In vitro, HCV suppresses HBV replication (90–92). In co-infected patients, high HCV viremia is often observed with low HBV DNA titers (93–95). Dominance of HBV and dual reciprocal interactions has also been demonstrated (96–98). One of the factors underlying the dominance of one virus is the timing of acquisition. Simultaneous infection with both viruses has been reported. In one small series of five cases, HBsAg appeared later, and at lower level and serum ALT was less than HBV mono-infection (99). In endemic countries where HBV is mostly transmitted vertically, hepatitis C presents as a superinfection (100). It has been linked to 23.1% chance of fulminant hepatitis in the setting of co-infection compared to 2.9% in mono-infected HCV individuals (101). In chronic HBV, superinfection with HCV can lead to HBeAg seroconversion and HBsAg loss (102, 103). When those patients were followed-up over a 20-year period, they observed higher rates of hepatic decompensation (48 vs 34%) and HCC (32 vs 10%) compared to
Hepatitis C in Special Populations
111
HBV mono-infection. When hepatitis B is the superinfection (rarer), fulminant hepatitis can also be seen (104). In one study, encephalopathy or ascites formation was present in 29 vs 0% in acute HBV monoinfection (105). Many studies focused on the accelerated liver disease progression in the HBV/HCV co-infection. Dual infection results in an accelerated rate of fibrosis (96). This leads to a higher risk of cirrhosis and decompensated liver disease (88, 96). Co-infection is an independent risk factor for HCC development (106, 107). In a study of individuals with compensated cirrhosis, the risk of developing HCC was 2.0 (per 100 person years) in HBV, 3.7 in HCV, and 6.4 in co-infection. In the HBV/HCV co-infected group, there was a 45% chance of HCC occurrence at 10 years. Up to a ninefold increase in risk compared to HCV mono-infection has also been reported (108, 109). This study and others support synergism between HBV and HCV in carcinogenesis (106, 107). Patients should be followed closely every 3–6 months with imaging and alpha-fetoprotein levels. Recently, investigators evaluated the cause of death in patients with chronic HCV and/or HBV (110). All-cause mortality was significantly increased in the three groups. In the co-infected, standardized mortality ratio (SMR) was 8.5 compared to 2.3 in HBV and 5.8 in HCV. Excess liver-related mortality was, respectively, 46.2, 21.7, and 35.5. There is no established standard of care for co-infection with HCV and HBV (111). Many studies evaluated standard interferon-alpha monotherapy, which has activity against both viruses (112, 113–117). The results for HCV were comparable to HCV mono-infected (SVR rates of 17–44%). Response of HBV and loss of HBeAg were very different between studies. The combination of interferon plus RBV was then assessed and HCV SVR rates were increased (43–69%) (118–120). In one study, 42 patients were enrolled (120). At 6 months, HBV DNA was suppressed in 31%, 50% had an HBeAg seroconversion, and 14% lost HBsAg. One of the observations made during those trials is the frequent HBV rebound in viremia once HCV is cleared (hepatitis flare). One trial investigated the combined use of standard interferon (12 months) and lamivudine (12 + 6 months) in eight patients (121). Half achieved an SVR. Only three had HBV DNA undetectable at month 18 (5 at month 6) and two seroconverted their HBeAg. Peg-IFN and RBV is the standard of care for HCV mono-infection and for chronic HBV, peg-IFN monotherapy is an option. Two case reports of the use of peg-IFN-alpha-2b + RBV in co-infection have been published (122, 123). The two patients achieved SVR. One had an HBeAg seroconversion while the other had a HBsAg seroconversion. Based on these data, the Hep-Net B/C Co-infection Study Group
112
Dieterich et al.
initiated a trial to prospectively evaluate the efficacy of this regimen for 48 weeks. Nineteen patients (HCV dominant) were enrolled. Ten had genotype 1, and nine had genotypes 2 and 3 infections. Seventy four percent achieved an SVR. Two out of six patients with HBV DNA viremia at the start were suppressed (33%). HBV viremia was detected in 4 out of 13 patients with HBV DNA undetectable at the start of treatment. One of them required treatment with an HBV polymerase inhibitor. Safety did not differ from the mono-infected patients. This trial suggested that peg-IFN + RBV should be the treatment of choice for co-infection (HCV dominant) and that response to HCV in co-infected patient is equivalent to that of mono-infected patients. The first step in evaluating a co-infected patient with HBV/HCV is to assess which virus is dominant to determine treatment needs (111). This is done by ordering a complete serological and virological panel for both infections. A threshold of 104 IU/ml is used for HBV DNA levels. The three scenarios below can help to guide treatment. First scenario: High HCV RNA level and HBV DNA <104 IU/ml: standard of care for HCV treatment (peg-IFN + RBV) and follow HBV DNA closely.1 Second scenario: High HCV RNA level and high HBV DNA >104 IU/ml: peg-IFN + RBV X 3 months. If HBV DNA does not respond add entecavir or adefovir. Continue treatment for HCV according to genotype.2 Third scenario: High HBV DNA and undetectable HCV RNA: Start HBV treatment with HBV polymerase inhibitors.
4. ETHNIC VARIATIONS IN HCV 4.1. Latinos and African Americans3 Latinos are the largest minority in the United States with, in 2004, 40.5 million people representing 14.2% of the total U.S. population (124). According to the U.S. Census Bureau, “Hispanic” or “Latino” refers to persons who trace their origin or descent to Mexico, Puerto Rico, Cuba, Spanish-speaking Central and South America countries, and other Spanish cultures (124). Healthcare is more difficult to access for this population because of cultural and linguistic barriers, 1
Our preference would be to use peg-IFN + RBV for 3 months, then add entecavir or tenofovir, complete HCV treatment and continue polymerase inhibitor after peg-IFN + RBV stop. 2 See Foot note 1. 3 In the text, comparison between Latinos and African Americans is made with Caucasians because reference data are more complete for this population.
Hepatitis C in Special Populations
113
socioeconomic factors (lack of medical insurance), and possible discrimination from the medical care community. Few data exist on the prevalence of hepatitis C in the U.S. Latino population and derive mostly from the third National Health and Nutrition Examination Survey (NHANES III) in which only Mexican Americans were represented. From 1988 to 1994, the prevalence of anti-HCV antibodies was 2.1% in this group compared to 1.5% in the non-Hispanic whites and 3.2% in the non-Hispanic black population (125). In the same cohort, but from 1999 to 2002, the prevalence of hepatitis C was 1.3% compared to 1.5% in non-Hispanic whites and 3.0% in non-Hispanic blacks (126). Even though Mexican Americans constitute about 2/3 of the U.S. Latino population, those data can hardly be applied to this very diverse community living in the United States. For example, a random seroprevalence survey in 21-to-64-year-old adults from Puerto Rico in 2001–2002 found a prevalence of anti-HCV antibodies as high as 6.3% (127, 128). The principal risk factor for acquisition of hepatitis C in the United States is IVDU as it is for the general population. However, more risky behavior was observed among Mexican Americans and Puerto Ricans who injected more often, were more prone to share paraphernalia, and not disinfect skin prior to injection (129, 130). In the U.S. Census Bureau survey of March 2004, African Americans constituted 12.5% of the U.S. population with 36.1 million people (124). To compare with Latinos (Mexican Americans in this cohort), data from the NHANES III showed in non-Hispanic blacks, a prevalence of anti-HCV antibody, from 1988 to 1994, of 3.2% compared to 1.5% in the non-Hispanic whites (125) and of 3.0% in the survey of 1999–2002 (125, 126). Hence, in this population, prevalence of hepatitis C is, at least, double that of Caucasians. Non-Hispanic black men between 40 and 49 years old had the highest prevalence with 9.8%. Americans are mostly infected with genotype 1 virus, but an even greater proportion of African Americans carry this genotype (90%) compared to Latinos (74%) and Caucasians (76%) (131). Another peculiarity of this group is the higher occurrence of viremia with seropositivity. This suggests a less propensity to spontaneously clear the infection compared to other populations. Non-Hispanic blacks had 86.2% positivity of HCV RNA vs 73.6% in Mexican Americans vs 67.6% in non-Hispanic whites. Also, there was a difference according to gender in this population. Men had viremia in 97.8% compared to 70.2% in women (125). Latinos infected with hepatitis C are more likely to be males, co-infected with HIV and have acquired HCV at a younger age compared to Caucasians (132). By themselves, all those characteristics have a negative impact on the prognosis of liver disease in hepatitis
114
Dieterich et al.
C which has been demonstrated to be more aggressive in Latinos overall (129, 133). They have higher serum ALT, AST, and bilirubin and lower serum albumin levels compared to Caucasians, Asians, or African Americans (134). The majority of studies in this population report higher necroinflammatory grades on liver biopsy, faster progression of liver fibrosis, higher frequency of cirrhosis, and accelerated time to cirrhosis (129, 135–137). It is noteworthy that chronic alcohol use is also a cause of more rapid fibrosis progression and is frequent in this population (129). Data on HCC prevalence is sparse in Latinos. In one report from Florida, Latinos were twice as likely as Caucasians or African Americans to be diagnosed with HCC; there was no mention of the underlying liver disease in this population (138). Apart from the faster rate of fibrosis and cirrhosis, other underlying conditions in this population such as diabetes and obesity have been independently associated with HCC (139, 140). Insulin resistance, diabetes, obesity, and steatosis are more prevalent in this population (130, 141). In fact, Latino ethnicity is an independent risk factor for hepatic steatosis which leads to faster progression of fibrosis (see section on IR and diabetes) (137, 142). Multiple studies show a slower progression of liver disease in African Americans (143–145). They report lower mean serum ALT values, necroinflammatory activity at liver biopsy, and liver fibrosis scores. Slower progression of fibrosis is also found (145). Contradictory results were also published where investigators found no difference between those two populations (135). However, mean alpha-fetoprotein (AFP) values are higher in cirrhotic African Americans compared to Caucasians, and the risk of developing HCC, which is rising in the United States, is further increased in this population by a factor of 3 (146, 147). Those patients also have a two to three times higher mortality rates when HCC is diagnosed compared to non-Hispanic whites. The Latino population has a lower chance of SVR compared to Caucasians. In a few retrospective studies, Latino ethnicity is associated with lower SVR (148, 149). One of them aimed at determining factors associated with treatment outcome found a SVR rate of 23% in Latinos compared to 39% in Caucasians and 61% in Asians (only 14% in African Americans) (149). Latinos are underrepresented in all major prospective clinical trials that evaluated the efficacy of the actual treatment: peg-IFN + RBV. There is only one prospective trial designed to evaluate the standard of care in Latinos vs non Latino Caucasians infected with genotype 1 HCV: The Latino Trial (150). Emerging data show that, as hypothesized, SVR rates are lower in the Latinos: 33.5 vs 49.3% in Caucasians. Investigators reported a higher rate of treatment discontinuation in the Latino group, but for efficacy rather than safety
Hepatitis C in Special Populations
115
reasons. Many factors are thought to be responsible for the lower chance of response to treatment: higher stages of fibrosis, cirrhosis, comorbidities such as IR and diabetes, obesity, steatosis, and genetics. African Americans have a lower chance of response to peg-IFN + RBV therapy compared to Caucasians (151–153). Contrary to the Latinos, many studies have been conducted that studied treatment response in African Americans. When this observation was first reported with standard interferon treatment, investigators suggested that it was the result of the greater proportion of genotype 1 in this group (156). Prospective trials were then undertaken. In 2004, two trials were published and each demonstrated a lower SVR in African Americans. One used peg-IFN alpha-2b + RBV (98% genotype 1) and SVR rates were 19 vs 52% in Caucasians (153, 154). A second trial used peg-IFN alpha2a + RBV and SVR rates were 26 vs 39% (155). In 2005, a trial evaluated double dose peg-IFN alpha- 2b + weight-based RBV in treatmentexperienced patients (156). African Americans needed double dosing to have a SVR rate equivalent to other groups. The VIRAHEP-C study in 2006 (peg-IFN alpha-2a + RBV for 48 weeks) confirmed a real difference in treatment response, with SVR rates of 28% in African Americans vs 52% in Caucasians (151). This is not exclusive to genotype 1 infection: another study reported a SVR rate of 44% in African Americans treated for HCV genotype 2 or 3 infections compared to 84% in Caucasians (157). In 2007, the WIN-R trial evaluated the role of weight-based RBV plus peg-IFN alpha-2b (155, 158). Weight-based dosing was associated with a higher chance of response (SVR 21 vs 10%), but still lower than the 37% in Caucasians. Overall, treatment is well tolerated in this population. One trial reported a higher rate of neutropenia (37 vs 18%), but a lower rate of anemia necessitating dose reduction (24 vs 32%) (155). The possible factors that have been suggested to underlie this lower treatment response in African Americans, apart from the genotype, are genetic immune response to interferon, different HCV kinetics, insufficient medication dosages and adherence (159).
5. HCV AND INSULIN RESISTANCE/DIABETES There is an increased prevalence of insulin resistance and diabetes in HCV. Insulin resistance (IR) is a state in which a given concentration of insulin is associated with a subnormal glucose response (160). In the normal state, insulin inhibits liver gluconeogenesis and increases glucose uptake by muscle and fat tissues in order to bring back the blood glucose to an optimal level. Insulin resistance is characterized by a failure to respond to insulin secretion resulting in hyperglycemia which
116
Dieterich et al.
further stimulates the production of insulin by pancreatic beta-cells, leading to hyperinsulinemia. The most frequently used tests to estimate insulin resistance are the Homeostatic Model Assessment (HOMA) and the Quantitative Insulin Sensitivity Check Index (QUICKI) score which are far more convenient to perform than the hyperinsulinemiceuglycemic clamp, the gold standard (161, 162). See Fig. 1. HOMA-IR
QUICKI
I0 (uU/mL) X G0 (mmol/L)
1
22.5
log (I0 uU/ml) + log (G0 mg/dl)
Fig. 1. HOMA-IR and QUICKI calculation. HOMA-IR, HOmeostatic Model of Assessment of Insulin Resistance; QUICKI, QUantitative Insulin sensitivity ChecK Index score; G0 , fasting glucose; I0 , fasting insulin.
Insulin resistance and diabetes are two frequent comorbidities in the general population and their prevalence is increasing (163). In patients chronically infected with the hepatitis C virus, the prevalence has been found to be even higher with 40–70% fulfilling the criteria for diagnosis of IR (164). Moreover, in patients over 40 years of age, HCV has been associated with a two-fold increase in the incidence of diabetes type II (165). Multiple mechanisms have been proposed for the association between IR and HCV, but are not yet well understood (166). The risk factors associated with the development of diabetes mellitus in the general population apply to patients with HCV, but there are also some findings specific to HCV (165). One study found that hepatitis C virus is associated with IR, independently of visceral fat (167). Virusspecific factors influence the development of the IR state associated with chronic hepatitis C. More than one study emphasized the relationship between IR and high viral load (167–170). Insulin resistance is commonly found in genotypes 1 and 4 compared to other genotypes (168). Steatosis is more common in chronic HCV and can be related to IR. Compared to seronegative patients, HCV patients are two to four times more likely to present with liver steatosis (166). Steatosis can manifest with any of the HCV genotypes, but the inherent pathophysiology for its development appears to differ in genotype 3-infected patients compared to non-genotype 3 infections. In the first case, steatosis is thought to result from direct viral cytopathic effects on the liver, independent of IR, and without metabolic risk factors (142, 171). In other genotypes, steatosis is closely associated with IR and can be referred
Hepatitis C in Special Populations
117
to as “metabolic steatosis” (172). Those two types of steatosis behave differently, at least in terms of impact on treatment response. Apart from genotype 3 and IR, other factors such as older age (over 40 years), high body mass index (BMI), diabetes mellitus, liver inflammation, fibrosis, and chronic alcohol use have been independently correlated to steatosis (173). In genotypes other than 3 with metabolic steatosis, IR is an independent predictor of advanced hepatic fibrosis. In genotype 3, the presence of steatosis is not associated with progressive liver disease, but the liver fibrosis is related to IR (174). In another study, in all genotypes, IR was a predictor of liver fibrosis, independent of steatosis (168). Patients with insulin resistance and diabetes in chronic HCV have more severe liver disease and decreased response to treatment compared to the general population. This points out the need for targeted interventions. Numerous studies have established a link between IR and liver fibrosis, which is a prerequisite to cirrhosis (171, 175–178). As mentioned earlier, HCC risk is correlated to obesity and diabetes, two states characterized by IR. IR and steatosis are both associated with a decreased chance of SVR. For a complete review of studies in this field, the reader is referred to Harrison, S.A. (166). In genotype 1-infected patients, pre-treatment IR, as measured by the HOMA-IR score, inversely correlated with SVR rates. In one study, peg-IFN + RBV led to an overall SVR rate of 43.4%. When SVR rates were analyzed according to HOMA-IR scores, investigators found a 60.5% SVR in patients without IR vs only 32.8% in those with an HOMA-IR greater than 2. SVR rates steadily decreased at higher HOMA-IR scores (179). In patients who responded to treatment, HOMA-IR scores decreased significantly during treatment; others reported the same results (180). In a study of genotypes 2 and 3 patients, those with a HOMA-IR of less than 2 had a 6.5-fold increase in SVR. In addition, BMI and hepatic fibrosis were independently correlated to IR (181). We know from a few studies that IR influences virological response from the beginning of treatment. For example, HCV RNA decreases significantly less at 24 hours in patients with higher HOMA-IR scores. With a HOMA-IR score of 4 or more, no one attained a complete early virological response (EVR) (182). In another study, every patient with HOMA-IR of less than 2 achieved an EVR (partial or complete) compared to only 61.5% of those with higher scores. In HIV co-infected patients undergoing treatment, IR also affected chances of RVR and EVR (183, 184). Independent from IR, steatosis decreases chances of SVR. The role that genotypes play in steatosis is still unclear at present (185–187). Until now, the majority of studies focused on IR in relation to treatment response. IR does decrease the chance of SVR. At least one ques-
118
Dieterich et al.
tion remains: does improving baseline IR result in higher SVR rates? There are no available data at the moment to answer this question, and guidelines do not yet address screening for IR or how to manage it. Trials are underway to determine the effectiveness of insulin sensitizers (metformin and thiazolidinediones) in lowering IR in patients with HCV, and the impact on SVR. Results from one study, the INSPIREDHCV, were recently published (188). Patients with HCV and IR who previously failed treatment were enrolled to receive the standard of care + pioglitazone 15 mg. Five patients were enrolled and the study was stopped because of no satisfactory EVR. Explanations for this failure are multiple. First, pioglitazone was started simultaneously with pegIFN + RBV and no single patient had a satisfactory HOMA-IR score (<2) at week 12 of treatment. Allowing for an optimal HOMA-IR score prior to treatment makes more sense, and the pioglitazone dose was probably too low. Patients had advanced liver disease: two patients had cirrhosis and two others had a stage 3 fibrosis (Metavir score) at liver biopsy 3 and 4 years earlier. So those results clearly do not discourage further studies with different approaches. Based on expert opinion, patients should be tested for IR at baseline when treatment is considered, at least to serve as an indicator of treatment response. We also encourage patients to lose weight, exercise and get better control of their diabetes, if needed, prior to treatment. When IR is present, insulin sensitizers such as metformin or thiazolidinediones appear to be safe in this population and are an interesting option (189). They should be used with the goal of improving IR before peg-IFN + RBV treatment is instituted until we have more data from the ongoing trials.
6. HCV IN CHRONIC KIDNEY DISEASES (CKD) There is a higher prevalence of HCV infection in patients with CKD, especially in those on hemodialysis (HD), than in the general population. Anti-HCV seroprevalence among HD patients ranges between 7 and 40% in developed countries and between 8 and 10% in the United States (190, 191). Conversely, the reported decline in HCV prevalence in recent years is associated with reduced blood product requirements through routine use of erythropoietin in patients with chronic kidney disease (CKD) and anemia, successful serologic screening of blood donors and universal precautionary measures to prevent nosocomial HCV transmission within dialysis units (190). The natural history of HCV in CKD is unclear because these patients have comorbid conditions such as diabetes and cardiovascular disease that reduce long-term survival. Serious complications of ESLD may
Hepatitis C in Special Populations
119
not manifest during the shortened life span of a patient maintained on HD due to the usual slow progression of HCV (192, 193). Nonetheless, several studies suggest that HCV-associated liver disease is a major cause of morbidity and mortality in patients with CKD (191). A metaanalysis that studied the effect of HCV on mortality showed that the summary estimate for adjusted RR of all-cause mortality with antiHCV was 1.34 (95% CI, 1.13–1.59) (190). Data from international renal transplantation registries indicate that the death rate for dialysis patients with cirrhosis is 35% higher than in patients without it (194). Additionally, a multi-center, multinational study reported an excess of hepatocellular carcinoma (HCC) in CKD patients, most likely attributable to an increased prevalence of chronic viral hepatitis (195). Finally, there is data to suggest that HCV infection is a risk factor in the development of diabetes mellitus in pre- and post-transplant patients (196). A number of small clinical trials have evaluated standard IFN monotherapy in HCV-infected patients on maintenance HD. A metaanalysis of 24 trials indicates a summary estimate of the SVR rate as 39% (95% CI, 32; 46), and 33% (95% CI, 19; 47) for genotype 1. Despite higher SVR rates in HD patients than in patients with normal renal function, there is lower tolerability to therapy and a high dropout rate of 19% (95% CI, 13; 26) (197). Improved response rates with peg-IFN in large trials showed promise of possible use in CKD patients. There are no recorded significant differences in peg-IFN alpha-2a clearance between patients with normal and impaired kidney function (creatinine clearance >100 ml/min vs 20–40 ml/min) (198). However, the pharmacokinetics of peg-IFN alpha-2a during HD may vary due to permeability and dialyzer pore size (199). Longer half-life with pegylation and the high rate of adverse events with treatment have yielded limited data from several small, uncontrolled studies (190). Lack of information about appropriate ribavirin dosing and concerns about side effects have precluded use of ribavirin in dialysis patients (200–202). Ribavirin undergoes renal clearance and causes dose-related hemolysis that can be severe in patients with baseline anemia. Furthermore, HD does not change the serum concentration of ribavirin. There have been only a few very small studies on combination therapy with peg-IFN and ribavirin (203–206). Despite high SVR rates (>50%) and effective management of ribavirin-induced anemia in these small cohorts, more experience with combination therapy and larger prospective controlled clinical trials are necessary. HCV infection is associated with decreased survival after renal transplantation (RT) (207, 208). Furthermore, there is no safe and effective HCV treatment post RT. A meta-analysis of clinical trials of IFN-
120
Dieterich et al.
based therapy in RT recipients showed a summary estimate for SVR and dropout rate of 18.0% (95% CI, 7.0–29%) and 35% (95% CI, 20–50%), respectively (209). The most frequent adverse event was graft dysfunction from acute rejection refractory to corticosteroid therapy. Consequently, there is a directive toward HCV treatment before kidney transplant. Pre-transplant IFN may reduce the occurrence of de novo or recurrent glomerulonephritis post-transplant (21) as well as the incidence of post-transplant diabetes mellitus (210, 211). HCV is associated with increased morbidity and mortality in CKD patients and affects outcomes after RT. Some studies have reported impressive SVR rates with IFN-based therapy despite significant adverse events and high dropout rates. Treatment prior to RT decreases post-transplantation complications. More prospective, controlled clinical trials are necessary to optimize HCV therapy for this population.
7. CONCLUSIONS Hepatitis C treatment is a challenge for both the patient and the caregiver. Every patient needs to be viewed with an open mind, as an individual case and not only as a member of a particular risk group. Treatment should not be denied to a patient based on the poor statistical response rate of their risk group. Prognostic factors for populations do not apply to individuals. In summary, when evaluating a member of a special population, efforts should be made to customize treatment both to the patient and to the virologic response in order to maximize chances of success.
REFERENCES 1. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: A cross-sectional analysis of the US adult AIDS clinical trials group. Clin Infect Dis. 2002 Mar 15;34(6):831–7. 2. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA. 2002 Jul 10;288(2):199–206. 3. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis. 2005 Sep 15;192(6):992–1002. 4. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis. 2005 Sep 15;192(6):992–1002. 5. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med. 2003 Feb 4;138(3):197–207. 6. Amon JJ, Garfein RS, Ahdieh-Grant L, Armstrong GL, Ouellet LJ, Latka MH, et al. Prevalence of hepatitis C virus infection among injection drug users in the United States, 1994–2004. Clin Infect Dis. 2008 Jun 15;46(12):1852–8.
Hepatitis C in Special Populations
121
7. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: Host, viral, and environmental factors. JAMA. 2000 Jul 26;284(4):450–6. 8. Vandelli C, Renzo F, Romano L, Tisminetzky S, De Palma M, Stroffolini T, et al. Lack of evidence of sexual transmission of hepatitis C among monogamous couples: Results of a 10-year prospective follow-up study. Am J Gastroenterol. 2004 May;99(5):855–9. 9. Ye L, Peng JS, Wang X, Wang YJ, Luo GX, Ho WZ. Methamphetamine enhances hepatitis C virus replication in human hepatocytes. J Viral Hepat. 2008 Apr;15(4):261–70. 10. Briat A, Dulioust E, Galimand J, Fontaine H, Chaix ML, Letur-Konirsch H, et al. Hepatitis C virus in the semen of men coinfected with HIV-1: Prevalence and origin. AIDS. 2005 Nov 4;19(16):1827–35. 11. Needlestick infects nurse with two viruses. Aids Alert. 1996 Oct;11(10):114–5. 12. Ridzon R, Gallagher K, Ciesielski C, Ginsberg MB, Robertson BJ, Luo CC, et al. Simultaneous transmission of human immunodeficiency virus and hepatitis C virus from a needle-stick injury. N Engl J Med. 1997 Mar 27;336(13):919–22. 13. Zanetti AR, Tanzi E, Romano L, Principi N, Zuin G, Minola E, et al. Multicenter trial on mother-to-infant transmission of GBV-C virus. the lombardy study group on Vertical/Perinatal hepatitis viruses transmission. J Med Virol. 1998 Feb;54(2):107–12. 14. Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, et al. Motherto-child transmission of hepatitis C virus: Evidence for preventable peripartum transmission. Lancet. 2000 Sep 9;356(9233):904–7. 15. Marine-Barjoan E, Berrebi A, Giordanengo V, Favre SF, Haas H, Moreigne M, et al. HCV/HIV co-infection, HCV viral load and mode of delivery: Risk factors for mother-to-child transmission of hepatitis C virus? AIDS. 2007 Aug 20;21(13):1811–5. 16. McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database Syst Rev. 2006 Oct 18;(4)(4):CD005546. 17. European Paediatric Hepatitis C Virus Network. A significant sex – but not elective cesarean section – effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis. 2005 Dec 1;192(11):1872–9. 18. Mok J, Pembrey L, Tovo PA, Newell ML, European Paediatric Hepatitis C Virus Network. When does mother to child transmission of hepatitis C virus occur? Arch Dis Child Fetal Neonatal Ed. 2005 Mar;90(2):F156–60. 19. Sharma D, Spearman P. The impact of cesarean delivery on transmission of infectious agents to the neonate. Clin Perinatol. 2008 Jun;35(2):407,20, vii–viii. 20. Sherman KE, O Brien J, Gutierrez AG, Harrison S, Urdea M, Neuwald P, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993 Oct;31(10):2679–82. 21. Bonacini M, Govindarajan S, Blatt LM, Schmid P, Conrad A, Lindsay KL. Patients co-infected with human immunodeficiency virus and hepatitis C virus demonstrate higher levels of hepatic HCV RNA. J Viral Hepat. 1999 May;6(3):203–8. 22. Gretch D, Corey L, Wilson J, dela Rosa C, Willson R, Carithers R,Jr, et al. Assessment of hepatitis C virus RNA levels by quantitative competitive RNA
122
23.
24.
25.
26. 27.
28.
29. 30.
31.
32.
33.
34.
35.
36.
Dieterich et al. polymerase chain reaction: High-titer viremia correlates with advanced stage of disease. J Infect Dis. 1994 Jun;169(6):1219–25. Martinez-Sierra C, Arizcorreta A, Diaz F, Roldan R, Martin-Herrera L, Perez-Guzman E, et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis. 2003 Feb 15;36(4):491–8. Chung RT, Evans SR, Yang Y, Theodore D, Valdez H, Clark R, et al. Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects. AIDS. 2002 Sep 27;16(14):1915–23. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: A systematic review of longitudinal studies. J Viral Hepat. 2006 Jan;13(1):34–41. Shores NJ, Maida I, Soriano V, Nunez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients. J Hepatol. 2008 May 5. Fox J, Nastouli E, Thomson E, Muir D, McClure M, Weber J, et al. Increasing incidence of acute hepatitis C in individuals diagnosed with primary HIV in the united kingdom. AIDS. 2008 Mar 12;22(5):666–8. Mohsen AH, Easterbrook PJ, Taylor C, Portmann B, Kulasegaram R, Murad S, et al. Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut. 2003 Jul;52(7):1035–40. Bonacini M. Liver injury during highly active antiretroviral therapy: The effect of hepatitis C coinfection. Clin Infect Dis. 2004 Mar 1;38 Suppl 2:S104–8. Brau N, Salvatore M, Rios-Bedoya CF, Fernandez-Carbia A, Paronetto F, Rodriguez-Orengo JF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006 Jan;44(1):47–55. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet. 2003 Nov 22;362(9397): 1708–13. Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, et al. Liverrelated deaths in persons infected with the human immunodeficiency virus: The D:A:D study. Arch Intern Med. 2006 Aug 14–28;166(15):1632–41. Mehta SH, Thomas DL, Torbenson M, Brinkley S, Mirel L, Chaisson RE, et al. The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection. Hepatology. 2005 Jan;41(1):123–31. Mocroft A, Soriano V, Rockstroh J, Reiss P, Kirk O, de Wit S, et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV? AIDS. 2005 Dec 2;19(18):2117–25. Soriano V, Garcia-Samaniego J, Bravo R, Gonzalez J, Castro A, Castilla J, et al. Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. hepatitis-HIV spanish study group. Clin Infect Dis. 1996 Sep;23(3):585–91. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997 Mar 22;349(9055):825–32.
Hepatitis C in Special Populations
123
37. Fierer DS, Uriel AJ, Carriero DC, Klepper A, Dieterich DT, Mullen MP, et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIVinfected men: A prospective cohort study. J Infect Dis. 2008 Sep 1;198(5): 683–6. 38. Bonacini M. Diagnosis and management of cirrhosis in coinfected patients. J Acquir Immune Defic Syndr. 2007 Jul 1;45 Suppl 2:S38,46; discussion S66–7. 39. Merchante N, Giron-Gonzalez JA, Gonzalez-Serrano M, Torre-Cisneros J, Garcia-Garcia JA, Arizcorreta A, et al. Survival and prognostic factors of HIVinfected patients with HCV-related end-stage liver disease. AIDS. 2006 Jan 2;20(1):49–57. 40. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective followup study of 384 patients. Gastroenterology. 1997 Feb;112(2):463–72. 41. Soriano V, Sulkowski M, Bergin C, Hatzakis A, Cacoub P, Katlama C, et al. Care of patients with chronic hepatitis C and HIV co-infection: Recommendations from the HIV-HCV international panel. AIDS. 2002 Apr 12;16(6):813–28. 42. Garcia-Samaniego J, Rodriguez M, Berenguer J, Rodriguez-Rosado R, Carbo J, Asensi V, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001 Jan;96(1):179–83. 43. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA. 2002 Jul 10;288(2):199–206. 44. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis. 2005 Sep 15;192(6):992–1002. 45. Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: The swiss HIV cohort study. Lancet. 2000 Nov 25;356(9244):1800–5. 46. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections. Hepatology. 2002 Jan;35(1):182–9. 47. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000 Jan 5;283(1):74–80. 48. Thomas DL. The challenge of hepatitis C in the HIV-infected person. Annu Rev Med. 2008;59:473–85. 49. Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. 2007 Sep 1;196(5):670–6. 50. Strader DB, Wright T, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004 Apr;39(4):1147–71. 51. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317–25. 52. Nunes D, Fleming C, Offner G, O Brien M, Tumilty S, Fix O, et al. HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagno-
124
53.
54.
55.
56.
57.
58.
59. 60.
61.
62. 63.
64.
65.
66.
Dieterich et al. sis of hepatitis C virus-related liver disease. J Acquir Immune Defic Syndr. 2005 Dec 15;40(5):538–44. de Ledinghen V, Douvin C, Kettaneh A, Ziol M, Roulot D, Marcellin P, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr. 2006 Feb 1;41(2):175–9. Foucher J, Chanteloup E, Vergniol J, Castera L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): A prospective study. Gut. 2006 Mar;55(3):403–8. Zinkernagel AS, von Wyl V, Ledergerber B, Rickenbach M, Furrer H, Battegay M, et al. Eligibility for and outcome of hepatitis C treatment of HIVcoinfected individuals in clinical practice: The swiss HIV cohort study. Antivir Ther. 2006;11(2):131–42. Dore GJ, Torriani FJ, Rodriguez-Torres M, Brau N, Sulkowski M, Lamoglia RS, et al. Baseline factors prognostic of sustained virological response in patients with HIV-hepatitis C virus co-infection. AIDS. 2007 Jul 31;21(12):1555–9. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29;351(5):438–50. Lissen E, Clumeck N, Sola R, Mendes-Correa M, Montaner J, Nelson M, et al. Histological response to pegIFNalpha-2a (40 KD) plus ribavirin in HIV-hepatitis C virus co-infection. AIDS. 2006 Nov 14;20(17):2175–81. Soriano V, Puoti M, Sulkowski M, Mauss S, Cacoub P, Cargnel A, et al. Care of patients with hepatitis C and HIV co-infection. AIDS. 2004 Jan 2;18(1):1–12. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV international panel. AIDS. 2007 May 31;21(9): 1073–89. Edlin BR, Seal KH, Lorvick J, Kral AH, Ciccarone DH, Moore LD, et al. Is it justifiable to withhold treatment for hepatitis C from illicit-drug users? N Engl J Med. 2001 Jul 19;345(3):211–5. Sulkowski MS. The HIV-coinfected patient: Managing viral hepatitis. J Acquir Immune Defic Syndr. 2007 Jul 1;45 Suppl 2:S36–7. Guidelines for prevention and treatment of opportunistic infections in HIVinfected adults and adolescents. Recommendations of the NIH, the CDC and the HIVMA/IDSA. In press June 18, 2008. Alberti A, Clumeck N, Collins S, Gerlich W, Lundgren J, Palu G, et al. Short statement of the first european consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol. 2005 May;42(5): 615–24. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA. 2004 Dec 15;292(23):2839–48. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451–9.
Hepatitis C in Special Populations
125
67. Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004 Sep 3;18(13):F27–36. 68. Nunez M, Miralles C, Berdun MA, Losada E, Aguirrebengoa K, Ocampo A, et al. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: The PRESCO trial. AIDS Res Hum Retroviruses. 2007 Aug;23(8):972–82. 69. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA. 2004 Dec 15;292(23):2839–48. 70. Payan C, Pivert A, Morand P, Fafi-Kremer S, Carrat F, Pol S, et al. Rapid and early virological response to chronic hepatitis C treatment with IFN alpha2b or PEG-IFN alpha2b plus ribavirin in HIV/HCV co-infected patients. Gut. 2007 Aug;56(8):1111–6. 71. Rodriguez-Torres, M. et al. On-treatment responses at week 4 and 12 can be used to predict sustained virologic response rates in HIV-HCV co-infected patients with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). 2008;Abstract P-1073. CROI 15th, Boston. 72. Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis. 2004 Apr 15;38(8):e79–80. 73. Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J Viral Hepat. 2006 Oct;13(10):683–9. 74. Jacobson IMea. Efficacy of pegInterferon + ribavirin treatment in HIV/HCV-coinfected patients receiving abacavir + lamivudine or tenofovir + either lamivudine or emtricitabine as nucleoside analogue backbone. 2008;Abstract #1074. 15th CROI, Boston. 75. Gonzalez-Garcia Jea. The use of tenofovir + lamivudine / emtricitabine is associated with an improved response to pegInterferon + ribavirin in HIV/HCV-coinfected patients receiving HAART: The gesida 50/06 study. 2008;Abstract # 1076. 15th CROI, Boston. 76. Pineda JA, Mira JA, Gil Ide L, Valera-Bestard B, Rivero A, Merino D, et al. Influence of concomitant antiretroviral therapy on the rate of sustained virological response to pegylated interferon plus ribavirin in hepatitis C virus/ HIV-coinfected patients. J Antimicrob Chemother. 2007 Dec;60(6):1347–54. 77. Gilleece YC, Browne RE, Asboe D, Atkins M, Mandalia S, Bower M, et al. Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin. J Acquir Immune Defic Syndr. 2005 Sep 1;40(1):41–6. 78. Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS. 2006 May 12;20(8):1157–61. 79. Vogel M, Bieniek B, Jessen H, Schewe CK, Hoffmann C, Baumgarten A, et al. Treatment of acute hepatitis C infection in HIV-infected patients: A retrospective analysis of eleven cases. J Viral Hepat. 2005 Mar;12(2):207–11. 80. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recom-
126
81.
82.
83. 84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
Dieterich et al. mendations from the HCV-HIV international panel. AIDS. 2007 May 31;21(9): 1073–89. Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al Tawil A, Khalifa KE, et al. Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy on sustained virologic response. Gastroenterology. 2006 Mar;130(3):632–8. Gaeta GB, Stornaiuolo G, Precone DF, Lobello S, Chiaramonte M, Stroffolini T, et al. Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter italian study. J Hepatol. 2003 Dec;39(6): 1036–41. Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology. 1995 Oct;22(4 Pt 1):1101–8. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol. 2008 Apr;23(4):512–20. Jilg W, Sieger E, Zachoval R, Schatzl H. Individuals with antibodies against hepatitis B core antigen as the only serological marker for hepatitis B infection: High percentage of carriers of hepatitis B and C virus. J Hepatol. 1995 Jul;23(1): 14–20. Reddy GA, Dakshinamurthy KV, Neelaprasad P, Gangadhar T, Lakshmi V. Prevalence of HBV and HCV dual infection in patients on haemodialysis. Indian J Med Microbiol. 2005 Jan;23(1):41–3. Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M, Campise MR, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation. 2005 May 15;79(9):1132–6. Fong TL, Di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology. 1991 Jul;14(1):64–7. Raimondo G, Brunetto MR, Pontisso P, Smedile A, Maina AM, Saitta C, et al. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology. 2006 Jan;43(1):100–7. Schuttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol. 2002 Dec;37(6):855–62. Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol. 1993 Oct;67(10):5823–32. Chen SY, Kao CF, Chen CM, Shih CM, Hsu MJ, Chao CH, et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem. 2003 Jan 3;278(1):591–607. Jardi R, Rodriguez F, Buti M, Costa X, Cotrina M, Galimany R, et al. Role of hepatitis B, C, and D viruses in dual and triple infection: Influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology. 2001 Aug;34(2):404–10. Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol. 1998 Jul;36(7):2084–6. Fattovich G, Tagger A, Brollo L, Giustina G, Pontisso P, Realdi G, et al. Hepatitis C virus infection in chronic hepatitis B virus carriers. J Infect Dis. 1991 Feb;163(2):400–2.
Hepatitis C in Special Populations
127
96. Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F, et al. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol. 1998 Jan;28(1):27–33. 97. Sato S, Fujiyama S, Tanaka M, Yamasaki K, Kuramoto I, Kawano S, et al. Coinfection of hepatitis C virus in patients with chronic hepatitis B infection. J Hepatol. 1994 Aug;21(2):159–66. 98. Ohkawa K, Hayashi N, Yuki N, Masuzawa M, Kato M, Yamamoto K, et al. Long-term follow-up of hepatitis B virus and hepatitis C virus replicative levels in chronic hepatitis patients coinfected with both viruses. J Med Virol. 1995 Jul;46(3):258–64. 99. Mimms LT, Mosley JW, Hollinger FB, Aach RD, Stevens CE, Cunningham M, et al. Effect of concurrent acute infection with hepatitis C virus on acute hepatitis B virus infection. BMJ. 1993 Oct 30;307(6912):1095–7. 100. Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004 Apr;126(4):1024–9. 101. Chu CM, Yeh CT, Liaw YF. Fulminant hepatic failure in acute hepatitis C: Increased risk in chronic carriers of hepatitis B virus. Gut. 1999 Oct;45(4):613–7. 102. Liaw YF, Lin SM, Sheen IS, Chu CM. Acute hepatitis C virus superinfection followed by spontaneous HBeAg seroconversion and HBsAg elimination. Infection. 1991 Jul–Aug;19(4):250–1. 103. Dai CY, Yu ML, Chuang WL, Lin ZY, Chen SC, Hsieh MY, et al. Influence of hepatitis C virus on the profiles of patients with chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2001 Jun;16(6):636–40. 104. Liaw YF, Yeh CT, Tsai SL. Impact of acute hepatitis B virus superinfection on chronic hepatitis C virus infection. Am J Gastroenterol. 2000 Oct;95(10): 2978–80. 105. Sagnelli E, Coppola N, Messina V, Di Caprio D, Marrocco C, Marotta A, et al. HBV superinfection in hepatitis C virus chronic carriers, viral interaction, and clinical course. Hepatology. 2002 Nov;36(5):1285–91. 106. Benvegnu L, Fattovich G, Noventa F, Tremolada F, Chemello L, Cecchetto A, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer. 1994 Nov 1;74(9):2442–8. 107. Chiaramonte M, Stroffolini T, Vian A, Stazi MA, Floreani A, Lorenzoni U, et al. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer. 1999 May 15;85(10):2132–7. 108. Kaklamani E, Trichopoulos D, Tzonou A, Zavitsanos X, Koumantaki Y, Hatzakis A, et al. Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma. JAMA. 1991 Apr 17;265(15):1974–6. 109. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer. 1998 Jan 30;75(3):347–54. 110. Duberg AS, Torner A, Davidsdottir L, Aleman S, Blaxhult A, Svensson A, et al. Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study. J Viral Hepat. 2008 Jul;15(7):538–50. 111. Keeffe EB, Dieterich DT, Han SHB, Jacobson IM, Martin P, Schiff ER, Tobias H. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin.Gastroenterol.Hepatol. In press.
128
Dieterich et al.
112. Zignego AL, Fontana R, Puliti S, Barbagli S, Monti M, Careccia G, et al. Relevance of inapparent coinfection by hepatitis B virus in alpha interferontreated patients with hepatitis C virus chronic hepatitis. J Med Virol. 1997 Apr;51(4):313–8. 113. Weltman MD, Brotodihardjo A, Crewe EB, Farrell GC, Bilous M, Grierson JM, et al. Coinfection with hepatitis B and C or B, C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment. J Viral Hepat. 1995;2(1):39–45. 114. Liaw YF, Chien RN, Lin SM, Yeh CT, Tsai SL, Sheen IS, et al. Response of patients with dual hepatitis B virus and C virus infection to interferon therapy. J Interferon Cytokine Res. 1997 Aug;17(8):449–52. 115. Utili R, Zampino R, Bellopede P, Marracino M, Ragone E, Adinolfi LE, et al. Dual or single hepatitis B and C virus infections in childhood cancer survivors: Long-term follow-up and effect of interferon treatment. Blood. 1999 Dec 15;94(12):4046–52. 116. Guptan RC, Thakur V, Raina V, Sarin SK. Alpha-interferon therapy in chronic hepatitis due to active dual infection with hepatitis B and C viruses. J Gastroenterol Hepatol. 1999 Sep;14(9):893–8. 117. Villa E, Grottola A, Buttafoco P, Colantoni A, Bagni A, Ferretti I, et al. High doses of alpha-interferon are required in chronic hepatitis due to coinfection with hepatitis B virus and hepatitis C virus: Long term results of a prospective randomized trial. Am J Gastroenterol. 2001 Oct;96(10):2973–7. 118. Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM, Chen DS. Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients. Hepatology. 2003 Mar;37(3):568–76. 119. Hung CH, Lee CM, Lu SN, Wang JH, Tung HD, Chen CH, et al. Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection. J Gastroenterol Hepatol. 2005 May;20(5): 727–32. 120. Chuang WL, Dai CY, Chang WY, Lee LP, Lin ZY, Chen SC, et al. Viral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy. Antivir Ther. 2005;10(1):125–33. 121. Marrone A, Zampino R, D Onofrio M, Ricciotti R, Ruggiero G, Utili R. Combined interferon plus lamivudine treatment in young patients with dual HBV (HBeAg positive) and HCV chronic infection. J Hepatol. 2004 Dec;41(6): 1064–5. 122. Rautou PE, Asselah T, Saadoun D, Martinot M, Valla D, Marcellin P. Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-alpha2b plus ribavirin treatment in a patient with hepatitis B and C coinfection. Eur J Gastroenterol Hepatol. 2006 Sep;18(9):1019–22. 123. Potthoff A, Deterding K, Trautwein C, Rifai K, Manns MP, Wedemeyer H. Sustained HCV-RNA response and hepatitis bs seroconversion after individualized antiviral therapy with pegylated interferon alpha plus ribavirin and active vaccination in a hepatitis C virus/hepatitis B virus-coinfected patient. Eur J Gastroenterol Hepatol. 2007 Oct;19(10):906–9. 124. U.S. census bureau, current population survey, annual social and economic supplement, 2004, ethnicity and ancestry statistics branch, population division.
Hepatitis C in Special Populations
129
125. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999 Aug 19;341(8):556–62. 126. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006 May 16;144(10):705–14. 127. Perez CM, Suarez E, Torres EA. Epidemiology of hepatitis C infection and its public health implications in puerto rico. P R Health Sci J. 2004 Jun;23(2 Suppl):11–28. 128. Perez CM, Suarez E, Torres EA, Roman K, Colon V. Seroprevalence of hepatitis C virus and associated risk behaviours: A population-based study in san juan, puerto rico. Int J Epidemiol. 2005 Jun;34(3):593–9. 129. Rodriguez-Torres M, Rios-Bedoya CF, Rodriguez-Orengo J, Fernandez-Carbia A, Marxuach-Cuetara AM, Lopez-Torres A, et al. Progression to cirrhosis in latinos with chronic hepatitis C: Differences in puerto ricans with and without human immunodeficiency virus coinfection and along gender. J Clin Gastroenterol. 2006 Apr;40(4):358–66. 130. Rodriguez-Torres M. Latinos and chronic hepatitis C: A singular population. Clin Gastroenterol Hepatol. 2008 May;6(5):484–90. 131. Lepe R, Layden-Almer JE, Layden TJ, Cotler S. Ethnic differences in the presentation of chronic hepatitis C. J Viral Hepat. 2006 Feb;13(2):116–20. 132. Cheung RC, Currie S, Shen H, Ho SB, Bini EJ, Anand BS, et al. Chronic hepatitis C in latinos: Natural history, treatment eligibility, acceptance, and outcomes. Am J Gastroenterol. 2005 Oct;100(10):2186–93. 133. Rodriguez-Torres M, Govindarajan S, Sola R, Clumeck N, Lissen E, Pessoa M, et al. Hepatic steatosis in HIV/HCV co-infected patients: Correlates, efficacy and outcomes of anti-HCV therapy: A paired liver biopsy study. J Hepatol. 2008 May;48(5):756–64. 134. Celona AF, Yu MC, Prakash M, Kuo T, Bonacini M. Hepatitis C in a los angeles public hepatitis clinic: Demographic and biochemical differences associated with race-ethnicity. Clin Gastroenterol Hepatol. 2004 Jun;2(6):459–62. 135. Bonacini M, Groshen MD, Yu MC, Govindarajan S, Lindsay KL. Chronic hepatitis C in ethnic minority patients evaluated in los angeles county. Am J Gastroenterol. 2001 Aug;96(8):2438–41. 136. Lepe R, Layden-Almer JE, Layden TJ, Cotler S. Ethnic differences in the presentation of chronic hepatitis C. J Viral Hepat. 2006 Feb;13(2):116–20. 137. Verma S, Wang CH, Govindarajan S, Kanel G, Squires K, Bonacini M. Do type and duration of antiretroviral therapy attenuate liver fibrosis in HIV-hepatitis C virus-coinfected patients? Clin Infect Dis. 2006 Jan 15;42(2):262–70. 138. Shea KA, Fleming LE, Wilkinson JD, Wohler-Torres B, McKinnon JA. Hepatocellular carcinoma incidence in florida. ethnic and racial distribution. Cancer. 2001 Mar 1;91(5):1046–51. 139. Ohki T, Tateishi R, Sato T, Masuzaki R, Imamura J, Goto T, et al. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clin Gastroenterol Hepatol. 2008 Apr;6(4):459–64. 140. Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology. 2008 Jun;47(6):1856–62.
130
Dieterich et al.
141. Caballero AE. Diabetes in the hispanic or latino population: Genes, environment, culture, and more. Curr Diab Rep. 2005 Jun;5(3):217–25. 142. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001 Jun;33(6):1358–64. 143. Crosse K, Umeadi OG, Anania FA, Laurin J, Papadimitriou J, Drachenberg C, et al. Racial differences in liver inflammation and fibrosis related to chronic hepatitis C. Clin Gastroenterol Hepatol. 2004 Jun;2(6):463–8. 144. Sterling RK, Stravitz RT, Luketic VA, Sanyal AJ, Contos MJ, Mills AS, et al. A comparison of the spectrum of chronic hepatitis C virus between caucasians and african americans. Clin Gastroenterol Hepatol. 2004 Jun;2(6):469–73. 145. Wiley TE, Brown J, Chan J. Hepatitis C infection in african americans: Its natural history and histological progression. Am J Gastroenterol. 2002 Mar;97(3):700–6. 146. Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: Results from the HALT-C trial. J Hepatol. 2005 Sep;43(3):434–41. 147. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: An update. Ann Intern Med. 2003 Nov 18;139(10):817–23. 148. Gaglio PJ, Rodriguez-Torres M, Herring R, Anand B, Box T, Rabinovitz M, et al. Racial differences in response rates to consensus interferon in HCV infected patients naive to previous therapy. J Clin Gastroenterol. 2004 Aug;38(7): 599–604. 149. Hepburn MJ, Hepburn LM, Cantu NS, Lapeer MG, Lawitz EJ. Differences in treatment outcome for hepatitis C among ethnic groups. Am J Med. 2004 Aug 1;117(3):163–8. 150. Rodriguez-Torres, M. et al. Virologic responses to peginterferon alfa2a/Ribavirin in treatment-naive latino vs non-latino whites infected with HCV genotype 1: The LATINO study. 2008;Abstract. EASL 43th Annual Meeting. Milan. 151. Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, et al. Peginterferon and ribavirin treatment in african american and caucasian american patients with hepatitis C genotype 1. Gastroenterology. 2006 Aug;131(2):470–7. 152. Jacobson IM, Brown RS,Jr, McCone J, Black M, Albert C, Dragutsky MS, et al. Impact of weight-based ribavirin with peginterferon alfa-2b in african americans with hepatitis C virus genotype 1. Hepatology. 2007 Oct;46(4):982–90. 153. Muir AJ, Bornstein JD, Killenberg PG, Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-hispanic whites. N Engl J Med. 2004 May 27;350(22): 2265–71. 154. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. the international hepatitis interventional therapy group. Gastroenterology. 2000 Nov;119(5):1317–23. 155. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black american patients with chronic HCV genotype 1. Hepatology. 2004 Jun;39(6):1702–8.
Hepatitis C in Special Populations
131
156. Gross, J. et al. Double-dose peginterferon alfa-2b with weight-based ribavirin improves response for interferon/ribavirin non-responders with hepatitis C: Final results of ”RENEW”. 2005;AALSD, 56th Annual Meeting, San Francisco. 157. Shiffman ML, Mihas AA, Millwala F, Sterling RK, Luketic VA, Stravitz RT, et al. Treatment of chronic hepatitis C virus in african americans with genotypes 2 and 3. Am J Gastroenterol. 2007 Apr;102(4):761–6. 158. Jacobson IM, Brown RS,Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: A randomized trial. Hepatology. 2007 Oct;46(4):971–81. 159. Ramamurthy M, Muir AJ. Treatment of hepatitis C in special populations. Clin Liver Dis. 2006 Nov;10(4):851–65. 160. Moller DE, Flier JS. Insulin resistance – mechanisms, syndromes, and implications. N Engl J Med. 1991 Sep 26;325(13):938–48. 161. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412–9. 162. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000 Jul;85(7):2402–10. 163. Ioannou GN, Bryson CL, Boyko EJ. Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes. J Diabetes Complications. 2007 Nov– Dec;21(6):363–70. 164. Conjeevaram HS, Kleiner DE, Everhart JE, Hoofnagle JH, Zacks S, Afdhal NH, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007 Jan;45(1):80–7. 165. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000 Oct 17;133(8):592–9. 166. Harrison SA. Insulin resistance among patients with chronic hepatitis C: Etiology and impact on treatment. Clin Gastroenterol Hepatol. 2008 Aug;6(8):864–76. 167. Yoneda M, Saito S, Ikeda T, Fujita K, Mawatari H, Kirikoshi H, et al. Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in nonobese and nondiabetic patients. J Viral Hepat. 2007 Sep;14(9):600–7. 168. Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, et al. Insulin resistance in chronic hepatitis C: Association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008 Feb;134(2):416–23. 169. Harrison SA. Correlation between insulin resistance and hepatitis C viral load. Hepatology. 2006 May;43(5):1168; author reply 1168–9. 170. Hsu CS, Liu CJ, Liu CH, Wang CC, Chen CL, Lai MY, et al. High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int. 2008 Feb;28(2):271–7. 171. Hui JM, Kench J, Farrell GC, Lin R, Samarasinghe D, Liddle C, et al. Genotypespecific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol. 2002 Aug;17(8):873–81. 172. Camma C, Bruno S, Di Marco V, Di Bona D, Rumi M, Vinci M, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology. 2006 Jan;43(1):64–71.
132
Dieterich et al.
173. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data. Gastroenterology. 2006 May;130(6):1636–42. 174. Bugianesi E, Marchesini G, Gentilcore E, Cua IH, Vanni E, Rizzetto M, et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis. Hepatology. 2006 Dec;44(6):1648–55. 175. Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, et al. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol. 2005 Jan;42(1):41–6. 176. Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology. 2003 Dec;125(6):1695–704. 177. Svegliati-Baroni G, Bugianesi E, Bouserhal T, Marini F, Ridolfi F, Tarsetti F, et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut. 2007 Sep;56(9):1296–301. 178. D Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005 Jul;100(7):1509–15. 179. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005 Mar;128(3):636–41. 180. Lo Iacono O, Venezia G, Petta S, Mineo C, De Lisi S, Di Marco V, et al. The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2007 May 15;25(10):1181–91. 181. Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol. 2008 Jan;48(1):28–34. 182. Bortoletto, G. et al. Insulin resistance (IR) defined by the homeostasis model of assessment insulin resistance (HOMA-IR) index has a direct effect on early kinetics during pegylated-interferon therapy for chronic hepatitis C. 2006;The 58th Annual Meeting of the AASLD, Boston. Abstract # 275. 183. Bongiovanni M, Ranieri R, Casana M, Tordato F, Cicconi P, Tincati C, et al. Insulin resistance affects early virologic response in HIV-infected subjects treated for hepatitis C infection. J Acquir Immune Defic Syndr. 2008 Feb 1;47(2):258–9. 184. Nasta P, Gatti F, Puoti M, Cologni G, Bergamaschi V, Borghi F, et al. Insulin resistance impairs rapid virologic response in HIV/hepatitis C virus coinfected patients on peginterferon-alfa-2a. AIDS. 2008 Apr 23;22(7):857–61. 185. Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003 Jul;38(1):75–85. 186. Thomopoulos KC, Theocharis GJ, Tsamantas AC, Siagris D, Dimitropoulou D, Gogos CA, et al. Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 2005 Feb;17(2):149–53.
Hepatitis C in Special Populations
133
187. Harrison SA, Brunt EM, Qazi RA, Oliver DA, Neuschwander-Tetri BA, Di Bisceglie AM, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005 Jun;3(6):604–9. 188. Overbeck K, Genne D, Golay A, Negro F, on behalf of the Swiss Association for the Study of the Liver (SASL). Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin. J Hepatol. 2008 Aug;49(2):295–8. 189. Han H, Boxer AS, Adler M, Matloff JL, Vachon M, Carriero D, Dieterich DT. Assessing hepatotoxicity of thiazolidinediones (TZDs), metformin, and/or statin therapy in chronic hepatitis C (HCV) patients. Hepatology 2008;48(suppl 1): 475A 190. Martin P, Fabrizi F. Hepatitis C virus and kidney disease. J Hepatol. 2008 Jun 26. 191. Moylan CA, Muir AJ. Treatment of hepatitis C in special populations. Clin Liver Dis. 2005 Nov;9(4):567,77, v. 192. Kalia H, Lopez PM, Martin P. Treatment of HCV in patients with renal failure. Arch Med Res. 2007 Aug;38(6):628–33. 193. Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with endstage renal disease. Hepatology. 2002 Jul;36(1):3–10. 194. Marcelli D, Stannard D, Conte F, Held PJ, Locatelli F, Port FK. ESRD patient mortality with adjustment for comorbid conditions in lombardy (italy) versus the United States. Kidney Int. 1996 Sep;50(3):1013–8. 195. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, et al. Cancer in patients on dialysis for end-stage renal disease: An international collaborative study. Lancet. 1999 Jul 10;354(9173):93–9. 196. Bloom RD, Sayer G, Fa K, Constantinescu S, Abt P, Reddy KR. Outcome of hepatitis C virus-infected kidney transplant candidates who remain on the waiting list. Am J Transplant. 2005 Jan;5(1):139–44. 197. Fabrizi F, Dixit V, Messa P, Martin P. Interferon monotherapy of chronic hepatitis C in dialysis patients: Meta-analysis of clinical trials. J Viral Hepat. 2008 Feb;15(2):79–88. 198. Martin, P. et al. Pegylated (40KD) interferon alfa-2a (pegasys) is unaffected by renal impairment. ;Hepatology 2000;32:370A. 199. Barril G, Quiroga JA, Sanz P, Rodriguez-Salvanes F, Selgas R, Carreno V. Pegylated interferon-alpha2a kinetics during experimental haemodialysis: Impact of permeability and pore size of dialysers. Aliment Pharmacol Ther. 2004 Jul 1;20(1):37–44. 200. Tan AC, Brouwer JT, Glue P, van Leusen R, Kauffmann RH, Schalm SW, et al. Safety of interferon and ribavirin therapy in haemodialysis patients with chronic hepatitis C: Results of a pilot study. Nephrol Dial Transplant. 2001 Jan;16(1):193–5. 201. Bruchfeld A, Stahle L, Andersson J, Schvarcz R. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection – a pilot study. J Viral Hepat. 2001 Jul;8(4):287–92. 202. Mousa DH, Abdalla AH, Al-Shoail G, Al-Sulaiman MH, Al-Hawas FA, AlKhader AA. Alpha-interferon with ribavirin in the treatment of hemodialysis patients with hepatitis C. Transplant Proc. 2004 Jul–Aug; 36(6):1831–4. 203. Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat. 2006 May;13(5):316–21.
134
Dieterich et al.
204. Rendina M, Schena A, Castellaneta NM, Losito F, Amoruso AC, Stallone G, et al. The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant. J Hepatol. 2007 May;46(5):768–74. 205. van Leusen R, Adang RP, de Vries RA, Cnossen TT, Konings CJ, Schalm SW, et al. Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant. 2008 Feb;23(2):721–5. 206. Carriero D, Fabrizi F, Uriel AJ, Park J, Martin P, Dieterich DT. Treatment of dialysis patients with chronic hepatitis C using pegylated interferon and low-dose ribavirin. Int J Artif Organs. 2008 Apr;31(4):295–302. 207. Mathurin P, Mouquet C, Poynard T, Sylla C, Benalia H, Fretz C, et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology. 1999 Jan;29(1):257–63. 208. Hanafusa T, Ichikawa Y, Yazawa K, Kishikawa H, Fukunishi T, Kanai T, et al. Hepatitis C virus infection in kidney transplantation and a pilot study of the effects of interferon-alpha therapy. Transplant Proc. 1998 Feb;30(1):122–4. 209. Fabrizi F, Lunghi G, Dixit V, Martin P. Meta-analysis: Anti-viral therapy of hepatitis C virus-related liver disease in renal transplant patients. Aliment Pharmacol Ther. 2006 Nov 15;24(10):1413–22. 210. Cruzado JM, Casanovas-Taltavull T, Torras J, Baliellas C, Gil-Vernet S, Grinyo JM. Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance. Am J Transplant. 2003 Mar;3(3):357–60. 211. Gursoy M, Guvener N, Koksal R, Karavelioglu D, Baysal C, Ozdemir N, et al. Impact of HCV infection on development of posttransplantation diabetes mellitus in renal allograft recipients. Transplant Proc. 2000 May;32(3):561–2.
Extrahepatic Manifestations of Chronic Hepatitis C Infection Douglas Meyer, MD and Henry C. Bodenheimer Jr., MD CONTENTS I NTRODUCTION S PECTRUM OF E XTRAHEPATIC M ANIFESTATIONS C ONCLUSIONS R EFERENCES
Key Principles
• Extrahepatic manifestations (EHM) of chronic hepatitis C (HCV) affect a variety of organ systems and may present with significant mortality and morbidity. • These EHM are not the direct result of viral infection but are secondary to the host immune response. • Vascular manifestations are due to the presence of cryoglobulinemia, which causes deposition of immune complexes in the small vessels of the skin, presenting with palpable purpura. • An association is noted between HCV and lymphoproliferative disorders, most commonly B-cell non-Hodgkin lymphoma. • Renal disorders, most commonly membranoproliferative glomerulonephritis (MPGN) has the strongest association with HCV associated cryoglobulinemia.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 5, C Humana Press, a part of Springer Science+Business Media, LLC 2009
135
136
Meyer and Bodenheimer
• Dermatologic manifestations include pruritus, porphyria cutanea tarda, and lichen planus. • Thyroid diseases, in particular, autoimmune thyroid disease, are commonly associated with HCV and may be exacerbated by interferon therapy. • Rheumatologic and neurologic diseases associated with HCV include arthritis, myositis, and peripheral neuropathy. • Many of the EHM of HCV are modified or improved by antiviral therapy. The most durable effects are noted in those who achieve a sustained virological response (SVR).
1. INTRODUCTION The association between chronic hepatitis C viral (HCV) infection and extrahepatic manifestations of disease was first reported in the early 1990s (1). The signs and symptoms of chronic HCV include vascular, renal, dermatologic, endocrine, rheumatologic, neurologic, and ophthalmologic presentations (Table 1). The prevalence of chronic HCV in the United States is approximately 2% of the adult population (2). The prevalence of at least one clinical extrahepatic manifestation in chronically infected HCV patients is approximately 40–75% (3, 4) (Table 2). About 10% of patients with extrahepatic manifestations of HCV infection present with significant morbidity and mortality (5). HCV not only infects hepatocytes but can replicate in other cells, in particular, circulating peripheral monocytes (6–9). In order to accurately assess whether extrahepatic replication is actually occurring in cell types and tissue besides the hepatocyte and liver, more sensitive assays than are currently available will be required (10). This assay must be able to accurately differentiate negative-strand HCV RNA from positive strand RNA since the negative-strand RNA is the intermediate replicative molecule signifying true extrahepatic replication (11). However, most extrahepatic manifestations associated with HCV are not the direct result of the viral infection and replication but instead are secondary to the host immune response. HCV results in upregulation of the host humoral immune system with the subsequent generation of monoclonal and polyclonal autoantibodies. These antibodies form immune complexes that deposit in small- and medium-sized blood vessels of various organs where complement activation results in extrahepatic injury (12, 13). Some extrahepatic manifestations can improve with HCV treatment and even resolve after successful eradication of the virus. However, there must be caution when administering
Extrahepatic Manifestations of Chronic Hepatitis C Infection Table 1 Extrahepatic Manifestations of Chronic Hepatitis C Infection Vascular: Type II cryoglobulinemia Lymphoproliferative disorders: Non-Hodgkin’s lymphoma Renal: Membranoproliferative glomerulonephritis Dermatological: Leukocytoclastic vasculitis Porphyria cutanea tarda Lichen planus Necrolytic acral erythema Endocrine: Thyroid abnormalities Diabetes mellitus Rheumatological: Polyarteritis nodosa Non-deforming polyarthritis Sicca syndrome Systemic lupus erythematosus Anti-phospholipid syndrome Autoantibodies Osteosclerosis Ophthalmological: Mooren ulcer Neurological: Peripheral neuropathy Cerebral vasculitis Neurocognitive dysfunction Pulmonary: Idiopathic pulmonary fibrosis Cardiac: Cardiomyopathy
137
138
Meyer and Bodenheimer Table 2 Prevalence of Leading Clinical Signs and Symptoms of Extrahepatic Manifestations of Chronic Hepatitis C Infection Arthralgia Sensory neuropathy Myalgia Pruritus Xerostomia Xerophthalmia
19–23% 9–17% 10–15% 6–15% 12% 10%
HCV therapy in patients with extrahepatic manifestations because some manifestations may be exacerbated during interferon therapy.
2. SPECTRUM OF EXTRAHEPATIC MANIFESTATIONS 2.1. Vascular Cryoglobulins are immunoglobulins which reversibly precipitate in serum at low temperatures. There are three types of cryoglobulins: I, II, and III (14). Type I cryoglobulins are either monoclonal IgG or IgM, type II consists of two or more classes of immunoglobulin of which one is monoclonal IgM with rheumatoid factor activity; type III also consists of two or more classes of immunoglobulin with polyclonal IgM, demonstrating rheumatoid factor activity or anti-IgG activity. Type II is also called mixed essential cryoglobulinemia and is found in more than half of patients chronically infected with HCV (15–17), of whom only 10% are symptomatic (5, 17, 18). Cryoglobulins are more commonly found in HCV patients with cirrhosis, high viral load, and longer duration of disease (19–21). HCV genotype is not associated with the prevalence of cryoglobulinemia (22–24). The production of cryoglobulins appears to be driven by chronic antigen stimulation of the host immune system by HCV (12). Patients with symptomatic cryoglobulinemia tend to be older, have longer duration of disease, higher levels of rheumatoid factor and cryoglobulins as compared to patients with asymptomatic cryoglobulinemia (25). The classical triad of symptoms in patients with HCV associated cryoglobulinemia is palpable purpura, weakness, and arthralgia. The most common skin manifestation of HCV-associated cryoglobulinemia is recurrent palpable purpura. Leg ulcers and nodules are less common
Extrahepatic Manifestations of Chronic Hepatitis C Infection
139
(5, 24). Palpable purpura is due to cryoglobulin-associated vasculitis with deposition of immune complexes in the small vessels of the skin (26). Symptomatic patients can also present with renal manifestations usually membranoproliferative glomerulonephritis due to deposition of immune complexes in the glomeruli of the kidney (15, 27–29). The next most commonly affected organ system is the nervous system. This commonly presents as symmetrical distal polyneuropathy. A less common presentation is mononeuritis multiplex (30). HCV RNA has been isolated from small- or medium-sized blood vessels of the affected nerves (30, 31). Diagnosis is usually made by identification of type II cryoglobulins in the serum. The diagnosis also can be made by detecting the immune complex of cryoglobulins and HCV antigen or RNA in the affected tissue. There can be false-negative results due to low serum concentration, errors in sample collection, or failure of the laboratory to detect the cryoglobulin (32). The goal of treatment of cryoglobulinemia is to eradicate the virus, not just to ameliorate the symptoms of cryoglobulinemia (33–35). Sustained loss of HCV is usually associated with persistent loss of cryoglobulinemia and long-term resolution of symptoms while relapse after HCV therapy results in the reappearance of cryoglobulins and symptoms (32, 33). Several randomized controlled trials have evaluated the addition of corticosteroids to antiviral therapy in symptomatic HCV-related cryoglobulinemia. Corticosteroids result in more rapid and longer-lasting virological response but no improvement in sustained virological response (SVR) (36). Plasmapheresis, high dose steroids, and/or immunosuppressive agents have been used in patients with severe HCV-related cryoglobulin vasculitis (37). Rituximab, a monoclonal antibody to CD20, has been shown to be effective in open-label studies in the treatment of cryoglobulin-related vasculitis refractory to interferon therapy (38–40).
2.2. Lymphoproliferative Disorders There is an association between chronic HCV particularly in patients with type II cryoglobulinemia and lymphoproliferative disorders (41). Up to 13% of patients with B-cell non-Hodgkin lymphoma (NHL) have HCV antibody (42). Furthermore, 10% of patients with mixed cryoglobulinemia, the vast majority of whom have chronic HCV, developed NHL over a 10-year follow-up period (27). The mechanism for this association is not yet established but is believed to be due to the binding of HCV E2 antigen to host CD81 receptor leading to B-cell proliferation (43, 44). Mutations, in certain genetically predisposed patients, develop in response to this chronic antigen stimulation and lead to
140
Meyer and Bodenheimer
monoclonal proliferation of B cells resulting in lymphoma (42). One possible genetic mutation is the t(18;14) translocation, which leads to overexpression of bcl-2 oncogene, resulting in inhibition of apoptosis of B cells (45). The monoclonal B cells proliferate in the liver and bone marrow. The association of NHL with HCV and mixed cryoglobulinemia is most commonly found in patients with follicular lymphoma and lymphoplasmacytoid/immunocytoma subtypes, which are low-grade lymphomas (46–48). In addition, there is a strong association of HCV and mucosa-associated lymphoid tissue (MALT) lymphoma (49, 50). The majority of HCV-related lymphomas are extranodal located mostly in the liver and salivary glands (51, 52). There are studies showing HCV therapy results in the regression of low-grade lymphoma particularly if there is eradication of the virus (53). Furthermore, Zuckerman and co-workers showed there is a loss of the t(18;14) mutation with interferon and ribavirin therapy, which correlated with eradication of the virus (54). High-grade lymphomas associated with HCV usually require chemotherapy.
2.3. Renal Membranoproliferative glomerulonephritis (MPGN) has the strongest association with HCV and near complete association with type II cryoglobulinemia (15). HCV RNA, in patients with MPGN, is found in antigen–antibody complexes in the bloodstream and glomeruli. HCV has also been reported to be associated to a lesser degree with membranous and proliferative glomerulonephritis, focal segmental glomerular sclerosis, fibrillary and immunotactoid glomerulopathy (27, 55, 56). MPGN usually is a late manifestation of HCV-associated cryoglobulinemia and typically presents with hypertension, nephrotic-range proteinuria, microscopic hematuria, rapid decline in renal function, or chronic renal insufficiency (57, 58). Renal manifestations are a leading contributor to morbidity and mortality in HCV-related cryoglobulinemia (58). Laboratory findings include circulating type II cryoglobulins and decreased C3 and C4 complement levels (15). HCV RNA is detected in the serum and there is 1,000-fold increase in HCV RNA level in cryoprecipitate as compared to the serum (59). There are subendothelial depositions in the glomeruli consisting of IgM with rheumatoid factor, IgG, and complement (30). Electron microscopy reveals cryoprecipitates containing HCV RNA and antibody to nucleocapsid core antigen (28).
Extrahepatic Manifestations of Chronic Hepatitis C Infection
141
HCV interferon monotherapy alone may ameliorate proteinuria and elevated serum creatinine levels found in these patients, however, relapse off therapy with the recurrence of viremia and MPGN commonly occurs (30, 32). The addition of short-term prednisone to interferon therapy has been shown to help control severe MPGN (60). Longterm usage of prednisone is associated with significant side effects and enhanced viral replication. There were concerns regarding the use of ribavirin in HCV in those with underlying renal disease resulting in severe hemolytic anemia. Sabry and coworkers treated 16 patients with interferon and ribavirin for 12 months after 3 months of interferon monotherapy (61). Seven patients had the dosage of ribavirin reduced mostly as a result of anemia. Only one patient cleared HCV while on therapy. There was no follow-up data but renal disease, viremia, albumin, and complement levels all significantly improved on therapy. Pegylated interferon is used in the treatment of patients with HCV-associated renal disease. In one report 4 patients were treated with pegylated interferon and ribavirin in cryoglobulin-related MPGN and 14 patients received standard interferon and ribavirin. Three of the four patients treated with pegylated interferon had response to treatment compared to 9 of 14 receiving standard interferon. Albumin levels improved in responders as compared to nonresponders; however, serum creatinine was stable in both groups (62). There are no established guidelines for the treatment of HCVassociated MPGN. All patients should be treated with pegylated interferon and ribavirin if renal function allows, since this combination of therapy has the highest sustained viral response rate. Plasmapheresis and steroid bolus can be used as treatment during acute or severe MPGN. Case reports have detailed long-term histological improvement in HCV-related renal disease if the virus is successfully eradicated. Recent case reports have treated HCV-related MPGN unresponsive to interferon therapy and immunosuppression with rituximab resulting in improvement in proteinuria accompanied by a decreased or stable HCV viral load (38, 63). Rituximab is theorized to be of benefit since it works on the CD20 antigen of B cells. B cells are the cells that sustain the type II mixed cryoglobulinemia (38–40).
2.4. Dermatological The prevalence rate of pruritus was 15% in the large prospective study performed by the MULTIVIRC group evaluating extrahepatic manifestations in patients with chronic HCV (4). The authors theorized the mechanism of the association of chronic HCV and pruritus
142
Meyer and Bodenheimer
is the formation of antibody–antigen complexes, which deposit in the skin. Treatments have included PUVA, bile salt-binding agents, ursodiol, and interferon therapy (64, 65). Leukocytoclastic vasculitis is vasculitis affecting small blood vessels in many organ systems including the skin and is characterized by palpable purpura and petechiae usually on the lower extremities. Vasculitis may also present with skin ulcers or livedo reticularis on the lower extremities. This syndrome may be due to the deposition of immune complexes in walls of small blood vessels. There is an association with chronic HCV via type II cryoglobulinemia. HCV antigens and RNA are detected in blood vessel walls seen on the skin biopsy of these lesions in approximately 40% of affected patients (26). During interferon therapy, there is improvement in the skin lesions and symptoms, which can completely resolve with sustained loss of the virus (65–67). Clinical response is associated with decrease in the serum cryoglobulin levels. Sustained viral response does not always guarantee clinical improvement. HCV therapy is more effective in treating the dermatological manifestations of type II cryoglobulinemia than the renal manifestations (60, 68). Interferon monotherapy often results in clinical improvement in the skin lesions; however, recurrence in skin lesions off therapy is common due to the low sustained viral response with interferon monotherapy (67, 69). Patients who achieve SVR with pegylated interferon and ribavirin enjoy long-term resolution of symptoms (35, 70). Combination of pegylated interferon with ribavirin presently is the preferred therapy of HCV-related type II cryoglobulinemia presenting with dermal manifestations. Porphyria cutanea tarda (PCT) is characterized by photosensitivity, skin fragility, vesicles, and bullae. In addition, there may be hyperor hypo-pigmentation and skin thickening. PCT typically is seen in conjunction with hepatic iron overload. There are two forms of porphyria cutanea tarda type 1 and 2. Type 1 is the more common sporadic form characterized by decreased uroporphyrinogen decarboxylase activity found only in the hepatocytes. Type 2 is the rare familial autosomal dominant form characterized by reduced uroporphyrinogen decarboxylase activity found in other cell types besides hepatocytes. There is a strong association between PCT and chronic HCV, in particular in Mediterranean countries (71, 72). The prevalence of HCV in type 1 PCT patients ranges from 57 to 91% (71–74). The mechanism by which HCV triggers type 1 PCT is not known since the virus does not directly affect uroporphyrinogen decarboxylase activity. Pathogenesis may be related to the iron overload in the liver commonly associated with HCV (75). Studies have shown improvement in dermatologic
Extrahepatic Manifestations of Chronic Hepatitis C Infection
143
manifestations with interferon therapy in some patients with PCT but not all, and patients with PCT may have a decreased response to interferon therapy (76). Lichen planus is a skin lesion characterized by flat-topped, violaceous papules that can present anywhere on the epidermis and may also involve the mucous membrane. Most cases of lichen planus are self-limited; however, oral lesions are more likely to be chronic and can even be pre-malignant. The prevalence of HCV in patients with lichen planus is 10–38% (77). This association between lichen planus and chronic HCV usually occurs in the setting of advanced liver disease (78). The pathogenesis of lichen planus is unknown but is thought to be T-cell immune mediated, and HCV-specific CD4 and CD8 T cells have been identified in the lesions of lichen planus (79). First line therapy for the treatment of cutaneous and oral lichen planus usually is topical or intralesional steroids and antihistamines for the cutaneous form and topical anesthetics for the oral form. Interferon therapy has a variable effect on lichen planus (80, 81). Other dermatological manifestations associated with chronic HCV include pyoderma gangrenosum, erythema nodusum, erythema multiforme, and urticaria (82–84). The pathogenic association of these syndromes with HCV is not well established. Necrolytic acral erythema is a rare condition associated with HCV that is characterized by sloughing skin lesions. It is reported to show improvement with a combination of interferon, ribavirin, and oral zinc (85, 86).
2.5. Endocrine Thyroid diseases, in particular autoimmune thyroid disease, are commonly associated with HCV. Hypothyroidism is seen in 3.5–13% of untreated chronic HCV patients (87, 88). The prevalence of thyroid antibodies is seen in up to 12.5% of HCV patients regardless of the stage of disease and is more prevalent in older women (88, 89). In addition, the prevalence of thyroid disease and thyroid antibodies is significantly higher in HCV patients with type II mixed cryoglobulinemia than the general population (90). Interferon therapy may induce anti-thyroid antibodies or unmask underlying thyroid disease including Hashimoto’s thyroiditis or Graves’ disease, which may not resolve after discontinuation of the interferon therapy (88, 89). Interferon-associated hypothyroidism is usually treated with hormone replacement. The development of hyperthyroidism on interferon therapy may require discontinuation of therapy (91). HCV patients, especially older women, are most at risk for the development of thyroid disease during interferon therapy particularly if
144
Meyer and Bodenheimer
they have elevated pre-treatment titers of anti-thyroid antibodies especially anti-thyroid peroxidase antibodies (92, 93).
2.6. Rheumatologic Arthralgia and myalgia are associated with chronic HCV. One large prospective cohort study of 1,614 chronic HCV patients reported a prevalence of arthralgia of 23% and myalgia of 15% (4). Arthralgia occurs more often in HCV patients with type II cryoglobulinemia than in those patients without cryoglobulinemia (4, 94). The prevalence of HCV-associated arthritis ranges from 4 to11% (95, 96). The most common presentation of HCV-associated arthritis is a symmetrical non-deforming polyarthritis most commonly affecting metacarpalphalangeal joints, proximal interphalangeal joints, wrists, and ankles (96). The prevalence of positive rheumatoid factor in HCV patients is reported to be as high as 75% but generally most of these patients do not have clinical features of rheumatoid arthritis (3, 19, 96). One diagnostic test to help differentiate HCV-associated arthritis with positive rheumatoid factor from true rheumatoid arthritis is serum antibodies to cyclic citrullinated peptides (anti-CCP), which will be positive in true rheumatoid arthritis (97–99). HCV-associated arthritis as compared to rheumatoid arthritis usually is less intense and does not result in joint deformities. The treatment of HCV-associated arthritis includes NSAIDs, steroids, hydroxychloroquine, and methotrexate (100, 101). Interferon therapy has been used to treat HCV-associated arthritis in patients who did not respond to other treatments (95). Clinical studies differ in the response rate to interferon therapy ranging from 17 to 76% (95). There are case reports of HCV associated with dermatomyositis and polymyositis (102, 103). The exact mechanism for this association of HCV and myositis is not clear; however, there is a report detailing the detection of HCV RNA in muscle fibers of two symptomatic patients suggesting that the myositis is a direct result of the HCV (104). There is a strong association between HCV and sicca syndrome, which is characterized by xerophthalmia and xerostomia due to lymphocytic sialoadenitis (105–107). This association is seen more in middle-aged women with long-standing hepatitis C (19). Approximately 10–19% of HCV patients have symptoms of sicca syndrome (4, 105–107). The prevalence of HCV in patients with sicca syndrome was 19% in one study (163). HCV-associated sicca syndrome differs from the classic Sj¨ogren syndrome by the lack of anti-SSA and anti-SSB antibodies and glandular tubule involvement (106, 108– 111). These patients tend to have milder histological findings of
Extrahepatic Manifestations of Chronic Hepatitis C Infection
145
lymphocytic sialoadenitis (grade I–II) than seen in the classical Sj¨ogren syndrome (106). The mechanism by which HCV results in sicca syndrome is not clearly established. The virus has not conclusively been shown to replicate in or directly infect salivary gland tissue (37, 105, 112). There may be molecular mimicry between the envelope E2 protein of HCV and salivary glands resulting in the stimulation of the host immune system against the salivary glands (113). Patients with HCV-related sicca syndrome frequently have cryoglobulins in the sera and lower complement levels than patients with classical or primary Sj¨ogren syndrome suggesting a host immune-mediated mechanism rather than direct effect of the virus (107, 109). HCV-associated sicca syndrome is reported to improve with combination IFN and RBV therapy, if SVR is achieved (114). Polyarteritis nodosa (PAN) is a necrotizing vasculitis of mediumsized arteries affecting multiple organs. The prevalence of HCV in patients with PAN ranges from 5 to 12% (115, 116). HCV-related PAN shares many clinical features with small-sized blood vessel vasculitis associated with type II cryoglobinemia including palpable purpura, arthralgia, myalgia, and peripheral neuropathy. However, PAN has a more significant association with life-threatening systemic vasculitis than does type II cryoglobulinemia, in the form of cerebral angiitis and ischemic abdominal pain (117). PAN patients with chronic HCV as compared that those without HCV have more cutaneous involvement, lower complement levels, and more advanced liver disease (115). HCV has been found in 6–13% of patients with systemic lupus erythematosus (SLE) (118–120). HCV-associated SLE had lower levels of complement, anti-dsDNA antibodies, and cutaneous involvement than SLE patients without chronic hepatitis C (119). Antiphospholipid syndrome is characterized by the triad of positive antiphospholid antibodies, thrombocytopenia, and a thrombotic event. Whether there is an association between hepatitis C and antiphospholipid syndrome is controversial (121, 122). Several reports have shown an association between hepatitis C infection and the presence of anti-cardiolipin antibodies, resulting in an increased prevalence of thrombocytopenia, portal hypertension, and thrombotic events (3, 121). The prevalence of anti2-glycoprotein-1 antibodies and clinical thrombosis; however, is much less in HCV than in patients with classical antiphospholipid syndrome (3, 122, 123). Osteosclerosis is a rare disorder characterized by diffuse bone pain with x-rays revealing sclerosis and thickening of long bone cortices. There are case reports associating chronic hepatitis C infection and osteosclerosis (124, 125).
146
Meyer and Bodenheimer
There is a high prevalence of autoantibodies ranging from 40 to 76% in patients with chronic hepatitis C infection (3, 126, 127). The most common autoantibodies in chronic hepatitis C infection are rheumatoid factor and cryoglobulins. Other autoantibodies with high prevalence include non-organ-specific autoantibodies such as antinuclear antibody, anti-smooth muscle antibody and anti-liver kidney microsomal type 1 antibody, and the organ-specific anti-thyroid antibodies. The association of autoantibodies and chronic HCV has not been shown to lead to a higher prevalence of autoimmune disease except in the setting of interferon therapy (128, 129). HCV patients with autoantibodies, in particular anti-thyroid antibodies, are at increased risk for precipitation or exacerbation of autoimmune disease during interferon therapy as opposed to those without autoantibodies (130, 131). There are reports of autoimmune cytopenias being associated with HCV in interferon treatment na¨ıve patients (132). The prevalence of HCV in patients with idiopathic thrombocytopenia (ITP) ranges from 10 to 19% (132, 133).
2.7. Neurological Peripheral neuropathy found in patients with chronic HCV is usually associated with type II cryoglobulinemia and has manifestations ranging from symmetrical distal polyneuropathy to mononeuritis multiplex (134). Peripheral neuropathy can be sensory, sensory-motor or rarely pure motor, symmetrical or asymmetrical. CNS involvement is very infrequently seen with type II cryoglobulinemia (135). White matter lesions are seen on magnetic resonance imaging in these patients, who suffer a higher rate of neurocognitive dysfunction than controls. The level of serum cryoglobulins correlate with the extent of impaired cognitive function. The mechanism of peripheral neuropathy is believed to be related to vasculitis from cryoglobulin deposition in small blood vessels supplying the nerves (32, 135). These patients present with serum cryoglobulins and decreased complement levels (135). Combination antiHCV consisting of pegylated or standard interferon with ribavirin has a high clinical response rate of up to 75% in treatment of cryoglobulinrelated vasculitis (34, 60, 65). Resolution of clinical symptoms including peripheral neuropathy and CNS abnormalities depends on whether SVR is achieved. Patients who relapse or do not respond to HCV therapy usually have neurological symptoms recur within months of stopping therapy. High dose intravenous steroids or plasma exchange may be used to treat life threatening organ involvement due to type II mixed cryoglobulinemia (34).
Extrahepatic Manifestations of Chronic Hepatitis C Infection
147
Hilsabeck and coworkers assessed neurocognitive dysfunction in HCV patients and found impairments in attention and psychomotor speed as compared to normative means but not to patients with alcoholic liver disease (136, 137). The authors showed greater cognitive dysfunction in patients with higher stages of fibrosis. Studies have evaluated brain metabolism in HCV patients with magnetic resonance spectroscopy (138, 139). In HCV patients with minimal hepatic fibrosis there was abnormal metabolism seen in the white matter and basal ganglia not seen in patients with chronic hepatitis B infection. A possible mechanism for abnormal brain metabolism seen in HCV patients is extrahepatic replication of HCV in the CNS. There is evidence showing replication of HCV in peripheral blood mononuclear cells (9, 140). These infected circulating monocytes may replace microglia that have turned over in the CNS (141). Negativestrand HCV RNA, a marker of extrahepatic replication of HCV has been found in various brain structures during autopsy (142). Genomic sequencing of the HCV found in brain tissue has been shown to contain mutations in the 5 end of the genome resulting in reduced translation and replication of the virus (143). The presence of HCV in the CNS may be an important mechanism for viral relapse after antiviral therapy. Another possible mechanism for CNS manifestations is the effect of cytokines derived from the host immune system in response to HCV. There has only been one study to date evaluating this theory, which showed no correlation between fatigue and circulating IL-1 and TNF levels (144). Fatigue is considered an extrahepatic manifestation of HCV (145). The prevalence of fatigue in untreated HCV patients ranged from 49 to 66% and is significantly more prevalent than in healthy controls (146, 147). The mechanism for HCV resulting in fatigue has not been established. Authors have suggested social and psychiatric factors may contribute to fatigue in HCV patients (148, 149). In a multi-center trial evaluating oral ribavirin monotherapy in the treatment of chronic hepatitis C, there was improvement in fatigue without decrease in the level of viremia (150).
2.8. Pulmonary Chronic HCV has been variably associated with idiopathic pulmonary fibrosis (IPF) (151, 152). The prevalence of anti-HCV antibodies in Italian patients with IPF was 13.3% (152).
148
Meyer and Bodenheimer
2.9. Cardiac Reports have shown an association between chronic HCV and hypertrophic and dilated cardiomyopathy (153). Prevalence of HCV ranged from 6.3 to 10.6% in dilated and hypertrophic cardiomyopathy patients, respectively, as compared to healthy volunteer blood donors. HCV RNA was detected in the heart on autopsy in 11.5 and 26% of patients with dilated and hypertrophic cardiomyopathy, respectively (154). The mechanism by which HCV results in cardiomyopathy has not been established.
3. CONCLUSIONS The main target of chronic HCV is the hepatocyte. However, there are many diverse extrahepatic manifestations of chronic HCV which are due to the activation of the host immune system in response to the infection. The extrahepatic manifestations that have clearly been shown to be associated with HCV are induced by formation of type II cryoglobulins due to chronic viral antigen stimulation of the host immune system. These extrahepatic manifestations are potentially curable with successful eradication of the virus after HCV treatment. The less established extrahepatic manifestations of HCV are of uncertain pathogenesis and usually have only epidemiologic data supporting the association.
REFERENCES 1. Pascual M., Perrin L., Giostra E, Schifferli JA. Hepatitis C virus patients with cryoglobulinemia type II. J Infect Dis 1990;162:569–70. 2. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of HCV infection in the United States, 1988 through 1994. N Engl J Med 1999 Aug 19;341(8): 556–62. 3. Cacoub P, Renou C., Rosenthal E., et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine 2000;79:47–56. 4. Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum 1999 Oct;42(10):2204–12. 5. Vassilopoulos D, Calbrese LH. Hepatitis C virus infection and vasculitis. Implications of antiviral and immunosuppressive therapies. Arthritis Rheum 2002;46:585–97. 6. Ferri C, Monti M, LaCivita L, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993 Dec 15;82(12):3701–4. 7. Muller HM, Pfaff E, Goeser T, et al. Peripheral blood leukocytes serve as a possible extrahepatic site for hepatitis C virus replication. J Gen Virol 1993 Apr;74 (Pt 4):669–76.
Extrahepatic Manifestations of Chronic Hepatitis C Infection
149
8. Zignego A, Macchia D, Monti M, et al. Infection of peripheral mononuclear blood cells by hepatitis C virus. J Hepatol 1992 Jul;15(3):382–6. 9. Lerat H, Rumin S, Habersetzer F, et al. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 1998 May 15;91(10):3841–9. 10. Blackard JT, Kemmer N, Sherman KE. Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences. Hepatology 2006 Jul;44(1):15. 11. Sangar D, Carroll A. A tale of two strands: reverse-transcriptase polymerase chain reaction detection of HCV replication. Hepatology 1998 Nov;28(5): 1173–6. 12. Ferri C, Zignego AL, Pileri SA, et al. Cryoglobulins. J Clin Pathol 2002 Jan;55(1):4 13. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol 2006 Jan;18(1):54–63. 14. Brouet JC, Clauvel JP, Danon F. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 1974 Nov;57(5):775–88. 15. Misiani F, Bellavita P, Fenili D et al. HCV infection in patients with essential mixed cryoglobinemia. Ann Intern Med 1991;117:573–7. 16. Agnello V, Chung RT, Kaplan LM. A role for HCV infection in type II cryoglobulinemia. N Engl J Med 1992 Nov 19;327(21):1490–5. 17. Ferri C, Zignego AL. Relation between infection and autoimmunity in mixed cryoglobulinemia. Curr Opin Rheumatol 2000 Jan;12(1):53–60. 18. Debandt M, Ribard P, Meyer O et al. Type II IgM monoclonal cryoglobulinemia and HCV infection. Clin Exp Rheumatol 1991,9:659–660. 19. Pawlotsky JM, Roudot-Thoraval F, Simmonds P, et al. Extrahepatic immunologic manifestations in chronic HCV and HCV serotypes. Ann Intern Med 1995 Feb 1;122(3):169–73. 20. Zignego AL, Ferri C, Giannini C, et al. HCV genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 1996 Jan 1;124(1 Pt 1):31–4. 21. Kayali Z, Buckwold VE, Zimmerman B, et al. Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis. Hepatology 2002 Oct;36(4 Pt 1):978–85. 22. Frangeul L, Musset L, Cresta P, et al. HCV genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia. J Hepatol 1996 Oct;25(4):427–32. 23. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of HCV and liver damage. Gastroenterology 1994 May;106(5):1291–300. 24. Sene D, Ghillani-Dalbin P, Thibault V, et al. Long term course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol 2004 Nov;31(11):2199–206. 25. Vassilopoulos D, Younossi ZM, Hadziyannis E, et al. Study of host and virological factors of patients with chronic HCV infection and associated laboratory or clinical autoimmune manifestations. Clin Exp Rheumatol 2003 Nov–Dec;21(6 Suppl 32):S101 26. Sansonno D, Cornacchiulo V, Iacobelli AR, et al. Localization of HCV antigens in liver and skin tissues of chronic HCV-infected patients with mixed cryoglobulinemia. Hepatology 1995 Feb;21(2):305–12. 27. Yamabe H, Johnson RJ, Gretch DR, et al. HCV infection and membranoproliferative glomerulonephritis in Japan. Am Soc Nephrol 1995 Aug;6(2):220–3.
150
Meyer and Bodenheimer
28. Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with HCVHCVHCV infection. N Engl J Med 1993 Feb 18;328(7):465–70. 29. Johnson RJ, Gretch DR, Couser WG, et al HCVHCVHCV-associated glomerulonephritis. Effect of alpha-interferon therapy. Kidney Intl 1994 Dec;46(6): 1700–4. 30. Authier FJ, Bassez G, Payan C, et al. Detection of genomic viral RNA in nerve and muscle of patients with HCV neuropathy. Neurology 2003 Mar 11;60(5):808–12. 31. Ferri C, La Civita L, Cirafisi C, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol 1992 Jun;19(6):889–95. 32. Misiani R., Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with HCV. N Engl J Med 1994;330:751–6. 33. Cacoub P, Ratziu V, Myers RP, et al. Impact of treatment on extrahepatic manifestations in patients with chronic hepatitis C. J Hepatol 2002;36:812–8. 34. Cacoub P, Lidove O, Maisonobe T, et al. Interferon-alpha and ribavirin treatment in patients with HCV-related systemic vasculitis. Arthritis Rheum 2002 Dec;46(12):3317–26. 35. Cacoub P, Saadoun D, Limal N, et al. PEGylated interferon alfa-2b and ribavirin treatment in patients with HCVHCVHCV-related systemic vasculitis. Arthritis Rheum 2005 Mar;52(3):911–5. 36. Dammacco F, Sansonno D, Han JH, et al. Natural interferon-alpha versus its combination with 6-methyl prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood 1994;84: 3336–43. 37. Vassilopoulos D, Calabrese LH. Rheumatic manifestations of HCV infection. Curr Rheumatol Rep 2003 Jun;5(3):200–4. 38. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003 May 15;101(10):3827–34. 39. Lamprecht P. Lerin-Lozano C, Merz H, et al. Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2003 Dec;62(12):1230–3. 40. Sansonno D, De Re V, Lauletta G, et al. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 2003 May 15;101(10):3818–26. 41. Rasul I, Shepherd FA, Kamel-Reid S, et al. Detection of occult low-grade Bcell non-Hodgkin’s lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia. Hepatology 1999 Feb;29(2):543–7. 42. Gisbert JP, Garcia-Buey L, Pajares JM, et al. Prevalence of HCV infection in Bcell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 2003 Dec;125(6):1723–32. 43. Flint M, McKeating JA. The role of the hepatitis C virus glycoproteins in infection. Rev Med Virol 2000;10:101–17. 44. Pileri P, Uematsu Y, Campagnoli S, et al. Binding of HCV to CD81. Science 1998 Oct 30;282(5390):938–41. 45. Zignego A, Giannelli F, Marrocchi ME, et al. T(14;18) translocation in chronic HCV infection. Hepatology 2000 Feb;31(2):474–9.
Extrahepatic Manifestations of Chronic Hepatitis C Infection
151
46. De Rosa G, Gobbo MI, De Renzo A, et al. High prevalence of HCV infection in patients with B-cell lymphoproliferative disorders in Italy. Am J Hematol 1997 Jun;55(2):77–82. 47. Mazzaro C, Zagonel V, Monfardini S, et al. HCV and non-Hodgkin’s lymphomas. Br J Haematol 1996 Sep;94(3):544–50. 48. Silvestri F, Pipan C, Barillari G, et al. Prevalence of HCVHCVHCV infection in patients with lymphoproliferative disorders. Blood 1996 May 15;87(10): 4296–301. 49. De Vita S, De Re V, Sansonno D, et al. Gastric mucosa as an additional extrahepatic localization of HCV viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis. Hepatology 2000 Jan;31(1):182–9. 50. Luppi M, Longo G, Ferrari MG, et al. Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br J Haematol 1996 Aug;94(2):373–5. 51. De Vita S, Sacco C, Sansonno D, et al. Characterization of overt B-cell lymphomas in patients with HCV infection. Blood 1997 Jul 15;90(2):776–82. 52. De Vita S, Zagonel V, Russo A, et al. HCV non-Hodgkin’s lymphomas and hepatocellular carcinoma. Br J Cancer 1998 Jun;77(11):2032–5. 53. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of HCV infection. N Engl J Med 2002 Jul 11;347(2):89–94. 54. Zuckerman E, Zuckerman T, Sahar D, et al. The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with HCV infection. Blood. 2001 Mar 15;97(6):1555–9. 55. Stehman-Breen C, Alpers CE, Fleet WP, et al. Focal segmental glomerular sclerosis among patients infected with HCV Nephron 1999 Jan;81(1):37–40. 56. Markowitz GS, Cheng JT, Colvin RB, et al. Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 1998 Dec;9(12):2244–52. 57. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Intl 1995 Feb;47(2):618–23. 58. D’Amico G. Renal involvement in HCVHCVHCV: cryoglobulinemic glomerulonephritis. Kidney Int 1998 Aug;54(2):650–71. 59. Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006 Feb;69(3):436–9. 60. Zuckerman E, Keren D, Slobodin G, et al. Treatment of refractory, symptomatic, HCVHCVHCV related mixed cryoglobulinemia with ribavirin and interferonalpha. J Rheumatol 2000 Sep;27(9):2172–8. 61. Sabry AA, Sobh MA, Sheaashaa HA, et al. Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy. Nephrol Dial Transplant 2002 Nov;17(11):1924–30. 62. Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in HCVassociated cryoglobulinemic MPGN. Am J Kidney Dis 2004 Apr;43(4):617–23. 63. Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 2004 Dec;19(12):3054–61. 64. Kanazawa K, Yaoita H, Tsuda F, et al. Association of prurigo with HCV infection. Arch Dermatol 1995 Jul;131(7):852–3.
152
Meyer and Bodenheimer
65. Casato M, Lagana B, Antonelli G, et al. Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood 1991 Dec 15;78(12):3142–7. 66. Naarendorp M, Kallemuchikkal U, Nuovo GJ. Longterm efficacy of interferonalpha for extrahepatic disease associated with HCV infection. J Rheumatol 2001 Nov;28(11):2466–73. 67. Ferri C, Marzo E, Longombardo G, et al. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 1993 Mar 1;81(5):1132–6. 68. Calleja JL, Albillos A, Moreno-Otero R, et al. Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in HCVHCVHCVassociated symptomatic mixed cryoglobulinaemia. Aliment Pharmacol Ther 1999 Sep;13(9):1179–86. 69. Mazzaro C, Pozzato G, Moretti M, et al. Long-term effects of alphainterferon therapy for type II mixed cryoglobulinemia. Haematologica. 1994 Jul– Aug;79(4):342–9. 70. Mazzaro C, Zorat F, Caizzi M, et al. Treatment with peg-interferon alfa-2b and ribavirin of HCV-associated mixed cryoglobulinemia: a pilot study. J Hepatol 2005 May;42(5):632–8. 71. DeCastro M, Sanchez J, Herrera JF, et al. HCV antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 1993 Apr;17(4):551–7. 72. Gisbert JP, Garcia-Buey L, Pajeres JM, et al. Prevalence of HCV infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol 2003 Oct;39(4):620–7. 73. Navas S, Bosch O, Castillo I, et al. Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospective study. Hepatology 1995 Feb;21(2): 279–84. 74. Fargion S, Poierno A, Cappellini MD, et al. HCV and porphyria cutanea tarda: evidence of a strong association. Hepatology 1992 Dec;16(6):1322–6. 75. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998 Jun;27(6):1661–9. 76. Okano J, Horie Y, Kawasaki H, et al. Interferon treatment of porphyria cutanea tarda associated with chronic hepatitis type C. Hepatogastroenterology 1997 Mar–Apr;44(14):525–8. 77. Sanchez-Perez J, DeCastro M, Buezo GF, et al. Lichen planus and HCV: prevalence and clinical presentation of patients with lichen planus and HCV infection. Br J Dermatol 1996 Apr;134(4):715–9. 78. Jubert C, Pawlotsky JM, Pouget F, et al. Lichen planus and HCVHCVHCV – related chronic active hepatitis. Arch Dermatol 1994 Jan;130(1):73–6. 79. Pilli M, Penna A, Zerbini A, et al. Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response. Hepatology 2002 Dec;36(6):1446–52. 80. Areias J, Velho GC, Cerqueira R, et al. Eur J Gastroenterol Hepatol 1996 Aug;8(8):825–8. Lichen planus and chronic hepatitis C: exacerbation of the lichen under interferon-alpha-2a therapy. 81. Doutre MS, Beylot C, Couzigou P, et al. Lichen planus and virus C hepatitis: disappearance of the lichen under interferon alfa therapy. Dermatology 1992;184(3):229.
Extrahepatic Manifestations of Chronic Hepatitis C Infection
153
82. Reichel M, Mauro TM. Urticaria and hepatitis C. Lancet 1990 Sep 29;336(8718):822–3. 83. Domingo P, Ris J, Martinez E, et al. Erythema nodosum and hepatitis C. Lancet 1990 Dec 1;336(8727):1377. 84. Antinori S, Esposito R, Aliprandi CA, et al. Erythema multiforme and hepatitis C. Lancet 1991 Feb 16;337(8738):428. 85. Hivnor CM, Yan AC, Junkins-Hopkins JM, et al. Necrolytic acral erythema: response to combination therapy with interferon and ribavirin. J Am Acad Dermatol 2004 May;50(5 Suppl):S121–4. 86. Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol 2000 Jun;136(6):755–7. 87. Tran A, Quaranta JF, Benzaken S, et al. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic HCV before interferon therapy. Hepatology 1993 Aug;18(2):253–7. 88. Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, et al. Thyroid autoimmune disorders in patients with chronic HCV before and during interferon-alpha therapy. Clin Endocrinol (Oxf) 1996 Jun;44(6):635–42. 89. Carella C, Amato G, Biondi B, et al. Longitudinal study of antibodies against thyroid in patients undergoing interferon-alpha therapy for HCV chronic hepatitis. Horm Res 1995;44(3):110–4. 90. Antonelli A, Ferri C, Fallahi P, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM 2004 Aug;97(8):499–506. 91. Roti E, Minelli R, Giuberti T, et al. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferonalpha. Am J Med 1996 Nov;101(5):482–7. 92. Nagayama Y, Ohta K, Tsuruta M, et al. Exacerbation of thyroid autoimmunity by interferon alpha treatment in patients with chronic viral hepatitis: our studies and review of the literature Endocr J 1994 Oct;41(5):565–72 93. Kodama T, Katabami S, Kamijo K, et al. Development of transient thyroid disease and reaction during treatment of chronic HCV with interferon. J Gastroenterol 1994 Jun;29(3):289–92. 94. Lovy MR, Starkebaum G, Uberoi S, et al. HCV presenting with rheumatic manifestations: a mimic of rheumatoid arthritis. J Rheumatol 1996 Jun;23(6):979–83. 95. Zuckerman E, Keren D, Rozenbaum M, et al. HCV related arthritis: characteristics and response to therapy with interferon alpha. Clin Exp Rheumatol 2000 Sep–Oct;18(5):579–84. 96. Rosner I, Rozenbaum M, Toubi E, et al. The case for HC Varthritis. Semin Arthritis Rheum 2004 Jun;33(6):375–87. 97. Lienesch D, Morris R, Metzger A, et al. Absence of cyclic citrullinated peptide antibody in nonarthritic patients with chronic HCV. J Rheumatol 2005 Mar;32(3):489–93. 98. Bombardieri M, Alessandri C, Labbadia G, et al. Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with rheumatoid arthritis from patients with chronic HCV-associated polyarticular involvement. Arthritis Res Ther 2004;6(2):R137–41. 99. Wener MH, Hutchinson K, Morishima C, et al. Absence of antibodies to cyclic citrullinated peptide in sera of patients with HCV infection and cryoglobulinemia. Arthritis Rheum 2004 Jul;50(7):2305–8.
154
Meyer and Bodenheimer
100. Palazzi C, Olivieri I, Cacciatore P, et al. Management of HCV-related arthritis. Expert Opin Pharmacother 2005 Jan;6(1):27–34. 101. Nissen MJ, Fontanges E, Allam Y, et al. Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon. Rheumatology (Oxford) 2005 Aug;44(8): 1016–20. 102. Ferri C, La Civita L, Fazzi B, et al. Polymyositis, lung fibrosis, and cranial neuropathy in a patient with HCVHCVHCV infection. Arthritis Rheum 1996 Jun;39(6):1074–5. 103. Nishikai M, Miyairi M, Kosaka S, et al. Dermatomyositis following infection with HCV. J Rheumatol 1994 Aug;21(8):1584–5. 104. Ito H, Ito H, Nagano M, et al. In situ identification of HCV RNA in muscle. Neurology 2005 Mar 22;64(6):1073–5. 105. Verbaan H, Carlson J, Eriksson S, et al. Extrahepatic manifestations of chronic HCV and the interrelationship between primary Sj¨ogren’s syndrome and HCV in Swedish patients. J Intern Med 1999 Feb;245(2):127–32. 106. Haddad J, Deny P, Munz-Gotheil C, et al. Lymphocytic sialadenitis of Sj¨ogren’s syndrome associated with chronic HCV liver disease. Lancet 1992 Feb 8;339(8789):321–3. 107. Ramos-Casals M, Garcia-Carrasco M, Cervera R, et al. HCV infection mimicking primary Sj¨ogren syndrome. A clinical and immunologic description of 35 cases. Medicine (Baltimore). 2001 Jan;80(1):1–8. 108. Jorgensen C, Legouffe MC, Perney P, et al. Sicca syndrome associated with HCV infection. Arthritis Rheum 1996 Jul;39(7):1166–71. 109. Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren syndrome associated with HCV: a multicenter analysis of 137 cases. Medicine (Baltimore). 2005 Mar;84(2):81–9. 110. Pawlotsky JM, Ben Yahia M, Andre C, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 1994 Apr;19(4):841–8. 111. King PD, McMurray RW, Becherer PR. Sj¨ogren’s syndrome without mixed cryoglobulinemia is not associated with HCV infection. Am J Gastroenterol 1994 Jul;89(7):1047–50. 112. Toussirot E, Le Huede G, Mougin C, et al. Presence of HCV RNA in the salivary glands of patients with Sj¨ogren’s syndrome and HCV infection. J Rheumatol 2002 Nov;29(11):2382–5. 113. Koike K, Moriya K, Ishibashi K, et al. Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for HCV envelope genes. Proc Natl Acad Sci USA 1997 Jan 7;94(1):233–6. 114. Doffoel-Hantz V, Loustaud-Ratti V, Ramos-Casals M, et al. Evolution of Sj¨ogren syndrome associated with HCV when chronic HCV is treated by interferon or the association of interferon and ribavirin Rev Med Interne 2005 Feb;26(2):88–94. French 115. Carson CW, Conn DL, Czaja AJ, et al. Frequency and significance of antibodies to HCV in polyarteritis nodosa. J Rheumatol 1993 Feb;20(2):304–9. 116. Cacoub P, Lunel-Fabiani F, Du LT, et al. Polyarteritis nodosa and HCVHCVHCV infection. Ann Intern Med 1992 Apr 1;116(7):605–6. 117. Cacoub P, Maisonobe T, Thibault V, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001 Jan;28(1):109–18.
Extrahepatic Manifestations of Chronic Hepatitis C Infection
155
118. Marchesoni A, Battafarano N, Podico M, et al. HCV antibodies and systemic lupus erythematosus. Clin Exp Rheumatol 1995 Mar–Apr;13(2):267. 119. Ramos-Casals M, Font J, Garcia-Carrasco M, et al. HCV infection mimicking systemic lupus erythematosus: study of HCV infection in a series of 134 Spanish patients with systemic lupus erythematosus. Arthritis Rheum 2000 Dec;43(12):2801–6. 120. Kowdley KV, Subler DE, Scheffel J, et al. HCV antibodies in systemic lupus erythematosus. J Clin Gastroenterol 1997 Sep;25(2):437–9. 121. Prieto J, Yuste JR, Beloqui O, et al. Anticardiolipin antibodies in chronic hepatitis C: implication of HCV as the cause of the antiphospholipid syndrome. Hepatology 1996 Feb;23(2):199–204. 122. Cacoub P, Musset L, Amoura Z, et al. Anticardiolipin, anti-beta2-glycoprotein I, and antinucleosome antibodies in HCV infection and mixed cryoglobulinemia. Multivirc Group. J Rheumatol 1997 Nov;24(11):2139–44. 123. Casals M, Cervera R, Lagrutta M, et al. Clinical features related to antiphospholipid syndrome in patients with chronic viral infections (HCV/HIV infection): description of 82 cases. Clin Infect Dis 2004 Apr 1;38(7):1009–16. 124. Khosla S, Hassoun AA, Baker BK, et al. Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults. J Clin Invest 1998 May 15;101(10):2165–73. 125. Manganelli P, Giuliani N, Fietta P, et al. OPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key? Clin Rheumatol 2005 Jun;24(3):296–300. 126. Czaja AJ, Carpenter H, Santrach PJ Immunologic features and HLA associations in chronic viral hepatitis. Gastroenterology 1995 Jan;108(1):157–64. 127. Fried MW, Draguesku JO, Shindo M, et al. Clinical and serological differentiation of autoimmune and HCVHCVHCV-related chronic hepatitis. Dig Dis Sci 1993 Apr;38(4):631–6. 128. Clifford BD, Donahue D, Smith L, et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995 Mar;21(3):613–9. 129. Bayraktar Y, Bayraktar M, Gurakar A, et al. A comparison of the prevalence of autoantibodies in individuals with chronic HCV and those with autoimmune hepatitis: the role of interferon in the development of autoimmune diseases. Hepatogastroeneterology 1997 Mar–Apr;44(14):417–25. 130. Custro N, Montalto C, Scafidi V, et al. Prospective study on thyroid autoimmunity and dysfunction related to chronic HCV and interferon therapy. J Endocrinol Invest 1997;20:374–80. 131. Deutsch M, Dourakis S, Manesis EK, et al. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa therapy. Hepatology 1997 Jul;26(1):206–10. 132. Silva M, Li X, Cheinquer H, et al. HCV-associated idiopathic thrombocytopenic purpura (ITP). Gastroenterology 1992;102:A889. 133. Pawlotsky JM, Bouvier M, Fromont P, et al. HCV infection and autoimmune thrombocytopenic purpura. J Hepatol 1995 Dec;23(6):635–9. 134. Lidove A, Cacoub P, Maisonobe T, et al. HCV infection with peripheral neuropathy is not always associated with cryoglobulinaemia. Ann Rheum Dis 2001 Mar;60(3):290–2.
156
Meyer and Bodenheimer
135. Tembl JI, Ferrer JM, Sevilla MT, et al. Neurologic complications associated with HCV infection. Neurology 1999 Sep 11;53(4):861–4. 136. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002 Feb;35(2):440–6. 137. Hilsabeck RC, Hassanein TI, Carlson MD, et al. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J Int Neuopsychol Soc 2003 Sep;9(6):847–54. 138. Weissenborn K, Krause J, Bokemeyer M, et al. HCVHCVHCV infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 2004 Nov;41(5):845–51.2005 139. Forton DM, Taylor-Robinson SD, Thomas HC, et al. Central nervous system changes in HCV infection. Eur J Gastroenterol Hepatol 2006 Apr;18(4): 333–8. 140. Forton DM, Allsop JM, Main J, et al. Evidence for a cerebral effect of the HCV. Lancet 2001 Jul 7;358(9275):38–9. 141. Laskus T, Radkowski M, Wang LF, et al. Uneven distribution of HCV quasispecies in tissues from subjects with end-stage liver disease: confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication. J Virol 2000 Jan;74(2):1014–7. 141. Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience. 1992;48(2):405–15. 142. Radkowski M, Wilkinson J, Nowicki M, et al. Search for HCV negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 2002 Jan;76(2):600–8. 143. Forton DM, Karayiannis P, Mahmud N, et al. Identification of unique HCV quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 2004 May;78(10):5170–83. 144. Gershon A, Margulies M, Gorczynski R, et al. Serum cytokine values and fatigue in chronic HCVHCVHCV. J Viral Hepatol 2000 Nov;7(6):397–402. 145. Poynard T, Cacoub P, Ratziu V, et al. Fatigue in patients with chronic hepatitis C. J Viral Hepat 2002 Jul;9(4):295–303. 146. Barkhuizen A, Rosen HR. Wolf S, et al. Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients. Am J Gastroenterol 1999 May;94(5):1355–60. 147. Kramer L, Hofer H, Bauer E, et al. Relative impact of fatigue and subclinical cognitive brain dysfunction on health-related quality of life in chronic HCV. AIDS 2005 Oct;19 Suppl 3:S85–92. 148. Hilsabeck RC, Hassanein TI, Perry W. Biopsychosocial predictors of fatigue in chronic hepatitis C. J Psychosom Res 2005 Feb;58(2):173–8. 149. Dwight MM, Kowdley KV, Russo JE, et al. Depression, fatigue, and functional disability in patients with chronic hepatitis C. J Psychosom Res 2000 Nov;49(5):311–7. 150. Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997 Aug;26(2):473–7. 151. Ueda T, Ohta K, Suzuki N, et al. Idiopathic pulmonary fibrosis and high prevalence of serum antibodies to HCV. Am Rev Respir Dis 1992 Jul;146(1): 266–8.
Extrahepatic Manifestations of Chronic Hepatitis C Infection
157
152. Meliconi R, Andreone P, Fasano L et al. Incidence of HCV infection in Italian patients with idiopathic pulmonary fibrosis. Thorax 1996 Mar;51(3):315–7. 153. Matsumori A, Matoba Y Sasayama S, et al. Dilated cardiomyopathy associated with HCV infection. Circulation 1995 Nov 1;92(9):2519–25.
Anti-HCV Agents in Development Ketan Kulkarni, MD and Ira M. Jacobson, MD CONTENTS I NTRODUCTION L IFE C YCLE AND S TRUCTURE OF HCV C URRENT T HERAPY OF C HRONIC HCV I NFECTION R EFINEMENT OF C URRENT T HERAPY S PECIFICALLY TARGETED A NTIVIRAL T HERAPY (STAT-C) D RUGS TARGETING THE H OST C ELL N ONSPECIFIC I MMUNOMODULATORS H EPATITIS C V IRUS VACCINATION C ONCLUSION R EFERENCES
Key Principles
• Almost half of all patients with chronic hepatitis C infection will not clear the virus with currently available therapy. • Advances in the understanding of HCV biology are allowing investigators to develop novel therapies designed to specifically target the hepatitis C virus.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 6, C Humana Press, a part of Springer Science+Business Media, LLC 2009
159
160
Kulkarni and Jacobson
• Specifically Targeted Antiviral Therapy for HCV (STAT-C) includes orally available small molecules, such as protease and polymerase inhibitors. • Early data have demonstrated the high antiviral activity of several STAT-C agents, although the emergence of resistance to such agents has also been identified. • The use of protease or polymerase inhibitors in combination with pegylated interferon (PEG-IFN) and ribavirin increases antiviral activity while also suppressing the selection of resistant variants. Therefore PEG-IFN, and probably ribavirin, will continue to remain a mainstay of HCV treatment for the foreseeable future. • The antiviral potency of agents in development will not only improve the rate of sustained virologic response but will likely also allow for a shorter duration of therapy. • Other emerging antiviral therapies include novel interferons, alternatives to ribavirin, nonspecific immunomodulators, and therapeutic vaccines for HCV. • Additional approaches for HCV therapy being investigated include compounds targeting intracellular host factors that play a role in viral replication or virion production. • The ultimate goal in the long term is to use combinations of new drugs that can completely eradicate HCV with minimal toxicity and possibly avoid the need for interferon.
1. INTRODUCTION Chronic hepatitis C virus (HCV) is a major public health problem and the leading cause of death from liver disease in the United States, affecting at least three million Americans (1). HCV is typically transmitted through contact with blood or blood products. Since the advent of serologic testing for HCV, recipients of blood products have been at very low risk of HCV infection, and even the rate of new hepatitis C infections among intravenous drug users has dramatically decreased (2). However, given the large number of people infected many years ago and the significant number of new infections that still occur, a large burden of chronic hepatitis C infection, increasingly culminating in advanced liver disease and hepatocellular carcinoma, will continue to exist. Acute infection with HCV is usually subclinical. Chronic infection develops in about 75% of individuals infected (3). Six genotypes of HCV have been identified, with genotype 1 accounting for a majority
Anti-HCV Agents in Development
161
of cases in the United States. Cirrhosis develops in 20–30% of patients with chronic HCV infection, typically occurring after several decades of infection (3). Among patients with cirrhosis, hepatocellular carcinoma can occur in as many as 4% of patients per year (4). The treatment of chronic hepatitis C has improved dramatically since interferon alpha was first approved in 1991. However, a significant percentage of patients with chronic HCV infection are still not able to clear the virus and achieve a sustained virologic response with the currently available treatment, pegylated interferon (PEG-IFN) alfa-2a or alfa-2b combined with ribavirin, especially those with HCV genotype 1 infection (4). Studies focusing on the refinement of existing drugs, through the development of novel interferons or alternatives for ribavirin, are in progress. As we have gained greater insight into the life cycle of the hepatitis C virus, elucidated the crystal structures of critical viral enzymes such as the serine protease and polymerase, and refined in vitro systems, treatments capable of direct HCV inhibition have been developed. Specifically targeted antiviral therapies for HCV (STAT-C), consisting of small molecules that target the viral replication cycle, represent the most promising advance in antiviral treatment. Over the next decade, the options for antiviral therapy aimed at HCV infection are expected to greatly increase, entailing improved efficacy of treatment and possibly reduced duration of therapy. It is hoped that, in the long term, the development of novel antiviral therapy will allow for the potential replacement of interferon and/or ribavirin with their attendant toxicities.
2. LIFE CYCLE AND STRUCTURE OF HCV HCV is a small, single-stranded RNA virus belonging to the Hepacivirus genus of the Flaviviridae family (5). Similar to most RNA viruses, the hepatitis C virus within an infected individual exists as a population of quasispecies, which are diverse but closely related variants of the hepatitis C virus. Diversity within the genome of hepatitis C quasispecies is mainly the result of mutations produced by the errorprone RNA-dependent RNA polymerase (6). The presence of quasispecies provides HCV with a survival advantage, allowing for the selection of variants to adapt to changing conditions, including the immune response or, in the therapeutic setting, specifically targeted antiviral drugs. The evaluation of the HCV life cycle has been hindered by the lack of effective cell culture systems and animal models to study the hepatitis C virus. An efficient cell culture system depends upon the availability of a host cell that allows viral entry and subsequent production and release
162
Kulkarni and Jacobson
of virions capable of infecting other susceptible cells (7). The development of HCV replicon systems, which consist of genomic viral RNA that replicates from a single origin of replication, was a significant step forward in HCV research. Transfection of HCV RNA into a human hepatoma cell line, Huh-7, allowed investigators to study HCV replication first-hand (8). The development of HCV replicon systems has resulted in the creation of new cell culture lines that provide researchers the opportunity to better understand the HCV life cycle. More recently, a major advance occurred with the development of cell culture systems that can support the production of infectious virions derived from a patient with fulminant hepatitis caused by genotype 2 infection (9, 10). This is expected to greatly facilitate the study of all aspects of the viral life cycle, including entry, uncoating, replication, assembly, and release. As a corollary, the production of a robust system supporting HCV genotype 1 infection would be a highly desirable goal. The HCV genome is composed of a 9.6 kb single-strand of positivesense RNA flanked by untranslated regions on either end (5, 7). Translation of the RNA genome yields a polyprotein precursor that is processed by cellular and viral proteases to form ten mature proteins. The structural proteins include the core protein and envelope glycoproteins E1 and E2 that form the virus particle. The HCV core protein forms the viral nucleocapsid and is thought to interact with host cellular proteins to affect their function (5). The manner in which the core protein modulates cell signaling and gene transcription is yet to be elucidated. The envelope glycoproteins are transmembrane proteins that are instrumental for viral entry into the host cell by inducing fusion between the viral envelope and the host cell membrane. Several candidate cell surface receptors have been identified that appear to act as cofactors in viral entry, including claudin-1, CD81, and the LDL receptor (11–13). A variety of nonstructural proteins coordinate viral replication with two viral proteases (NS2-3 and NS3-4A) being responsible for cleavage and maturation of the nonstructural proteins (5–7). HCV NS3 is a multifunctional protein, which contains a helicase domain that unwinds duplex RNA structures and a serine protease activity requiring NS4A as a noncovalent cofactor (14). As mentioned above, the NS3 serine protease is important for polyprotein processing. Analogous to most RNA viruses, HCV forms a membrane-associated complex to mediate replication. This complex consists of viral proteins, the RNA to be replicated, and a variety of altered host cell factors. Critical to the formation of the membrane-associated replication complex is NS4B, which is capable of inducing the creation of membranous webs that act as sites for complex assembly (14). Synthesis of the viral RNA is accomplished by the NS5B RNA-dependent RNA polymerase, a viral enzyme
Anti-HCV Agents in Development
163
not possessed by normal human cells and thus making it an attractive target for investigators (5–7, 14).
3. CURRENT THERAPY OF CHRONIC HCV INFECTION The goal of therapy for chronic hepatitis C infection is to eradicate the virus and prevent progression of liver disease associated with HCV infection. Successful treatment of chronic HCV infection is best demonstrated by the presence of undetectable virus in the blood 6 months after completion of treatment, termed a sustained virologic response (SVR). Swain and colleagues demonstrated that over 99% of patients maintained their response after SVR over a 4-year period (15). Prior studies have also shown that successful treatment of HCV infection leads to a reduction in the incidence of HCC and a delay in progression of fibrosis and inflammation, thus providing a strong rationale for pursuing the most effective treatment possible (16, 17). The first approved therapy for HCV infection was recombinant interferon alfa-2b, a cytokine that can upregulate the innate antiviral immune response by activating a variety of transcription factors and signal transducers, leading to the induction of genes encoding RNAses and inhibitors of viral protein translation. IFN-␣ is also important in inducing the immune system via activation of natural killer cells and memory T cells (4). However, administration of standard IFN-␣ alone was largely ineffective, resulting in a sustained virologic response (SVR) in only 15% of patients following 12 months of therapy while also resulting in significant adverse effects (18). The addition of ribavirin to interferon was a significant step forward, improving the rate of SVR to 40% (19). Further advances were made with the advent of pegylated interferon alpha (PEG-IFN), achieving an SVR in 54–56% of patients overall, and 42–46% of patients with genotype 1 HCV infection when used in combination with ribavirin (20–22). Hadziyannis et al. demonstrated that weight-based dosing of ribavirin (1000 mg of RBV for body weight less than 75 kg and 1200 mg of RBV for individuals greater than 75 kg) results in better treatment outcome for patients infected with genotype 1 HCV (21). Further affirmation of the superiority of weight-based RBV dosing for genotype 1, this time in a dosing scale of 800–1400 mg/day, over a flat 800 mg dose was provided by a large US trial (23). Both of these trials demonstrated the equivalent efficacy of 24 and 48 weeks of therapy for patients with HCV genotypes 2 and 3 (21, 23). In order to have the best opportunity to achieve an SVR, patients need to reliably take as much of the prescribed amount of pegylated interferon and ribavirin as possible, namely, at least 80% of the dose over 80% of the duration of antiviral therapy (24). The use of hematopoietic
164
Kulkarni and Jacobson
growth factors in response to anemia and leukopenia may also improve adherence to therapy, but a beneficial effect of the use of these agents on sustained virologic response has not been demonstrated in randomized clinical trials. Studies with both of the pegylated interferons demonstrated that failure to achieve a 2-log reduction in viral load by 12 weeks predicted ultimate failure of therapy to attain SVR so strongly, with a negative predictive value of 97–100%, as to warrant discontinuation of treatment (22, 25). More recent studies have further evaluated the role of viral kinetics in tailoring the optimal length of therapy. Many patients with a rapid virologic response (RVR; undetectable viral load at 4 weeks of treatment) may be able to achieve an SVR with truncated therapy although early cessation of therapy may slightly impair the optimal chance of sustained response (26–28). Documentation of the rate at which a patient achieves an undetectable viral load, which correlates with the likelihood of SVR, is particularly helpful when managing the adverse effects that patients may experience during the course of therapy. Patients who experience significant adverse effects while on antiviral treatment can be offered a shorter duration of therapy with a reasonable, if not quite optimal, opportunity for SVR if a RVR had been achieved. Conversely, data have shown that individuals with a slow virologic response may benefit from extending the duration of therapy to prevent relapse. Four studies, despite variability in definition of a slow response, ribavirin dose, and peginterferon formulation, have shown that genotype 1-infected patients with slow response have augmented rates of SVR if treatment is extended to 72 rather than 48 weeks (29–32).
4. REFINEMENT OF CURRENT THERAPY 4.1. Novel Interferons It is clear that interferon will continue to play a major role in the treatment of HCV infection for the foreseeable future, and PEG-IFN has been the mainstay of antiviral therapy against hepatitis C. New formulations of interferon are being evaluated, however, in hopes of reducing adverse events, providing more convenient administration, and resulting in more effective outcomes. Consensus interferon (CIFN) Three Rivers Pharmaceuticals is a recombinant type 1 interferon that contains the most common amino acid at each of the 166 positions of the naturally occurring interferon alpha subtypes. CIFN was developed with the rationale of creating an interferon that might lead to an enhanced response against HCV infec-
Anti-HCV Agents in Development
165
tion (33). CIFN has been proposed to have a potential role in the management of patients who were nonresponders to previous therapy (34). Bacon and colleagues recently presented final data from a multicenter trial which demonstrated that daily CIFN combined with RBV resulted in rates of SVR of 5 and 10% with CIFN doses of 9 and 15 mcg, respectively, among patients who were nonresponders to the combination of PEG-IFN and RBV. The highest rates of response were in noncirrhotic patients with substantial declines in viral load with their previous course of PEG-IFN and RBV treatment (35). Albumin interferon is another novel interferon consisting of interferon alfa-2b fused to human serum albumin, thereby extending its half-life and allowing the drug to be administered every 2–4 weeks. A phase 2 trial in treatment na¨ıve patients demonstrated SVR rates after 48 weeks of therapy of 58, 58, 55, and 51% with PEG-IFN alfa-2a 180 mcg weekly, albinterferon 900 mcg every 2 weeks (q 2 week), albinterferon 1200 mcg every 2 weeks, and albinterferon 1200 mcg every 4 weeks, respectively. Interestingly, the patients who received albinterferon every 4 weeks overall had slower response rates but did not have the high relapse rates generally expected with “slow responders” (36). A study using various doses of albumin interferon in nonresponders to peginterferon and ribavirin yielded a pooled SVR rate of 17% (37). A recent phase 3 trial in genotype 1 patients (ACHIEVE 1) demonstrated that the SVR rate (48.2%) of albumin interferon 900 mcg given every 2 weeks was non-inferior to the SVR rate (51%) of PEG-IFN alfa 2a and ribavirin (37a). The rate of serious adverse events was similar in the two groups, although discontinuations due to adverse events were 10% for albumin interferon and 4.1% for PEG-IFN alfa-2a. In the companion study, for genotype 2 and 3 patients (ACHIEVE 2/3) SVR occurred in 79.8% of the albumin interferon 900 mcg recipients and 84.8% of those receiving PEG-IFN alfa 2a, again demonstrating statistical noninferiority. The difference in SVR in this study was driven by a very high rate of SVR (95%) in Asian patients receiving PEG-IFN alfa-2a (37b). Albumin interferon represents a potential alternative formulation of interferon allowing for less frequent dosing.
4.2. Alternatives to Ribavirin Ribavirin (RBV) is a guanosine analogue discovered in 1972 with broad-spectrum activity against several viruses. When administered as a monotherapy, RBV has minimal effect against HCV. However, in combination with interferon it has been shown to increase the viral suppression seen with interferon alone, and to reduce relapse rates. The mechanism by which ribavirin suppresses hepatitis C virus
166
Kulkarni and Jacobson
when used with interferon has not been clearly established. Potential mechanisms of action that have been invoked include direct inhibition of HCV replication, competitive inhibition of the enzyme inosine 5 -monophosphatase which is involved in the synthesis of guanine nucleosides, an immunomodulatory effect, and induction of mutagenesis (38, 39). Ribavirin is associated with dose-related hemolytic anemia, skin reactions, and is teratogenic. Therefore alternatives to ribavirin have been sought that may mimic RBV in its effectiveness but minimize its adverse effects. Taribavirin, previously called viramidine (Valeant), is a prodrug converted to ribavirin that becomes activated in the liver. Phase 3 trials of taribavirin demonstrated superior hematologic safety compared to ribavirin, although it was associated with inferior rates of SVR (40). It is possible that higher, weight-based dosing of taribavirin may result in better outcomes, with a study designed to evaluate this hypothesis under way.
5. SPECIFICALLY TARGETED ANTIVIRAL THERAPY (STAT-C) 5.1. Protease Inhibitors The most promising potential advance in the therapy of chronic HCV infection lies in the development of orally available small molecules that specifically target the HCV replication cycle, termed specifically targeted antiviral therapy (STAT-C). As discussed above, the NS3/4A protease cleaves the polyprotein precursor into structural and nonstructural proteins and is vital to the life cycle of hepatitis C. The active site of the enzyme is long and shallow, initially leading to concerns about potential difficulty in developing molecules that will bind to that area (5–7). However, the first protease inhibitor evaluated, BILN 2061, a macrocyclic compound developed by structure-based drug design, demonstrated potent antiviral activity, resulting in a 3-log reduction in the HCV viral load by day 2 of administration. Unfortunately, cardiac toxicity in a monkey model precluded further investigation of the drug (41). Since then several other protease inhibitors have been developed with significant potential to become key agents in antiviral therapy. Telaprevir (VX-950, Vertex Pharmaceuticals Inc.) inhibits the NS3/4A protease through the formation of a covalently bound complex at the active site of the enzyme. A phase 1b trial demonstrated an impressive 4.4-log median reduction in the hepatitis C viral load by day 14 among genotype 1-infected patients treated with telaprevir 750 mg every 8 hours (42). Resistant variants develop within 1 week of initia-
Anti-HCV Agents in Development
167
tion of therapy with telaprevir, indicating that monotherapy will not be a viable option (43). In another small trial, it was shown that additional viral suppression was conferred by the combination of peginterferon alfa-2a with telaprevir, with fewer resistant variants emerging, and that standard combination therapy after 14 days of telaprevir dosing suppressed resistant variants that emerged during the initial dosing period (44). Chu and colleagues recently presented their data evaluating the replication capacity of telaprevir-resistant variants. Compared to wildtype HCV, most resistant variants are not as replicatively fit, suggesting that resistant variants will tend to disappear after cessation of treatment and the viral population will revert back to wild-type predominance (45). However, the time required for this process to occur to the extent that all variants become undetectable, if this occurs at all, has yet to be documented. When used in combination with pegylated interferon and ribavirin in yet another phase 1 study, HCV RNA became undetectable in 12 of 12 subjects by 28 days of therapy (46). The initial findings with telaprevir led to two phase 2 multicenter trials evaluating the efficacy and safety of telaprevir, administered orally at a dose of 750 mg every 8 hours in treatment-naive HCV genotype 1infected individuals in the United States and Europe, respectively. In the US trial (PROVE 1), patients were treated with 48 weeks of pegylated interferon alfa-2a and ribavirin (n = 75), or with 12 weeks of telaprevir combined with pegylated alfa-2a and ribavirin followed by 36 weeks (n = 79) or 12 weeks (n = 79) of standard combination therapy, or no additional therapy (n = 17) (47). Patients were required to have an RVR to be eligible to stop therapy at 12 or 24 weeks. Of patients in the telaprevir groups, 79% had undetectable HCV RNA at week 4. The rate of SVR was 61% in the 24-week group and 67% in those patients receiving triple therapy for 12 weeks followed by 36 weeks of standard combination therapy. By comparison, 41% of patients receiving standard of care and 35% of those receiving triple therapy for 12 weeks achieved an SVR. Viral breakthrough occurred in 7% of patients receiving telaprevir. Discontinuation for adverse events occurred in 11% of the control patients and 21% of the patients in the three telaprevir-based groups, with rash the most common reason (47). In the PROVE2 study (48), there was a 48-week control group (n = 82) as in PROVE1, but there was no 48 week telaprevir-containing arm. Instead, there was an arm in which patients received 12 weeks of triple therapy followed by 12 weeks of standard combination therapy (n = 81), a larger group than in PROVE1 receiving 12 weeks of triple therapy alone (n = 82), and a 12 week treatment group receiving telaprevir and pegylated interferon alone (n = 78). Unlike PROVE1, patients were not required to have an RVR in order to stop at the pre-specified
168
Kulkarni and Jacobson
time points. In patients receiving triple therapy for only 12 weeks, SVR occurred in 60%, compared with 69% (representing follow-up week 12 results in the interim analysis). End of treatment response in the control group was pending at the time of writing. Although the SVR rates in the 12- and 24-week groups were numerically close, relapse occurred more frequently in the 12-week arm. In both the 12- and 24-week groups the importance of RVR in optimizing results was illustrated by the much lower rates of relapse in patients with RVR. One of the most impactful features of PROVE2 was the finding of a much lower rate of SVR (36%) in the ribavirin-free arm, in which lower early response rates, higher ontreatment breakthrough rates, and higher post-treatment relapse rates were all noted. The toxicity profile of telaprevir was similar to that in PROVE1 (48). Intriguing preliminary results from PROVE3, an international trial of telaprevir in patients who have failed previous treatment with PEGIFN and ribavirin, were reported recently. This study contained a total of 453 patients divided into four arms: standard of care with PEG-IFN alfa 2a and ribavirin for 48 weeks; telaprevir combined PEG-IFN and ribavirin for 12 weeks followed by PEG-IFN and ribavirin for 12 additional weeks; triple therapy for 24 weeks followed by 24 weeks of PEGIFN and ribavirin; and telaprevir with PEG-IFN alone for 24 weeks. In patients with prior nonresponse to PEG-IFN and ribavirin, the rate of HCV RNA undetectability 12 weeks after cessation of therapy in the treatment group receiving 12 weeks of triple therapy followed by 12 weeks of standard therapy were 41% in prior nonresponders and 72% in relapsers, but much lower in the ribavirin-free arm at 11% and 36% (48a). Phase 3 trials are ongoing to further evaluate the efficacy of telaprevir-based therapy in treatment na¨ıve patients and prior treatment failures and to determine the optimal duration of therapy. The results of the telaprevir trials thus far raise hopes for substantial improvements in rates of response for treatment na¨ıve genotype 1 patients with the additional potential benefit of shortened therapy duration, particularly for rapid responders. Moreover, the addition of telaprevir to retreatment regimens have the potential to induce SVR in many patients with prior treatment failure, including the majority of prior relapsers. Finally, the PROVE2 has affirmed the importance of ribavirin in treatment regimens containing STAT-C drugs. Boceprevir (SCH503034, Schering-Plough) is another protease inhibitor currently in phase 2 trials that has demonstrated potent suppression of HCV. In a double-blind, placebo-controlled trial, boceprevir resulted in a mean maximum 2-log reduction in viral load after 2 weeks of therapy among genotype 1-infected patients who had
Anti-HCV Agents in Development
169
previously failed PEG-IFN treatment (50). Data presented by Zeuzem and colleagues demonstrated dose-related antiviral activity with patients tolerating all doses tested. An open-label, crossover phase 1 study to investigate the combination of PEG-IFN and boceprevir demonstrated a mean maximal reduction in HCV RNA of 2.9-log at a dose of 400 mg of boceprevir every 8 hours (51). When used in combination with PEG-IFN, 4 of 10 nonresponders to prior therapy became HCV-RNA negative during treatment. Phase 2 trials were subsequently initiated in prior nonresponders, followed by a trial in treatment-na¨ıve patients. Sustained response rates from the nonresponder study were 2% of control patients retreated with PEG-IFN alfa-2b and RBV versus 7–14% of in various arms given boceprevir 800 mg tid (lower initial doses were increased on the basis of interim analyses), PEG-IFN alfa-2b and RBV (52). The final results from SPRINT-1, a large international study evaluating boceprevir in combination with PEG-IFN alfa-2b and ribavirin, have shown substantial increases in rates of SVR relative to standard therapy (52). The study was designed to evaluate two important concepts: first, whether a lead-in phase with standard therapy alone for four weeks followed by the addition of boceprevir would results in higher rates of response and less viral breakthrough by decreasing viral levels prior to addition of the protease inhibitor; second, whether shortened therapy would be equally effective as the standard duration. Patients in the two leadin arms received PEG-IFN alfa-2b and ribavirin for four weeks followed by triple therapy for either 24 or 44 additional weeks. Patients in the non-lead-in arms received either 24 or 48 weeks of triple therapy. Patients in a low dose ribavirin (400–1000 mg) received 48 weeks of triple therapy, and control (RBV 800–1400 mg) patients received treatment for 48 weeks. The SVR rates in SPRINT-1 were 38% in the control group, 36% in the low dose ribavirin group (further affirming the importance not only of ribavirin but the maintenance of the standard dose in STATC based regimens); 55% and 56% in the shorter duration arms without and with lead-in dosing, and 67% and 75% in the longer duration arms without and with lead-in dosing (52). Rates of viral breakthrough were higher without lead-in dosing. Greater reductions in hemoglobin occurred with boceprevir, and the use of erythropoietin was associated with higher rates of SVR, opening up a potential role for further exploration of growth factors as adjuncts to treatment. Lead-in dosing is an important feature of the ongoing phase 3 boceprevir development program. Concerns about the low SVR rates in the boceprevir phase 2 nonresponder study are mitigated by the fact that this was a boceprevir dose ranging study in which some arms were also ribavirin-free, and most of
170
Kulkarni and Jacobson
the patients were null responders. Thus, the phase 3 program focuses on both treatment na¨ıve patients and patients with prior treatment failure. For all HCV drugs it is important to establish safety of administration in patients with hepatic impairment, given that cirrhotic patients have the greatest need in the short term for effective treatment. Preston et al. demonstrated through pharmacokinetic studies that there is no significant difference in the plasma concentration of boceprevir among patients with increasing degree of hepatic dysfunction, laying a foundation for further exploration of this protease inhibitor in the treatment of cirrhotic patients (53).
5.2. Polymerase Inhibitors In addition to protease inhibitors, polymerase inhibitors have great promise as a potential therapy that is specific for the hepatitis C virus. The NS5B protein contains the RNA polymerase and has been a focus of antiviral therapy development. RNA polymerase inhibitors consist of two classes of molecules, nucleoside analogues and non-nucleoside inhibitors (54). Nucleoside analogues are converted to nucleoside triphosphates after entry into the cell and their incorporation by the RNA polymerase results in premature termination of RNA replication. Conversely, non-nucleoside inhibitors bind to one of several alternate sites that change the conformation of the polymerase and confer allosteric inhibition. The most extensively investigated polymerase inhibitor to date has been valopicitabine. Valopicitabine (NM283, Idenix Pharmaceuticals, Inc.) is a nucleoside analogue of cytidine. The development program for the drug initially centered on the concept of replacing ribavirin. Treatment-na¨ıve patients demonstrated an early virologic response in 68% of patients when valopicitabine was used in combination with PEG-IFN starting at week 2 of treatment (55). However, significant gastrointestinal toxicity occurred, particularly with higher doses. More recent data documented a 53% end of treatment response among treatment-na¨ıve patients administered PEG-IFN and valopicitabine (56). When compared to combination therapy with PEG-IFN and RBV, valopicitabine and PEG-IFN resulted in greater HCV RNA suppression in individuals who had previously failed standard therapy. However, no sustained responses occurred, and based on the efficacy and safety profile of the drug the US Food and Drug Administration halted its development in the summer of 2007. The non-nucleoside inhibitor HCV-796 has also progressed to phase 2 trials with encouraging results. An early phase 1 study among treatment-na¨ıve patients of all genotypes demonstrated a peak reduction
Anti-HCV Agents in Development
171
in HCV RNA at day 4, with viral rebound occurring in some patients (57). Further analysis of these patients documented the emergence of viral variants. Combination therapy with PEG-IFN and HCV-796 also demonstrated potent viral suppression in a 14-day randomized, placebo-controlled phase 1b study (58). Preliminary results from the phase 2 study showed that 73% of treatment na¨ıve and 23% of nonresponders achieved an undetectable HCV viral load after 12 weeks of combination therapy with HCV-796, pegylated interferon, and ribavirin, compared to 45% of treatment-na¨ıve patients that underwent standard of care. However, 8% of patients had significant elevations in transaminases and two patients developed jaundice. Therefore, dosing of HCV-796 was suspended pending continued observation to assess safety of the medication (59). Two additional nucleoside polymerase inhibitors under development are R1626 (Roche Laboratories) and R7128 (Pharmasset, Inc). Results from a phase 2a study demonstrated that 81% of patients receiving the combination of R1626 1500 mg bid with peg-interferon alfa-2a 180 g/wk and RBV 1000–1200 mg/day were HCV RNA negative by week 4, with a mean viral load reduction of 5.2-log 10 IU/mL (60). Lesser but still impressive viral load reductions were seen without RBV. Furthermore, there has been no evidence for resistance after 2 weeks of monotherapy or 4 weeks of combination treatment, thus suggesting that R1626 may have a high barrier to the development of resistant viral mutants (61). Although most adverse events were mild, grade 4 neutropenia occurred in 39% of those receiving triple combination therapy including R1626 1500 mg bid, and 78% of those receiving PEG-IFN alfa-2a with R1626 3000 mg bid, compared to 10% in the standard of care group (60). Further studies with modified doses of R1626 and/or PEG-IFN alfa-2a are in progress to determine the optimal dose of both R1626 and PEG-IFN alfa-2a that will maximize response while minimizing side effects. A salient feature of this development program thus far is the attainment of very high RVR rates rivaling those attained with protease inhibitors—a significant departure from a prevailing earlier concept that protease inhibitors are uniquely suppressive. (Note added in proof: The development of R1626 was halted after observations of hematologic and ocular complications in the phase 2 program). A Phase 1 study of R7128 monotherapy has likewise demonstrated impressive early results, with a mean 2.7-log10 decline in viral load after 2 weeks of therapy, without viral breakthrough, among patients that had previously failed an interferon-containing regimen (62). A phase 2 trial is in progress, with an early report indicating that PEGIFN alfa-2a, ribavirin, and R7128 1500 mg bid induced RVR in 85% of patients, reinforcing the viral suppressive potential of polymerase
172
Kulkarni and Jacobson
inhibitors when combined with PEG-IFN and RBV (62a). Gane and colleagues subsequently presented the results of a study in which prior non-responders or relapsers to IFN-based therapy were treated with 1500 mg of R7128 BID, PEG-IFN and ribavirin. An RVR was achieved in 90% of patients receiving triple therapy compared to 60% of patients receiving standard therapy (62b). Early development of other nonnucleosides with promising antiviral activity is in progress. The role of combining protease inhibitors with polymerase inhibitors has been evaluated by Bichko and colleagues, who found that valopicitabine has similar efficacy against wild-type virus and variants resistant to protease inhibitors (63). The utility of combining protease and polymerase inhibitors in the treatment of HIV has been clearly established and further studies are need to better elucidate the role of combination therapy for HCV infection. However, it stands to reason that using a combination of drugs with different targets within the HCV replication cycle will help to better suppress the emergence of resistant variants and thus better maintain suppression of the virus. A number of investigators have studied in vitro combinations of protease and polymerase inhibitors and demonstrated enhanced viral suppression, prevention of resistance, and suppression of pre-existing variants to one or the other drug in the combination (64–66).
5.3. Anti-HCV Nucleic Acids In addition to suppressing HCV by inhibiting proteins and enzymes important in the life cycle of the virus, researchers are developing new ways to target the HCV genome by silencing key genes of HCV through the use of anti-HCV nucleic acids. The most common sites of the HCV genome that are targeted by anti-HCV nucleic acids include the 5 and 3 untranslated regions of the genome, since they are highly conserved (67). Antisense oligonucleotides are short, single-stranded nucleic acids that bind to a target area within the RNA genome and interfere with its function, thereby silencing that part of the genome. Ribozymes are catalytically active RNA molecules that can be modified to targetspecific RNA molecules, thereby disrupting the HCV genome. Trials of both classes of agents were thought to show initial promise either preclinically or clinically (67, 68), but their development was halted for safety and/or efficacy concerns (69). Small interfering RNA molecules (siRNA) have been shown to have promising effects in in vitro systems. In order for the promise of anti-HCV nucleic acids, including siRNAs, to become a reality, however, the development of a safe and
Anti-HCV Agents in Development
173
efficient delivery system is required that will specifically target the tissue or organ of choice (70).
6. DRUGS TARGETING THE HOST CELL While much of the current research into novel therapies for HCV has focused on targeting viral proteins that are necessary for replication, work is also underway to evaluate drugs that target host factors, thereby indirectly disrupting the viral life cycle. By disrupting host cellular processes, rather than virus-specific pathways, the development of resistance may not be as significant a problem. Furthermore, since these drugs would work through a different mechanism of action than virusspecific therapies, a synergistic effect with other antiviral therapies may be possible. Nitazoxanide (Alinia, Romark Laboratories, L.C.) is a thiazolide with broad-spectrum activity against intestinal parasites and anaerobic bacteria (71). Currently approved in the US for giardiasis and cryptosporidiosis, the antiviral affect of nitazoxanide (NTZ) was first realized among patients being treated for chronic parasitic infection who had concomitant hepatitis C. Although its precise mechanism of action in viral hepatitis is not entirely clear, effects on protein folding and on activation of eukaryotic initiation factors have been invoked (71). In vitro studies have demonstrated that NTZ can inhibit HCV, as well as HBV, replication. In addition, NTZ was equally effective in suppressing polymerase and protease-resistant HCV mutants (72). Rossignol and colleagues presented interim results of the efficacy of NTZ used in combination with pegylated interferon and ribavirin among HCV genotype 4-infected patients (73). While standard therapy with pegylated interferon and RBV resulted in undetectable HCV RNA at follow-up week 12 in 43% of treatment-na¨ıve patients, the combination of pegylated interferon, RBV, and NTZ resulted in 79% of patients achieving the same endpoint (73). Studies in the US in genotype 1-infected patients are currently in progress. Another class of drugs that has demonstrated antiviral activity against HCV infection is that of cyclosporine analogs. Cyclosporine inhibits the interaction between cyclophilin B and the hepatitis C NS5B protein, which is important in the regulation of the HCV RNA-dependent RNA polymerase. DEBIO-025 (Debiopharm), a synthetic compound that is a more potent inhibitor of cyclophilin B without the immunosuppressive activity of cyclosporine, has demonstrated significant antiviral ability in vitro (74). In vivo studies of chimeric mice with human hepatocytes demonstrated that the combination of DEBIO-025 and pegylated interferon decreased HCV viral load by 100-fold (75). A phase 1b
174
Kulkarni and Jacobson
trial of monotherapy DEBIO-025 among patients co-infected with HIV and HCV resulted in a 3.6-log reduction of the HCV viral load without the emergence of resistance in the short term (76). Further data on this compound have not yet appeared, nor on a compound, NIM811, with a similar mechanism of action. Glycoprotein processing, mediated by alpha-glucosidase, is a key step prior to release of the virion from the host cell. Inhibition of alphaglucosidase prevents proper folding of the HCV envelope and adversely affects viral maturation (6). Studies have demonstrated promising results when celgosivir (MX-3253, Migenix Inc), an alpha-glucosidase inhibitor, was administered to treatment-na¨ıve patients (77). Further studies are underway investigating combination therapy that includes celgosivir.
7. NONSPECIFIC IMMUNOMODULATORS Immunomodulator approaches that upregulate the innate immune system without directly affecting HCV are also being developed. Stimulation of toll-like receptors (TLR), which activates pathways of innate, cellular, and humoral immunity, can produce increased levels of interferon and cytokines that mediate an enhanced immune response against the hepatitis C virus (78). CpG oligonucleotides contain motifs resembling bacterial DNA and act as agonists to TLR-9. A phase 1b study of CPG 10101 (Actilon, Coley Pharmaceuticals) demonstrated dose-dependent increases in markers of immune activation as well as decreases in HCV RNA (79). Early results of CPG 10101 used in combination with PEG-IFN and RBV among patients who relapsed after prior treatment demonstrated improved response with triple therapy, although the 48 weekend of treatment response and SVR rates in the final intention to treat analysis were disappointing (80, 81). This drug, as well as a TLR-7 agonist, has had its development program halted because of various combinations of efficacy and safety concerns in animal models.
8. HEPATITIS C VIRUS VACCINATION Due to the significant worldwide burden of chronic HCV infection, the development of a vaccine to prevent HCV infection has been of paramount importance. However, the creation of a vaccine has been difficult given the propensity of hepatitis C to mutate and form quasispecies. An effective vaccine for HCV will induce a strong CD8+ T-cell response as well as B cells that produce antibodies against the envelope surface proteins of HCV to prevent cell entry. The development of
Anti-HCV Agents in Development
175
a vaccine for HCV has focused on a variety of approaches, including protein-based, DNA-based, and dendritic-based vaccinations (82). Studies have evaluated the use of glycoproteins E1 and E2 as immunogens to generate cellular and humoral immune responses. Initial studies involving vaccinated chimpanzees demonstrated either resistance to viral challenge or at least partial protection, thus supporting the feasibility of protein-based vaccination (83). However, as described previously, the ability of HCV to mutate, especially within the region of its genome that encodes the E2 glycoprotein, hinders the creation of an effective protein-based vaccination (82). DNA vaccinations, in which plasmid DNA constructs are injected intramuscularly, have been shown to induce a cytotoxic T-cell response (84). In addition, unlike protein-based vaccines, DNA vaccines are fairly easy to manufacture, making them amenable to widespread distribution. Research has focused on DNA vaccines utilizing plasmids that encode for structural proteins, such as the core protein, and nonstructural proteins, such as NS3, NS4, and NS5. Results from the mouse model demonstrate that a cellular and humoral response to DNA vaccines can be achieved, although there is still much work to be done to arrive at a true clinical benefit (85). When tested among a small number of chimpanzees, the DNA vaccine did not protect against infection, although it did alter the natural course of the infection (86). In order to make DNA vaccines more effective, new approaches are being investigated to increase the immunogenicity of the vaccine through concomitant activation of the innate immune system (82). Targeted molecular immunogens consisting of whole, heat-killed recombinant Saccharomyces cerevisiaeyeast modified to express protein targets that stimulate the immune system have been evaluated. GI5005 (GlobeImmune) is a tarmogen comprising yeast cells expressing NS3 and core protein. In a phase 1 trial, GI-5005 was administered at varying doses with the finding of normalization of ALT and viral load reductions in some patients and the demonstration of broad-based enhancement of T-cell responses to a variety of HCV epitopes (87). The key to the ability of vaccines to elicit an immune response lies in the ability of antigen presenting cells, such as dendritic cells, to take up antigens and activate the innate and adaptive immune system (88). The importance of dendritic cells is demonstrated by the observation that in patients with chronic hepatitis C, impaired function of antigen-presenting cells may be necessary for the virus to survive (89). Dendritic cell-based vaccines may ultimately prove to be an efficient method to induce an immune response specific to HCV, thus providing long-lasting protection from the virus.
176
Kulkarni and Jacobson
9. CONCLUSION Exciting advances are being made in antiviral therapy for chronic hepatitis C infection as researchers have gained greater insight into the life cycle of the virus. For years, therapy was based solely on interferon, with its broad spectrum of antiviral and immunomodulatory properties, and ribavirin, the mechanism of action of which against HCV is still much debated. Currently, a growing number of studies are being conducted to evaluate the role of specifically targeted antiviral therapy for HCV (STAT-C). These novel agents have proven to have a high level of antiviral activity but concomitantly have been associated with the selection of resistant variants. It will be important to characterize the patterns of resistance and the kinetics of both emergence and suppression of different variants with each class of drug. Protease inhibitors appear thus far to be associated with the more rapid emergence of resistance than nucleoside polymerase inhibitors. The evolution of HCV treatment in the near future will likely consist of the addition of one or more of the new drugs currently in development to peginterferon and ribavirin. There are already preliminary signals from phase 2 studies of the potential to maximize sustained response rates with shorter durations of treatment than the 1 year traditionally required for genotype 1 infection. The ultimate hope is that clinicians will be able to use combinations of orally available small molecules designed to specifically target HCV, perhaps including compounds that target host factors intrinsic to viral replication, virion production, or the immune response. Whether an immunomodulatory component of our treatment regimens will always be required is one of the central issues of the field. In the meantime, researchers are investigating refinements of current therapy, including novel interferons and alternatives to ribavirin, in parallel with the development of new agents. We stand at the dawn of a new era that promises to bring dramatic advances in our ability to treat this major public health problem. The rapid pace of development in the field of HCV therapy has generated a wealth of data about other novel agents not available when this manuscript was initially submitted. Although we have added very recent data from phase 3 trials as the chapter has gone to press, it has not been possible to add data on other agents, including but not limited to additional protease and polymerase inhibitors, NS5A inhibitors, and cyclophilin inhibitors. The interested reader is encouraged to review the abstracts from the 2008 meeting of the American Association for the Study of Liver Diseases (Hepatology 2008;48, number 4, Supplement) and the 2009 meeting of the European Association for the Study of the Liver (Journal of Hepatology 2009; 50(Suppl 1)). The latter meeting
Anti-HCV Agents in Development
177
featured the first presentation of an early trial combining an HCV protease and nucleoside polymerase inhibitor (R7227 and R7128) demonstrating marked antiviral activity (Gane E et al, J. Hepatology 2009; 50(Suppl 1):S380) and reinforcing hopes that combinations of antiviral agents will be a major future direction for investigation.
REFERENCES 1. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144:705–714. 2. Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000; 20:1–16. 3. Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39:1147–1171. 4. Hoofnagle JH, Seef LB. Peginterferon and ribavirin for chronic hepatitis C. NEJM 2006; 355:2444–2450. 5. Penin F, Dubuisson J, Rey FA, et al. Structural biology of hepatitis C virus. Hepatology 2004; 39(1):5–19. 6. Suzuki T, Aizaki H, Murakami K, et al. Molecular biology of hepatitis C virus. J Gastroenterol 2007; 42:411–423. 7. Brass V, Moradpour D, Blum HE. Molecular virology of hepatitis C virus: 2006 Update. Int J Med Sci 2006; 3(2):26–34. 8. Lohmann V, Korner F, Koch J, et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999; 285:110–113. 9. Kato T, Date T, Miyamoto M, et al. Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterol 2003; 125(6):1808–1817. 10. Lindenbach B, Evans M, Syder A, et al. Complete replication of hepatitis C virus in cell culture. Science 2005; 309:623–626. 11. Molina S, Castet V, Fournier-Wirth C, et al. The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C. J Hepatol 2007; 46(3):411–419. 12. Koutsoudakis G, Herrmann E, Kallis S, et al. The level of CD81 cell surface expression is a key determinant for productive entry of hepatitis C virus into host cells. J Virol 2007; 81(2):588–598. 13. Evans M, von Hahn T, Tscherne D, et al. Claudin-1 is a hepatitis C virus coreceptor required for a late step in entry. Nature 2007; 446:801–804. 14. Glenn JS. Novel therapies for the hepatitis C virus based on lessons from virology. Clin Gastroenterol and Hepatol 2005; 3:S86–S88. 15. Swain M, Lai M-Y, Shiffman M, et al. Durable sustained virological response after treatment with peginterferon Alfa-2a alone or in combination with ribavirin: 5-year follow-up and the criteria of a cure. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007, Barcelona, Spain. Abstract 1. 16. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alpha2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterol 2002; 122:1303–1313.
178
Kulkarni and Jacobson
17. Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005; 142:105–114. 18. Papatheodoridis GV, Katsoulidou A, Touloumi G, et al. Biochemical and virologic response of chronic hepatitis C after treatment with interferon-alpha for 6 or 12 months: predictors of sustained remission. Eur J Gastroenterol Hepatol 1996; 8(5):469–475. 19. Poynard T, Marcellin P, Lee SS, et al. Randomized trial of interferon alpha2b plus ribavirin for 48 weeks of for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352:1426–1432. 20. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358(9286):958–965. 21. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346–355. 22. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13): 975–982. 23. Jacobson IM, Brown RS, Freilich B, et al. Peginterferon alpha-2b and weightbased or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007; 46(4):971–981. 24. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype 1-infected patients with chronic hepatitis C. Gastroenterol 2002; 123:1061–1069. 25. Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38(3):645–652. 26. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352(25): 2609–2617. 27. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44(1): 97–103. 28. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357(2):124–134. 29. S´anchez-Tapias JM, Diago M, Escart´ın P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131(2):451–460. 30. Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130(4):1086–1097. 31. Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders. Hepatology 2007; 46(6):1688–1694. 32. Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology 2008; 47(1):43–50.
Anti-HCV Agents in Development
179
33. Blatt LM, Davis JM, Klein SB, et al. The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. J Interferon Cytokine Res 1996; 16:489–499. 34. Fattovich G, Zagni I, Minola E, et al. A randomized trial of consensus interferon in combination with ribavirin as initial treatment for chronic hepatitis C. J Hepatol 2003; 39(5):843–849. 35. Bacon B, Regev A, Ghalib R, et al. The direct trial (daily consensus interferon and ribavirin: efficacy of combined therapy): treatment of non-responders to previous pegylated interferon plus ribavirin: sustained virologic response data. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 168. 36. Zeuem S, Yoshida EM, Benhamou Y, et al. Sustained virologic response rates with albinterferon alfa-2b plus ribavirin treatment in IFN-na¨ıve, chronic hepatitis C genotype 1 patients. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 180. 37. Nelson DR, Rustgi VK, Balan V, et al. Sustained virologic response with albinterferon alfa-2b/ribavirin treatment in prior interferon therapy non-responders. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 51. 37a. Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon Alfa-2b in combination with ribavirin in treatment-na¨ıve, chronic hepatitis c genotype 1 (chc g1) patients. The 44th Annual Meeting of the European Association for the Study of Liver. April 22–26, 2009, Copenhagen, Denmark. 37b. Nelson D, et al. The 44th Annual Meeting of the European Association for the Study of Liver. April 22–26, 2009, Copenhagen, Denmark. 38. Crotty S, Maag D, Arnold IJ, et al. The broad spectrum antiviral ribonucleoside ribavirin is an RNA mutagen. Nat Med 2000; 6:1375–1379. 39. Vo NV, Young KC, Lai MM. Mutagenic and inhibitory effects of ribavirin on hepatitis C RNA polymerase. Biochemistry 2003; 42:10462–10471. 40. Benhamou Y, Pockros P, Rodriguez-Torres M, et al. The safety and efficacy of viramidine plus pegIFN alpha-2b versus ribavirin plus pegIFN alpha-2b in therapy na¨ıve patients infected with HCV: phase 3 results (VISER1). The 41st Annual Meeting of the European Association for the Study of the Liver. April 26–30, 2006,Vienna, Austria. Abstract 751. 41. Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426:186–189. 42. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: A phase 1b, placebo-controlled, randomized study. Gastroenterology 2006; 131:997–1002. 43. McHutchison JG, Everson GT, Gordon S, et al. Results of an interim analysis of a phase 2 study of telaprevir (VX-950) with peginterferon alfa-2A and ribavirin in previously untreated subjects with hepatitis C. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007. Barcelona, Spain. Abstract 786. 44. Kieffer T, Sarrazin C, Miller J, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.. Hepatology 2007; 46(3):631–639. 45. Chu HM, Zhou Y, Bartels, at al. Telaprevire (VX-950)-resistant variants exhibit reduced replication capacity compared to wild-type HCV in vivo and in vitro. J Hepatol 2007; 46(Suppl 1):S230.
180
Kulkarni and Jacobson
46. Lawitz EJ, Rodriguez-Torres M, Muir A, et al. 28 days of hepatitis C protease inhibitor VX-950, in combination with PEG-interferon-ALFA-2a and ribavirin, is well tolerated and demonstrates robust antiviral activity effects. Gastroenterology 2006; 131:950–951. 47. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. NEJM 2009; 360(18):1827–1838. 48. H´ezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV Infection. NEJM 2009; 360(18):1839–1850. 48a. McHutchison JG, Shiffman ML, Terrault N, et al. A phase 2b study of telaprevir with peginterferon-alfa-2a and ribavirin in hepatitis C genotype 1 null and partial responders and relapsers following a prior course of peginterferon-alfa-2a/b and ribavirin therapy: PROVE3 interim results. Hepato 2008; 48(Suppl):431A. 49. Kieffer T, Zhou Y, Zhang E, et al. Evaluation of viral variants during a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-na¨ıve HCV genotype 1-infected patients. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract LB8. 50. Zeuzem S, Sarrazin C, Rouzire R, et al. Anti-viral activity of SCH 503034, a HCV protease inhibitor, administered as monotherapy in hepatitis C genotype-1 (HCV-1) patients refractory to pegylated interferon. The 56th Annual Meeting of the American Association for the Study oh Liver Diseases. Novemeber 11–15, 2005, San Fransisco, CA. Abstract 94. 51. Zeuzem S, Sarrazin C, Wagner F, et al. The HCV NS3 protease inhibitor SCH 503034 in combination with peg-IFN-alpha-2b in the treatment of HCV-1 pegIFN-alpha-2b non responders: Antiviral activity and HCV variant analysis. The 41st Annual Meeting of the European Association for the Study of the Liver. April 26–30, 2006, Vienna, Austria. Abstract 78. 52. Kwo P, Lawitz E, McCone J, et al. HCV SPRINT-1: Final results SVR 24 from a phase 2 study of boceprevir plus PEG Intron (peginterferon alfa-2b)/ribavirin in treatment na¨ıve subject with genotype-1 chronic hepatities C. J. Hepatology 2009; 50(Suppl 1):S4. 53. Preston RA, Alonso AB, Feely W, et al. SCH 503034 (Boceprevir), an Oral HCV Protease Inhibitor, Is Well-Tolerated in Patients with Varying Degrees of Hepatic Impairment. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007, Barcelona, Spain. Abstract 545. 54. Huang Z, Murray MG, Secrist JA. Recent development of therapeutics for chronic HCV infection. Antiviral Res 2006; 7:351–362. 55. Lawitz E, Nguyen T, Younes Z, et al. Valopicitabine (NM283) plus peg-interferon in treatment-na¨ıve hepatitis C patients with HCV genotype-1 infection: HCV RNA clearance during 24 weeks of treatment The 57th Annual Meeting of the AASLD. October 27–31, 2007, Boston, MA. Abstract 93. 56. Lawitz E, Nguyen T, Younes Z, et al. Clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection: results at 24 and 48 weeks. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007, Barcelona, Spain. Abstract 14. 57. Chandra R, Raible D, Harper D, et al. Antiviral activity of the non-nucleoside polymerase, HCV-796, in patients with chronic hepatitis C virus: Preliminary results from a randomized, double-blind, placebo-controlled, ascending multiple dose study (abstract). Gastroenterology 2006, 130:A748.
Anti-HCV Agents in Development
181
58. Viropharma, Inc.: Press release: ViroPharma announces positive data from phase 1b combination study of HCV-796 and pegylated interferon in hepatitis C patients, August 28, 2006. http://www.viropharma.com/therapeutic/hcv796. 59. Viropharma, Inc.: Press release: Potential Safety Issue Identified in Ongoing Phase 2 Clinical Study of HCV-796, August 10, 2007. http://www.viropharma. com/therapeutic/hcv796. 60. Pockros PJ, Nelson D, Godofsky E, et al. Robust synergistic antiviral effect of R1626 in combination with peginterferon alfa-2a, with or without ribavirin— Interim analysis of results of phase 2a study. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 167. 61. Pogram SL, Seshaadri A, Kosaka A, et al. A high barrier to resistance may contribute to the robust antiviral effect demonstrated by R1626 in HCV genotype 1-infected treatment na¨ıve patients. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 1298. 62. Reddy R, Rodriguez-Torres M, Gane E, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract LB9. 62a. Lalezeri J, Gane E, Rodriguez-Torres M, et al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor, R7128, in combination with peginterferon alfa-2a and ribavirin. 43rd Annual Meeting of the European Association for the Study of the Liver. April 23–27, 2008, Milan, Italy. 62b. Gane E, Rodriguez-Torres M, Nelson D, et al. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior nonresponders: results of R7128 1500 mg BID With PEG-IFN and ribavirin for 28 days. The 59th Annual Meeting of the AASLD. Oct 31–Nov 4, 2008, San Francisco, CA. 63. Bichko V, Lallos L, Soubasakos M, et al. Valopicitabine (NM283) is fully active against known HCV protease resistance mutations in vitro. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007. Barcelona, Spain. Abstract 427. 64. Ralston R, Bichko V, Chase R, et al. Combination of two hepatitis C virus inhibitors, SCH 503034 and NM107, provides enhanced anti-replicon activity and suppressed emergence of resistant replicons. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007. Barcelona, Spain. Abstract 795. 65. Howe AY, Ralston R, Chase R, et al. Favorable cross-resistance profile of two novel hepatitis C virus inhibitors, SCH-503034 and HCV-796, and enhanced antireplicon activity mediated by the combined use of both compounds. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007. Barcelona, Spain. Abstract 434. 66. McCowen M, et al. 14th International Symposium on Hepatitis C Virus and Related Viruses. September 9–13, 2007. Abstract P-265. 67. Romero-Lopez C, Sanchez-Luque J, Berzal-Herranz A. Targets and tools: Recent advances in the development of anti-HCV nucleic acids. Infect Disord 2006; 6:121–145. 68. McCaffrey A, Meuse L, Karimi M, et al. A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice. Hepatology 2003; 38:503.
182
Kulkarni and Jacobson
69. McHutchison JG, Patel K, Pockros P, et al. A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients. J Hepatol 2006; 44(1):88–96. 70. Trepanier JB, Tanner JE, Alfieri C. Oligonucleotide-based therapeutic options against hepatitis C virus infection. Antiviral Therapy 2006; 11:273–287. 71. Hoffman PS, Sisson G, Croxen MA, et al. Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob Agents Chemother 2007; 51(3):868–876. 72. Korba BE, Montero AB, Farrar K, et al. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Research 2007; 77(1):56–63. 73. Rossignol JF, Elfert A, El-Gohary Y, et al. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009; 136(3):856–862. 74. Paeshuyse J, Kaul A, De Clercq E, et al. The non-immunosupressive cyclosporine DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43(4):761–770. 75. Inoue K, Umehara T, Ruegg UT, et al. Evaluation of a cyclophilin inhibitor in hepatitis C virus-infected chimeric mice in vivo. Hepatology 2007; 45 (4): 921–928. 76. Fliask R, Horban A, Kierkus J, et al. The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and anti-HCV activity in treatment-na¨ıve HIV/HCV coinfected subjects. The 57th Annual Meeting of the AASLD. October 27–31, 2007, Boston, MA. Abstract 1130. 77. Yoshida E, Kunimoto D, Lee SS, et al. Results of a phase II dose ranging study of orally administered celgosivir as monotherapy in chronic hepatitis C genotype 1 patients. Gastroenterology 2006; 130: A784. Abstract S1059. 78. Fattovich G, Zagni I, Minola E, et al. A randomized trial of consensus interferon in combination with ribavirin as initial treatment for chronic hepatitis C. J Hepatol 2003; 39(5):843–849. 79. McHutchison J, Bacon BR, Gordon S, et al. Phase 1b, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus. Hepatology 2007; 46(5):1341–1349. 80. McHutchison J, Ghalib R, Lawitz E, et al. Early virologic response to CPG 10101, a new investigational antiviral TLR9 agonist, in combination with pegylated interferon and/or ribavirin, in prior relapse HCV responders: preliminary report of a randomized phase 1 study. Digestive Disease Week, 2006. May 20– 25, 2006. Los Angeles, CA. Abstract S1062. 81. Shiffman ML, Ghalib R, Lawitz E, et al. CPG 10101 (actilon) in combination with peglated interferon and/or ribavirin in chronic HCV genotype 1 infected patients with prior relapsed response: week 48 data. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11–15, 2007, Barcelona, Spain. Abstract 649. 82. Wintermeyer P and Wands JR. Vaccines to prevent chronic hepatitis C virus infection: current experimental and preclinical developments. J Gastroenterol 2007; 42:424–432. 83. Choo QL, Kuo G, Ralston R, et al. Vaccination of chimpanzees against infection by hepatitis C virus. Proc Natl Acad Sci USA 1994; 91:1294–1298.
Anti-HCV Agents in Development
183
84. Zajac AJ, Murali-Krishna K, Blattman JN, et al. Therapeutic vaccination against chronic viral infection: the importance of cooperation between CD4+ and CD8+ T cells. Curr Opin Immunol 1998; 10:444–449. 85. Encke J, Putlitz J, Geissler M, et al. Genetic immunization generates cellular and humoral immune responses against the nonstructural proteins in hepatitis C virus in a murine model. J Immunol 1998; 161:4917–1923. 86. Forns X, Payette PJ, Ma X, et al. Vaccination of chimpanzees with plasmid DNA encoding the HCV envelope E2 protein modified the infection after challenge with homologous monoclonal HCV. Hepatology 2000; 32:618–625. 87. Schiff ER, Everson GT, Tsai N, et al. HCV-specific cellular immunity, RNA reductions, and normalization of ALT in chronic HCV subjects after treatment with GI-5005, a yeast-based immunotherapy targeting NS3 and core: a randomized, double-blind, placebo controlled phase 1b study. The 58th Annual Meeting of the AASLD. November 2–6, 2007, Boston, MA. Abstract 1304. 88. Banchereau J and Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392:245–252. 89. Auffermann-Gretzinger S, Keefe EB, Levy S. Impaired dendritic cell maturation in patients with chronic, but nor resolved, hepatitis C virus infection. Blood 2001; 97:3171–3176.
Epidemiology, Screening, and Natural History of Chronic Hepatitis B Infection Shiv K. Sarin, MD and Manoj Kumar, MD CONTENTS I NTRODUCTION E PIDEMIOLOGY S CREENING H IGH -R ISK P OPULATIONS TO I DENTIFY HBV-I NFECTED P ERSONS NATURAL H ISTORY OF C HRONIC HBV I NFECTION S UMMARY AND F UTURE D IRECTIVES R EFERENCES
Key Principles
• Hepatitis B virus (HBV) infection continues to be a global public health problem despite large-scale efforts to eliminate this disease through education, screening, and vaccination programs. • An estimated 400 million individuals are chronically infected with HBV which results in nearly 1 million deaths each year from decompensated cirrhosis or HCC. • A wide variability exists in the prevalence rates of HBV worldwide with sub-Saharan Africa, mainland China, and many countries of Southeast Asia being hyperendemic in HBV.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 7, C Humana Press, a part of Springer Science+Business Media, LLC 2009
185
186
Sarin and Kumar
• Maternal–fetal transmission of hepatitis B virus is an important problem, particularly in endemic areas such as Southeast Asia and Africa. • Immunization against HBV has been a successful experience in various countries. It is hoped that universal vaccination campaigns will eventually reduce or eliminate the impact of this disease in many parts of the world.
1. INTRODUCTION Hepatitis B virus (HBV) infection continues to be a global public health problem despite large-scale efforts to eliminate this disease through education, screening, and vaccination programs. Universal vaccination can prevent most acute HBV infections, although in many developing countries the potential of universal immunization remains unfulfilled. In the Western world, as a consequence of widespread vaccination programs relatively few cases of acute HBV infection are encountered. However, in these developed countries, the significant number of individuals chronically infected with HBV will continue to present with major complications of chronic infection, including decompensated cirrhosis and hepatocellular carcinoma (HCC). Also, widespread migration from Asia, sub-Saharan Africa, the Caribbean, and other areas of high prevalence to Western countries (areas of low prevalence) has resulted in immigrant communities in which the prevalence of chronic HBV infection is similar to the rates observed in the country of origin.
2. EPIDEMIOLOGY 2.1. Global Patterns of HBV Infection HBV infection remains a global challenge, with one-third of the world’s population having serological evidence of current or previous infection. An estimated 400 million individuals are chronically infected with HBV which results in nearly 1 million deaths each year from decompensated cirrhosis or HCC (1). The virus accounts for 30% of all cases of cirrhosis and 53% of all cases of HCC worldwide (2). The prevalence of chronic HBV infection, defined as hepatitis B surface antigen (HBsAg) positivity for ≥6 months, varies widely, with rates ranging from 0.1 to 20% in different parts of the world (3). Regions may be designated as follows: (a) “High” prevalence (HBsAg positivity rates >8%), which include Asia (except Japan), parts of the Middle East, sub-Saharan Africa, and the Amazon basin; (b) “Intermediate” prevalence (HBsAg positivity rates of 2–7%), which include Japan, the
Natural History of Chronic Hepatitis B Infection
187
Indian subcontinent, parts of central Asia and the Middle East, Eastern and Southern Europe, as well as parts of South America; and (c) “Low” prevalence (<2% HBsAg positive), which include the United States, Northern Europe, Australia, and the southern part of South America (Fig. 1).
Fig. 1. Prevalence of HBsAg positivity across the world. High-prevalence regions include the Asia (except Japan), parts of the Middle East, sub-Saharan Africa, and the Amazon Basin. Intermediate-prevalence regions include Japan, the Indian subcontinent, parts of central Asia, and the Middle East, Eastern, and Southern Europe, as well as parts of South America. Low-prevalence regions include the United States, Northern Europe, Australia, and the southern part of South America.
Overall, 45% of the world population lives in “high” prevalence regions (4). In areas with a high HBV prevalence, serologic evidence of prior HBV infection (anti-hepatitis B core antibody (anti-HBc) or anti-HBs positivity) is present in the vast majority of individuals. High endemicity is perpetuated by frequent perinatal or childhood acquisition of HBV infection. Migration patterns of individuals from high to low endemic areas have had a significant impact on the epidemiology of hepatitis B (see below).
2.2. Patterns of HBV Infection in Specific Areas 2.2.1. A FRICA Sixty-five million of approximately 400 million people in the world chronically infected with HBV reside in Africa (5). Of the 1.3 million deaths attributed to HBV-related diseases recorded annually throughout the world, approximately 250,000 occur in Africa. Wide variations exist
188
Sarin and Kumar
in the prevalence of HBs antigenemia in Africa. The virus is hyperendemic (>8%) in sub-Saharan Africa, with the exception of Kenya, Zambia, Cote d’Ivoire, Liberia, Sierra Leone, and Senegal, which are areas of intermediate endemicity (2–8%). The northern African countries of Egypt, Tunisia, Algeria, and Morocco are regions of low endemicity (<2%), although pockets of high endemicity can occur within these countries (6) (Fig. 2). For example, in Tunisia prevalence rates are up to 13.3% in the south and central western regions (7, 8).
Fig. 2. Prevalence of HBsAg positivity in Africa. High-prevalence areas in Africa include sub-Saharan Africa, with the exception of Kenya, Zambia, Cote d’Ivoire, Liberia, Sierra Leone, and Senegal, which are areas of intermediate prevalence. The northern African countries of Egypt, Tunisia, Algeria, and Morocco are regions of low prevalence, although pockets of high prevalence can occur within these countries.
Generally, HBsAg prevalence is much higher in rural areas, and the risk of being HBsAg positive in rural areas is twice as high as in urban areas (6). HBsAg prevalence is lowest in asymptomatic blood donors and highest in patients with various clinical consequences of HBV infection. HBsAg prevalence increases with age (9). Exposure to HBV, as measured by the prevalence of anti-hepatitis B core (anti-HBc) ranges from 1.8 to 98% in the African population, with blood donors and children found on the lower end of the scale and patients with chronic liver disease or HCC showing a higher prevalence. Exposure rates increase with age. Exposure to HBV varies in different
Natural History of Chronic Hepatitis B Infection
189
regions of Africa, with western Africa showing anti-HBc prevalence greater than 85% and eastern Africa showing a prevalence ranging 65–85%. Exposure rates to HBV are higher in rural than in urban populations (10). The Baka pygmies of eastern Cameroon represent the population group in Africa with the highest exposure to HBV with an anti-HBc prevalence of 93.6% (11). Compared with other adult chronic HBV-infected patients, those in Africa have a lower rate of HBeAg positivity. Early loss of HBeAg occurs in both Bantu and Pygmy people in Cameroon, with a mean age of 31.6 and 29.5 years, respectively (12). Prevalence of HBeAg in chronic HBV-infected patients varies widely from <1 to 24% (6). Most primary HBV infections are transmitted either perinatally or horizontally before the age of 10 years. Horizontal transmission occurs through intrafamilial, and to a lesser extent interfamilial, routes (13). 2.2.2. U NITED S TATES OF A MERICA In the United States, HBV prevalence is relatively low, with HBsAg positivity ranging from 2 to 7% (3). Despite the relatively low endemicity of HBV, HBV infection remains a major public health problem and is a cause of significant morbidity and mortality in certain ethnic populations and among groups of people whose behavior puts them at high risk. Large regional differences exist in HBsAg prevalence rates within the United States (3) (Fig. 3). The emigration of people into the United States has also given rise to rapid changes in epidemiological patterns. The number of chronically HBV-infected (HBsAg-positive) individuals in the United States is often quoted as being 1.25 million. However, a recent paper that incorporated immigration data suggested that at least 2 million residents of the United States may have chronic HBV infection (14, 15). In a study from the Mayo Clinic in Rochester, Minnesota, 86% of individuals with chronic HBV infection in one Minnesota county were born in foreign countries (16). Paradoxically, deaths because of HBV infection increased during the two decades before 1999 based on data from the US Certificates of Death Registry from the National Center for Health Statistics and the Healthcare Utilization Project despite the introduction of vaccination programs within the United States (17). A fourfold increase in the rate of age-adjusted death because of HBV was predominantly observed in men and nonwhites. Findings from Chu and colleagues (18) at major referral sites across the United States have highlighted the impact of immigration on the current demographics of HBV infection. The investigators found that patients presenting for the management of HBV infection, particularly at West Coast and Northeastern referral centers, are now predominantly Asian. Additional
190
Sarin and Kumar
Fig. 3. Prevalence of HBsAg positivity in Americas. In the United States, HBV prevalence is relatively low; however, large regional differences exist in HBsAg prevalence rates within the United States. In Latin America also, wide variations in HBsAg prevalence is seen. Prevalence is low in temperate Mexico, Colombia, Argentina, Chile, Uruguay, and some Caribbean islands; intermediate in Venezuela, Peru, Ecuador, Brazil, and parts of Central America, such as Guatemala and Honduras; and high in the Dominican Republic, Haiti, and the Amazon Basin.
findings suggest that these patients have a longer duration of HBV infection that was acquired early in life, as reflected by frequent chronic HBV infection with HBeAg negativity (19). In urban populations of the United States, transmission occurs through percutaneous or permucosal exposure to infected blood or other secretions. In adults, the predominant means of transmission are sexual intercourse, needlestick injuries in health-care workers and injection drug users. In North America, currently vertical transmission is rare because of the implementation of routine infant and childhood immunization programs. Despite these efforts, challenges remain with respect to intrafamilial transmission of HBV infection. Intrafamilial transmission has been clearly documented among Asian families who have recently immigrated to the United States. Studies among Asian American and Pacific Islander children who immigrated to the United States
Natural History of Chronic Hepatitis B Infection
191
found that household transmission of HBV remains relatively high at 0.5–1% annually (20), leading to the recommendation, starting in the 1980 s, that all family and household members of Asians infected with HBV undergo vaccination. A recent survey on 3,163 Asian American adult volunteers in the San Francisco found that 8.9% were chronically infected with HBV and 65.4% of the chronically infected adults were unaware that they were infected. Of those who were not chronically infected, 44.8% lacked protective antibodies against HBV and were likely susceptible to future infection. Men were twice as likely as women to be chronically infected (12.1% vs. 6.4%). Asian Americans born in East Asia, Southeast Asia, or the Pacific Islands were 19.4 times more likely to be chronically infected than those born in the United States (21). 2.2.3. L ATIN A MERICA In Latin America (Mexico, Central America, and South America), the total number of individuals chronically infected with HBV may exceed 6 million. The prevalence of HBsAg is low in temperate Mexico, Colombia, Argentina, Chile, Uruguay, and some Caribbean islands; moderate in Venezuela, Peru, Ecuador, Brazil, and parts of Central America, such as Guatemala and Honduras; and high in the Dominican Republic, Haiti, and the Amazon Basin (22). Hepatitis B infection has emerged as a serious problem in almost all the Amerindian communities studied in the Amazon Basin as well as in other Amazonian ecological systems from north and central South America, where it has been a major cause of morbidity and mortality. Of an estimated 4 million chronic HBV-infected subjects in South America alone, more than 30% are located in the Amazon Basin region (including areas of Colombia, Venezuela, Peru, and the northeastern region of Brazil) (23). In these regions, a wide prevalence of antibody to hepatitis B core antigen (anti-HBc), from 1.2 to 74%, has been reported in many small seroepidemiological studies (24, 25). An increase in prevalence is expected in South America due to immigration. Accordingly, in the state of Sao Paulo, a significantly higher rate of HBV infection exists in the people of Asian ethnicity than in the western populations (26). In urban populations, transmission occurs through percutaneous or permucosal exposure to infected blood or other secretions. In adults, the predominant means of transmission are sexual intercourse, needlestick injuries in health-care workers and injection drug users. Perinatal transmission plays an important role in areas where HBV infection is more prevalent among adults. In some areas of the Amazon Basin,
192
Sarin and Kumar
where most cases of acute HBV occur during the first years of life (27), there are inadequate measures to block transmission at birth, and the disease becomes evident during childhood. However, vertical transmission cannot be regarded as the sole source of endemicity in the area; other environmental, sociocultural, and sanitary factors specific to the geographical locale may contribute to the unique characteristics of the infection observed in this region. Certain cultural practices (e.g., tattooing, ear piercing, consumption of masato, sharing instruments for ritual scarification) and other factors (e.g., bat bites) have been reported to be associated with the transmission of HBV. 2.2.4. W ESTERN PACIFIC AND S OUTHEAST A SIA Western Pacific and Southeast Asia regions are one of the most populous regions, including more than 40 countries. The region comprises highly developed countries (such as Japan, Australia, and New Zealand), countries that are rapidly industrializing (such as Singapore, Malaysia, Indonesia, and the Republic of Korea), and countries which are less prosperous (such as the Philippines and Myanmar). Hepatitis B infection is hyperendemic in this region, with the exception of Australia, New Zealand, and Japan. The prevalence of HBV in the general population in the Asian region is variable with the highest rates in Taiwan (>10%) and Thailand (>8%) and lowest in Japan 0.8%. Much of the information on transmission of HBV in Southeast Asia and the western Pacific Region is based on inferences from crosssectional epidemiological studies. In hyperendemic countries, the agespecific prevalence of markers of infection increases steadily with increasing age, although some decline in the carrier rate and the prevalence of antibody is often seen in the last two decades of life. In these countries, most infections seem to occur: (a) either at or shortly after birth, when newborn babies are exposed to the infected blood or bloodstained secretions of carrier mothers; (b) before starting school, when the child is part of an extended family, some of whom may be chronic HBV-infected subjects; and (c) in early adult life, after the onset of sexual activity. Some infections may be transmitted by multiple use of nonsterile needles or instruments and transfusion of unscreened blood. While the modes of transmission of HBV are similar throughout the region, there are considerable variations in the importance of perinatal and household transmission and transmission by inoculation of blood, secretions, or sexual intercourse from country to country. In hyperendemic areas, most infections are acquired early in life, either from the child’s mother or some other person in the extended household. By contrast, in low-prevalence groups, most infections are acquired in early
Natural History of Chronic Hepatitis B Infection
193
adult life through intravenous drug abuse and unprotected sexual intercourse. Immigration has also contributed to the HBV-infected patients’ pool in the Pacific region especially Australia. In Australia, HBsAg prevalence rates reflect those found in the countries in which the individual’s parents or grandparents were born, being lowest (about 0.1%) in descendants of British migrants, higher (2–5%) among migrants and the children of migrants from the Mediterranean region, and highest (5–15%) among migrants from the Pacific islands and Southeast Asia (28). A considerable proportion of Australia’s chronic HBV-infected subjects have entered the country as refugees from Vietnam and Cambodia. The notification rate of HBV fell in Australia to 1.5 per 100,000 in 1997 but has since increased to 2.2 per 100,000 in 2001. This increase in notifications is thought to be due to the increase in migrants and refugees from high-prevalence countries. A recent study in central Sydney (New South Wales) found that almost 70% of those with chronic HBV were born overseas (29). 2.2.5. C HINA (M AINLAND ) China is an endemic area of HBV infection with 90% of the adult population having been infected. The national seroepidemiological survey on viral hepatitis conducted in 1992 showed that the prevalence of HBsAg positivity was 9.75% in the general population (30). It is estimated that each year 300,000 deaths in China are caused by chronic hepatitis B-related conditions. According to the 2007 Chinese Health Statistical Digest published by the Ministry of Health, the incidence of viral hepatitis is the highest among the 35 infectious diseases that require compulsory reporting since 1978 (31). In China, HBV infection is spread mainly through mother-to-infant (mostly perinatal) transmission and early childhood transmission. The Ministry of Health has recommended routine infant HBV immunization in rest of the China since 1992, but the families had to pay for the vaccination. Finally, in 2005, the Chinese government adopted a completely free HBV vaccination program for all neonates (32). According to a national survey, in 1999, the HBV vaccine coverage in infants under 12 months of age was 88.5 and 62.7% for urban and rural areas, respectively, with four economically privileged provinces having a coverage rate of more than 90% (33). Comparison of the two national surveys of vaccination coverage indicated that the estimated coverage of three doses of the hepatitis B vaccine increased substantially overall: from 70.7% among children born in 1997 to 89.8% among children born in 2003 (32). The positive impact of HBV vaccination has been demonstrated beyond doubt. In 1998, Lu et al. conducted a sampled survey on
194
Sarin and Kumar
hepatitis A, B, and C in Yunnan province, China. The prevalence of HBsAg was 2.0% in 452 serum samples collected from elementary school students in three different counties (34). Jia et al. (1999) reported hepatitis B vaccination of newborns in four capital cities and its suburbs involving 1,271 children in late 1997. The hepatitis B vaccine coverage rate in the cities (92.1%) was significantly higher than that in suburbs (77.0%). HBsAg decreased from 7.1% in nonvaccinated controls to 1.66% in vaccinees (35). In a study from Nanning, China, in 2004, during the 14 years after hepatitis B vaccination, the HBsAg-positive rates were found to be an average of 1.5%. The incidence of hepatitis B dropped from 3.27/10,000 to 0.17/10,000, a 94.8% decrease, in the group of 0–19-year-olds (36). 2.2.6. TAIWAN In the early 1980 s, 15–20% of the population of Taiwan was estimated to be chronically infected with HBV. A program of mass vaccination against hepatitis B was launched in 1984. In the first 2 years of the program, newborns of all HBsAg-positive mothers were vaccinated. Since 1986, all newborns, and then preschool children, primary school children, adolescents, young adults, and others have also been vaccinated. Vaccination coverage was greater than 90% for newborns and 79% of pregnant women being screened for HBsAg. The proportion of babies who were born to highly infectious HBV positive mothers and became chronically HBV infected decreased from 96 to 14%, whereas the decrease was from 12 to 4% for babies of less infectious mothers. Within 10 years of introduction of the vaccine, the HBsAg prevalence declined from 9.3 to 1.3% in children younger than 12 years in Taiwan (37). Similar changes in prevalence have been reported for HCC and fulminant hepatitis B (see below). 2.2.7. I NDIA HBsAg prevalence rates among blood donors range from 1 to 6% and in pregnant women from 2.6 to 9.5% (38). Community data on HBsAg and anti-HBs positivity in the Indian population are scarce. However, among studies in healthy individuals, the HBsAg and anti-HBs positivity has been reported to be 1.6–2.1% and 17.1–19.5%, respectively (39, 40). The HBsAg positivity rate varies regionally and overall was quoted to be as high as 4.7% (Fig. 4) (40). This is the weighted mean of various studies and includes high-risk populations. Lodha et al. did a systematic review of literature and concluded that the prevalence of hepatitis B in India was 1–2% (41). A recent meta-analysis found the prevalence in nontribal populations is 2.4% (95% CI: 2.2–2.7%) and the
Natural History of Chronic Hepatitis B Infection
195
Fig. 4. Prevalence of HBsAg positivity in India. Although India is considered to be an intermediate-prevalence zone, the HBsAg positivity rate is different in different regions of the country.
prevalence among tribal populations is considerably higher at 15.9% (CI: 11.4–20.4%) (42). Higher prevalence rates have been reported in high-risk populations. The HBsAg positivity among professional blood donors has been reported to be 15–20%. Morever, among health-care workers, HBsAg positivity has been reported to be 1.7–40% (38). Recently, studies have shown that within India hyperendemic regions for HBV infection may exist in tribal populations with HBsAg prevalence reaching upto 23% (42, 43). Indian studies on age-stratified HBsAg and anti-HBs positivity rates indicate that a chronic HBsAg positivity rate of 2–3% is reached by the age of 5 years (44) which does not increase further with age. However, the anti-HBs frequency continues to increase with age (45). This indicates that exposure to HBV infection occurs mainly in childhood. The predominant route of transmission among children is horizontal transmission during preschool and early school age. Studies evaluating HBV infection frequencies among household contacts also indicate that horizontal spread of HBV infection is the predominant route of transmission in this situation (46). The introduction of mandatory HBsAg screening of blood donors in India during the 1990 s has resulted in a marked decrease in posttransfusion HBV infection (38). Despite donor screening for HBsAg, about 25% of posttransfusion hepatitis is still due
196
Sarin and Kumar
to HBV (38). It may be possible to prevent posttransfusion hepatitis B by eliminating anti-HBc positive donors. However, due to a general shortage of donated blood in India, discarding anti-HBc positive blood remains problematic. Another possible route of transmission of HBV infection is the use of nondisposable glass syringes in rural India (47). Data on the significance in India of other routes of HBV transmission, such as tattooing, visits to barbers, body-piercing practices, and homosexual activities are limited. 2.2.8. M IDDLE E AST Studies in the Middle East show the prevalence of HBsAg to range from 3 to 11% overall. The highest prevalence rates have been reported from Saudi Arabia and the Republic of Yemen (48). In the Middle East, the majority of infections occur through childhood and perinatal transmissions. There is limited information on sexual transmission in these societies. Parenteral transmission in health institutions is limited due to routine screening of blood products. The number of intravenous drug users in the Middle East remains low compared to other regions, but there is little information on unsafe injection practices. Studies on the magnitude of perinatal and childhood transmission in the Middle East have produced differing results. While some studies suggest that childhood transmission is the major mode of transmission of HBV infection with perinatal transmission being uncommon, others propose that perinatal transmission plays an important role in contributing to the pool of chronic HBV-infected patients. Considering the heterogeneity of Middle East populations and the varying prevalence of chronic HBV infection among women of childbearing age, intercountry differences in the mode of transmission probably exist (48). 2.2.9. E UROPE The prevalence of HBsAg positivity ranges from <0.1% in northwest Europe to 1–5% in southern Europe. The highest rates are found in the south and east, particularly the central Asian republics. The highest reported rates in the countries of central and eastern Europe are in Bulgaria, Estonia, Latvia, Kazakhstan, Kyrgyzstan, Moldova, the Russian Federation, and Uzbekistan (49). Improvements in health-care delivery, better living standards, safer sexual practices, and implementation of immunization programs have led to decreasing HBsAg prevalence in many European countries including Italy, Greece, and Spain (50).
Natural History of Chronic Hepatitis B Infection
197
2.3. Patterns of HBV Transmission HBV is present in the blood, saliva, semen, vaginal secretions, menstrual blood, and, to a lesser extent, perspiration, breast milk, tears, and urine of infected individuals. The virus is resistant to breakdown, can survive outside the body, and is easily transmitted through contact with infected body fluids (3). Sexual activity and injection-drug use account for the majority of HBV transmission in low-prevalence areas (1). Perinatal (vertical) transmission is most common in Far East Asian countries and Oceania (3). Not all HBV infection in endemic areas is vertically transmitted. Early childhood (horizontal) transmission is particularly important in sub-Saharan Africa, Alaska, and Mediterranean countries where, in contrast to Asia, perinatal transmission is less common (1). The exact mode of early childhood transmission is unknown, but is thought to occur via unapparent blood or body fluid exposures from parents, siblings, or playmates that inoculate HBV into cutaneous scratches, abrasions, or onto mucosal surfaces. Person-to-person horizontal transmission occurs from intimate contact with exchange of bodily fluids or from parenteral exposure, such as illicit drug use. However, up to 40% of adults with acute HBV infection cannot or will not identify a specific route of exposure, which in part reflects the highly infectious nature of this virus even in the absence of recognized risk factors. In contrast with the acutely infected infant or child, the otherwise healthy adult with acute HBV is highly likely to successfully clear the infection. Paradoxically, the more symptomatic the acute illness, the more likely the HBV is to resolve without event and without progression to chronicity. This is because a brisk immune response is believed to produce more hepatocyte injury during viral clearance. Immunocompromised individuals, such as those infected with HIV, dialysis patients, and the elderly are more likely to have sub-clinical acute HBV and develop chronic infection. The recognition that an exacerbation of chronic HBV infection can mimic initial acute HBV infection led to a reevaluation of the rate of chronicity in healthy adults, which is now estimated to be less than 1% rather than the more frequently quoted rate of 5% (51). 2.3.1. S PECIFIC M ODES OF T RANSMISSION Mother-to-Child Transmission Maternal–fetal transmission of hepatitis B virus is an important problem, particularly in endemic areas such as Southeast Asia and Africa. The placenta forms an excellent barrier against transmission of this large virus, and intrauterine infection with HBV is rare. It does occur, however, probably as a result of transplacental leakage, as in threatened abortion and at the time of delivery.
198
Sarin and Kumar
If a mother is infected with HBV during pregnancy and develops acute hepatitis B, the infant’s infection depends on the gestational age at the time of maternal hepatitis. Acute hepatitis in the first to second trimester rarely causes HBV infection of the newborn, whereas hepatitis in the third trimester or during the postpartum period frequently leads to HBV infection of the newborn infant, which suggests that mother-toinfant transmission of HBV occur mainly in the perinatal period, rather than in utero. Vertical transmission of HBV from mother to infant occurs peripartum or in the initial months after birth. Transmission in utero can occur, but accounts for less than 2% of perinatal transmissions (52). Breast feeding is not considered a major route of mother-to-infant infection of HBV. HBeAg status has a putative role in facilitating vertical transmission of HBV from mother to child. Infants born to mothers who are both HBeAg and HBsAg positive have upto a 95% risk of acquiring HBV infection in the absence of immunoprophylaxis. By contrast, transmission rates range from 10 to 40% for infants born to HBeAg-negative mothers. Appropriate immunoprophylaxis interrupts transmission in more than 90% of cases. However, immunological blockade fails in approximately, 10% of neonates who later became chronically infected with HBV. It is currently thought that the major cause of unsuccessful immunological blockade is the intrauterine infection of HBV, which occurs when the placental barrier becomes infected (53). Blood and Tissue Donations Universal screening of blood donors with HBsAg has reduced the risk for transfusion-transmitted HBV. Many countries with low prevalence have also added tests for anti-HBc to detect chronically HBVinfected patients with low-level viremia who may not have detectable HbsAg (occult HBV). These two tests decrease infection rates to approximately 2.5–15.3 per million units of blood in low-prevalence areas (54). The United States, Canada, Japan, Australia, and some European countries perform the more sensitive nucleic acid tests in addition to these two serologic tests. The magnitude of the incremental yield and clinical benefit of nucleic acid tests over serologic tests in these low-prevalence areas, as well as the need for performing serologic tests in addition to nucleic acid tests, is unknown. Anti-HBc cannot be used as a screening test in high-prevalence areas because up to 90% of adults may have serologic evidence of either past or ongoing hepatitis B infection. Hence, combined HBsAg and anti-HBc screening would disqualify most volunteer blood donors. Therefore, in such countries, HBsAg alone is currently used for screening this population.
Natural History of Chronic Hepatitis B Infection
199
However, in high-prevalence areas, 3–30% of individuals who are antiHBc-positive and HBsAg-negative are HBV DNA positive in blood. It has been estimated that HBsAg-negative, HBV DNA positive blood carries an approximately 10% risk of transmitting HBV to susceptible recipients (55). With donor screening strategies using only HBsAg, the risk for transfusion-transmitted HBV infection in Taiwan was recently estimated to be 100 per million units, that is, at least 7–40 times higher than in low-prevalence areas (56). The yield of nucleic acid tests was projected to be 20 times greater in high-prevalence areas than in lowprevalence areas, where it is currently used, making it that much more cost-effective per infection prevented in these countries (55). However, nucleic acid tests vary in sensitivity and specificity and are too expensive for routine use in high-prevalence areas (57). Another potential mode of transmission for HBV is from organ or tissue donation. It has been estimated that undetected viremia at the time of donation may be more common among tissue donors than blood donors (58). Although the simplest way to prevent posttransplant infection is to exclude all anti-HBc-positive individuals as potential donors, this approach may be impractical in high-prevalence areas where the majority of the population has been previously exposed. Therefore, the addition of nucleic acid testing to strategies in the screening of tissue donors may be the best option for reducing the risk of transmission. Renal Replacement Therapy The prevalence of HBV infection in patients on renal replacement therapy varies considerably among different areas of the world varying from 1.5 to 53% among hemodialysis patients and 2.4–31% among renal transplant recipients (59). It is usually similar in dialysis patients and renal transplant recipients, but is increased compared with the general population, indicating that infections occur mainly during the time of dialysis. Two epidemiological patterns can be observed. First is a geographical distribution, which reflects the disease burden in the general population. It is higher in the Middle East and Far East compared with Western countries. Within Europe, a north–south gradient of increased prevalence has been reported. Second, countries with a lower socioeconomic status have a higher prevalence among dialysis patients, indicating lower resources for maintenance of hemodialysis units, HBV vaccination programs, and erythropoietin treatment (60). Repetitive blood transfusions are the single most important factor for hepatitis virus transmission, whereas infection through contaminated hemodialysis equipment occurs less frequently. Finally, patientto-patient transmission of HBV with transplanted organs has been reported. Sharing of supplies, instruments, or medications between
200
Sarin and Kumar
hemodialysis patients and reuse of dialyzers would in theory increase the spread of HBV between patients. Transmission by Unsafe Medical Practices Transmissions through contaminated and nonsterile injection practices and through inadequately sterilized medical instruments remain a significant problem in low-income areas. Unsafe injection practices coupled with the popular and sometimes unnecessary use of injections in low-income countries is a complex public health problem. Low-income countries include most of Africa, the Indian subcontinent, some Southeast Asian countries, and Mongolia. Infection control policies, guidelines, and practices to enhance the safety of patients and health workers have been widely researched, implemented, and evaluated in high-income countries. Consequently, the risk of nosocomial HBV infection due to unsafe injection practices in developed countries is extremely small. However, in low-income developing countries, unsafe injection practices are comparatively common, placing both patients and health workers at risk of infection with hepatitis B and other bloodborne viruses (61). Patients are at risk because both single-use disposable and reusable needles and syringes are reused, and the methods employed to clean and sterilize the equipment between patients are often suboptimal, if used at all. Health workers are at risk because they are required to handle used injecting equipment in order to clean and sterilize it for reuse. The number of HBV infections attributable to unsafe injection practices (defined as the reuse of a syringe or needle from patient to patient without sterilization) in low-income countries has been calculated as 8–16 million infections globally every year (62). The World Health Report (2002) reports that unsafe injection practices account for 30% of HBV infections worldwide. Episodes of HBV transmission from one patient to another in healthcare settings have also been reported from developed countries (63). In most cases, these transmissions resulted from noncompliance with recommended infection control practices that were designed to prevent cross contamination of medical equipment and devices. Health-Care Workers and Hepatitis B In the prevaccination era, transmission of HBV in medical settings was a severe public health problem. A high rate of HBV infections in health-care workers (HCW) was observed. HBV transmission was especially frequent in cases of direct contacts with blood, such as surgery, hemodialysis units, or oncology wards. However, the numbers
Natural History of Chronic Hepatitis B Infection
201
of HBV infections of HCW have dropped significantly during the last few decades due to vaccination. Because more than 95% of vaccines developed protective antibodies, the risk of vaccinated HCW to acquire HBV during their professional activities is now minimal. However, not all HCW are vaccinated or are responders to vaccine and, therefore, are at risk to acquire HBV infection. In a recent study from India, only 55% of the 2,162 HCWs screened had received vaccination, 28% were unvaccinated, and 17% were unaware of their vaccination status. Protective (>10 IU/ml) anti-HBs titers were seen in only 61.7%. One percent HCWs were HBsAg positive, 24.7% had past exposure (IgG anti-HBc positive), and occult HBV was detected in 5% of HCWs with past exposure (64). HCWs, who are chronically infected with HBV, represent a potential risk for their patients. Since the early 1970 s, HBV-infected HCWs have been identified as the source of infection for patients who underwent surgical procedures. The risk for patients becoming infected during surgical procedures depends on several factors including serum HBV DNA level and HBeAg positivity, skill, and medical condition of the HCW. Other factors include duration of surgery, volume of blood transmitted, and route of transmission (percutaneous vs. mucosal). Although various routes of transmission of HBV have been described, most HBV infections are caused by contact with infected blood. Sharp injuries with needles or other sharp devices can occur during the treatment of patients. During operative procedures, the risk for contact between the HCW’s and patient’s blood has been estimated to be 2.02–2.21% (65, 66). A recent survey on surgeons in training at 17 medical centers across the United States found that 83% of surgeons in training had had a needlestick injury during training (67). The estimated annual frequency of pathogen-specific percutaneous injuries was 1,168 for hepatitis B in a nationwide survey in Taiwanese health-care workers (68). The amount of infected blood transmitted affects the risk of transmission. The number of HBV particles transmitted by a needlestick and during delivery depends on the viral load and the volume of blood transmitted. HBeAg/anti-HBe status is often used as a marker of infectivity. However, serum HBeAg is at best an indirect measure of hepatitis B viremia because of possible mutations. The infection risk after exposure to HBV-infected blood depends on the viral load which has only been determined in a few investigations. Sera of transmitting surgeons were found to contain HBV DNA levels between 5.0 ×109 and 6.35× 104 g Eq./ml. The lowest measured HBV DNA level in serum from a transmitting surgeon was 4.0×104 g Eq./ml in a sample taken at least 3 months after transmission (69). The proportion of patients infected
202
Sarin and Kumar
with HBV after treatment by an infected HCW varies between 0.5 and 13.1% in different investigations (70). The risk estimate for HBV in a model including four determinants (prevalence of HBV in medical staff, frequency of percutaneous injuries, frequency of a sharp objects contact with susceptible patients, and frequency of HBV transmission after exposure, e.g., by needle-stick injuries) was 2,400 HBV transmissions per 1 million surgical procedures (71). For comparison, the corresponding risks for hepatitis C is about 140 per million (72), and for HIV, about 24 per million surgical procedures (71). In this calculation the influence of surgeons’ HBV titers was not considered, although this factor may have an important impact on the rate of HBV transmission. Overall, the available estimates indicate that the risk of HBV transmission from infected medical personnel to patients is much higher than that for HCV or HIV.
2.4. Effect of Vaccination on the Epidemiology of Chronic Hepatitis B Immunization against HBV has always been a successful experience in universal vaccination campaigns in different countries. It is well known that success is not achieved when the strategy is oriented to vaccinating only risk groups. It is estimated that 25–30% of persons with hepatitis B deny having any risk factor whatever for acquiring the infection and, therefore, are not identified as vaccination targets. In the United States, only after vaccination was recommended for all newborns in 1991, and in 1996, routine immunization of adolescents from 11 to 12 years of age, was a substantial reduction found in the incidence of hepatitis B (73). Despite availability of vaccines, their introduction in infant immunization programs globally was limited during the 1980 s; the use of these vaccines being largely confined to protecting individuals at risk. In 1990, Ghendon’s WHO strategy for global elimination of new cases of hepatitis B, Younde Meeting in 1991, and then the Fourteenth Meeting of the Global Advisory Group of the Expanded program on Immunization recommended the integration of hepatitis B vaccine into national immunization systems in all countries with a hepatitis B carrier prevalence (HBsAg) of 8% or greater. Following the endorsement of the recommendations of the Global Advisory Group by the World Health Assembly in 1992, the number of countries with hepatitis B vaccine incorporated within their national immunization program has been continuously rising. The introduction of hepatitis B vaccine into developing countries received a further boost with the formation of the Global
Natural History of Chronic Hepatitis B Infection
203
Alliance on Vaccines and Immunization (GAVI), which is an international coalition of immunization partners (74). Primary indicators of a positive impact of hepatitis B vaccination may include: (1) decline in acute cases of hepatitis B; (2) reduction in the proportion of deaths attributable to complications of HBV (cirrhosis or HCC); and (3) falling seroprevalence of HBsAg in the vaccinated population. Unlike the situation with other vaccine-preventable diseases, the efficacy of hepatitis B prevention programs is not based solely on surveillance of acute disease. In particular, because most infections in children are asymptomatic, acute disease surveillance will not reliably measure the initial impact of routine infant vaccination. However, trends in acute hepatitis B disease incidence can be used to evaluate the effectiveness of programs directed at adolescents and adults who are more likely to have symptomatic infections after HBV exposure. Because most of the HBV-associated morbidity and mortality is related to chronic infection, demonstrating a reduction in the prevalence of chronic infection in children is the major early indicator of success. The serious adverse outcomes due to chronic HBV infection occur several decades after exposure; thus, much of the benefit of infant immunization on prevention of cirrhosis and HCC will not be realized for decades after a program is started. The positive impact of HBV vaccination has been demonstrated beyond doubt. In July 1984, Taiwan was one of the first countries in the world to mandate infant immunization against HBV. Within 10 years of introduction of universal immunization, HBsAg prevalence declined from 9.3 to 1.3% in children younger than 12 years (37). The incidence of HCC in children aged 6–14 years declined from 0.7 per 100,000 between 1981 and 1986, to 0.57 per 100,000 between 1986 and 1990, and to 0.36 per 100,000 between 1990 and 1996 (75). The HBsAg prevalence among persons younger than 15 years of age has declined from 9.8% in 1984 to 0.7% in 1999, thereby converting a hyperendemic into low endemic country within 15 years of the introduction of the hepatitis B immunization program (76). In Formosa, the mortality rate from fulminant hepatitis B in nursing infants, between the years 1974 and 1984, before the universal vaccination era, was 5.36/100,000. This rate fell to 1.71/100,000 between 1985 and 1998, after the vaccination program was launched. Universal vaccination against hepatitis B in these high endemicity countries effectively reduced both perinatal and horizontal transmissions, thus diminishing the rates of chronic hepatitis B (76, 77). In Formosa, the incidence of chronic HBVinfected subjects diminished from 10 to 1% in children under the age of 15 years (77). In Thailand, in less than 10 years after initiation of a vaccination program, the overall HBsAg prevalence declined from 3.4
204
Sarin and Kumar
to 0.7% among 1–18-year-olds (78). Vaccination has impacted the incidence and prevalence of hepatitis B infection in other Asian countries, converting high-prevalence to intermediate-prevalence areas, with the possible exception of China (79). The persistence of higher prevalence in China has been attributed to vaccine coverage of only 25–30% of the population in this country (80). Similar effects have been reported from African countries as well. In the Gambian Hepatitis Intervention Study (81), the protective efficacy of the vaccine in preventing chronic infection in the first 3 years of life was estimated to be 95%. Despite a relatively high prevalence of HBV infection in the general population and women of childbearing age, integrating infant immunization within the current schedule of 6, 10, and 14 weeks had a significant impact on reducing the prevalence of chronic infection, as shown in South Africa where the HBsAg prevalence rate declined from 12.8% in 3-year-olds to 3.0% within 5 years of initiation of the vaccination program (82). Similarly, in Saudi Arabia, following the introduction of the vaccine, the overall HBsAg prevalence dropped from 6.7% in 1989 to 0.3% in 1997 in children aged 1–12 years (83). The effect of vaccination has also been marked in European countries. Italy was one of the few countries in Europe to introduce hepatitis B vaccination, initially based on a high-risk approach, but expanded to cover both infant and adolescents in 1991. Between 1985 and 1996, the prevalence of chronic HBV infection rate has fallen from 3.4 to 0.9% with the greatest decline in the age group 15–24 years (84, 85). In Bulgaria, following the introduction of HBV immunization in 1991, a coverage level of 71.3% was reached by 1992 and a dramatic decline in the reported annual incidence of acute hepatitis B in infants was seen, from 22 to 30 per 100,000 in the early 1980 s to 5.6 per 100,000 (86). In the United States, following the adoption of universal infant vaccination in 1991, the incidence of acute hepatitis B in children and adolescents has decreased by 89%, and the racial disparities in the prevalence of chronic HBV infection have narrowed (87). There has been a marked decrease in new infections following vaccination in Alaska, where HBV is endemic (88). This dramatic decline can be expected to result in a reduced incidence of cirrhosis and HCC in the coming decades. Therefore, effectiveness of routine infant hepatitis B immunization in significantly reducing or eliminating the prevalence of chronic HBV infection has been demonstrated in a variety of countries and settings. In general, the greatest impact has been achieved in high HBV endemic areas that have achieved high vaccine coverage among infants, and where the vaccine was administered at birth. However, HBV
Natural History of Chronic Hepatitis B Infection
205
vaccination programs have produced remarkable results even when the policy is not universal or consistent throughout a country. For example, a reduction in the HBsAg prevalence among children from 10.0 to 0.6% and from 18.7 to 2.2%, has been reported in Gambia and Senegal, respectively, the two African countries that have been able to implement vaccination in only a portion of their population (89). Many long-term hepatitis B immunization programs have demonstrated a greater than expected benefit in terms of disease reduction when compared with levels of vaccination coverage. A possible reason for this finding is that the pool of individuals that is highly infectious to others is greatly reduced by preventing chronic infections in children. Not only are new infections in children more likely to become chronic, but chronically infected children are likely to be HBeAg positive and highly infectious to others. Thus, by preventing infections in children, the number of HBeAg-positive persons declines rapidly over time because of the inherent clearance of HBeAg in older persons (90). At present, the development of mutants as a result of vaccination programs is of concern in high endemicity countries. The emergence of surface gene mutants, with mutations mainly occurring within the “a” determinant, has been observed in some vaccinees in several areas of the world. The mutants may go undetectable by current diagnostic assays and potentially cause breakthrough infections in a vaccinated population (91), thus posing a potential threat to the long-term success of vaccination programs. The prevalence of surface antigen gene mutants increases gradually 5–10 years after the programs are instituted. In Taiwan, the prevalence of “a” determinant mutants in HBV DNA positive children was 7.8% in 1984, significantly increased to 19.6% in 1989, peaked at 28.1% in 1994, and remained at 23.1% in 1999; it was higher in those fully vaccinated compared with those not vaccinated. However, the number of mutant infected children in each survey was stable in the first 5–10-year period but decreased 10–15 years post vaccination. More HBsAg positive “a” determinant mutants emerged in children fully vaccinated with plasma-derived vaccine than those given recombinant vaccine. Thus, although “a” determinant variants have an advantage in infecting immunized children, they do not threaten current HBV vaccination strategies in Taiwan (92).
2.5. Epidemiology of Special Situations 2.5.1. HBV HCV C OINFECTION The exact number of patients infected with both HCV and HBV is unknown. One Eastern European study found a rate of dual infection
206
Sarin and Kumar
in 0.68% of a randomly selected healthy population of over 2,200 individuals (93). In patients with chronic hepatitis B, estimates of the rates of HCV coinfection vary from 9 to30%, depending on the geographic region. One Italian study found that rates of dual infection increased with age, and was more common in patients over 50 years of age (94). These numbers may underestimate the true number of patients with both viral infections because no large-scale studies have been performed, and occult HBV (presence of HBV DNA in the sera and/or liver of persons who are HBsAg-negative) is a problem in patients with chronic hepatitis C (see later). Occult HBV infection has been found to be very common (45%) in HCV-infected injection-drug users in the United States (95). 2.5.2. HBV-HIV C OINFECTION There is evidence of prior HBV infection in approximately 90% of HIV-infected persons whereas chronic HBV infection (indicated by reactive HBsAg) is detected in 5–15% of HIV-infected persons globally (96). HIV infection is associated with the failure to seroconvert following acute infection and a greater risk of developing chronic hepatitis B infection compared to HIV seronegative person. Detection of HBV DNA in the serum in the absence of HBsAg has been reported in persons with HIV infection, particularly those with anti-HBc IgG alone. However, estimates of the prevalence of occult HBV infection vary considerably from 0 to 10% (97, 98). Further, in several studies, occult HBV infection has not been associated with elevation in serum ALT and the clinical significance in HIV-infected persons is uncertain. 2.5.3. E PIDEMIOLOGY OF O CCULT HBV Occult hepatitis B virus infection (HBV) can be defined as the longlasting persistence of viral genomes in the liver tissue (and in some cases also in the serum) of individuals negative for the HBsAg. The gold standard to test for occult HBV is the analysis of DNA extracts, from liver as well as from blood samples, performed by a “nested” PCR technique and the use of oligonucleotide primers specific for at least three different HBV genomic regions. With this approach, only the cases in which HBV DNA is detected using at least two different sets of primers may be considered positive for the occult infection (99). Occult HBV infection is a worldwide entity, although its distribution may reflect the general prevalence of the HBV in various geographic areas and in various populations. HCV-infected patients are the category of individuals with the highest prevalence of occult HBV. In particular, HBV DNA is detectable in about one-third of HBsAg-negative HCV carriers in the Mediterranean Basin and this prevalence is even higher in Far East
Natural History of Chronic Hepatitis B Infection
207
Asian countries. In a recent Lebanese study, the prevalence of occult HBV infection ranged from 11.9 to 44.4% in HCV-infected patients and it increased with increasing severity of the liver disease. Although Lebanon is an area of low endemicity for both HBV and HCV, occult HBV infection is common in HCV-infected patients (100). A variable prevalence (2–24%) of occult HBV infection has been reported in subjects with cryptogenic liver disease (101, 102). Besides patients with liver disease, individuals at high risk of parenterally transmitted infections have also been widely investigated for occult HBV. In general, a high prevalence has been reported, with 45% intravenous drug addicts in Baltimore (95) and 51% hemophiliacs in Japan (103) having occult HBV infection. The studies performed on hemodialysis patients provide widely divergent results, reporting a prevalence of occult HBV ranging from 0 to 36% (104). These discrepancies appear to be mainly dependent on the different sensitivity and specificity of the assays utilized in the various studies. Widely divergent prevalence of occult HBV, ranging from 0 to 89% (105, 106), has been reported in HIV positive individuals. This difference relates to the great difference in sensitivity and specificity of the assays used in these various studies. The study finding the highest prevalence of occult HBV both used a very sensitive HBV DNA amplification procedure and examined serial serum samples from each individual (105, 106). Since serum HBV DNA levels fluctuate even in occult HBV-infected patients, repeating the HBV DNA test over time is a useful tool in identifying the occult HBV cases. Among the populations of apparently healthy individuals, occult HBV has been extensively explored in blood donors and much less in the general population. Among blood donors, occult HBV infection is of rare occurrence in the western world, whereas it is frequently detected in the developing world. As far as the general population is concerned, a recent study evaluating occult HBV prevalence in HBsAgnegative residents of a Canadian Inuit community detected HBV DNA in 18% of anti-HBc-positive subjects and in 8% of HBV seronegative individuals, respectively (107), whereas occult HBV infection was detected in 3.4% among voluntary blood donors from India (102).
2.6. Molecular Epidemiology HBV, the hepadnavirus infecting humans, is classified into eight genotypes (A, B, C, D, E, F, G, and H) by phylogenetic analyses using alignments of whole genomes. HBV genotypes differ by at least 8%. Due to the genetic diversity of HBV, numerous subgenotypes of HBV have been described (108, 109) (Table 1; Fig. 5).
208
Sarin and Kumar Table 1 HBV Genotypes and Geographic Prevalence Subgenotype
A
B
C
D
F
Synonyms
A1
Aa, A
A2 A3 A4 A5 B1 B2 B3 B4 B5 B6 C1
Ae, A–A Ac
C2
Ce
C3 C4 C5 D1 D2 D3 D4 D5 F1 F2 F3 F4
Bj Ba
Cs
Geographic Origin
Reference
Africa, (Asia, South America), India Europe Gabon, Cameroon Mali Nigeria Japan Asia (excluding Japan) Indonesia, Philippines Vietnam Philippines Alaska South East Asia (Vietnam, Myanmar, Thailand, Southern China) Far East (Korea, Japan, Northern China) Micronesia Australia Philippines, Vietnam Mongolia, Belarus, Europe India South Africa, East India, Serbia Australia East India South and Central America South America Bolivia, Colombia, and Venezuela Argentina
(112, 118, 121) (122–124) (125) (125) (113, 115) (109) (109) (126, 127) (119) (128)
(109) (129) (127)
(118) (111, 112) (129) (111) (130, 131) (132) (133, 134) (133, 134)
Natural History of Chronic Hepatitis B Infection
209
Fig. 5. Geographic distribution of HBV genotypes and subgenotypes (reproduced with permission from reference 108).
HBV subgenotypes differ by at least 4%. In genotypes A, B, and C, epidemiological data show that the respective subgenotype pairs A1/A2 (formerly termed Aa/Ae) (110), B1,6/B2–5 (formerly Bj/Ba) (110), and C1/C2 (formerly Cs/Ce) differ substantially in many virological and probably some clinical parameters. Subgenotypes also show distinct geographic distribution. However, this is not true for genotype D with subgenotypes D1, D2, and D3 being described as widespread in the world; e.g., D3 was found in Asia (East India) (111), South Africa (112), and Europe (Serbia). HBV genotype B (HBV/B) can be divided into two major geographically distinct groups, provisionally designated “Bj” (“j” for “Japan”) and “Ba” (“a” for “Asia”) (113, 114). Molecular evolutionary analyses have shown that HBV/Ba includes four subgenotypes B2–B5 (113–115). Distinguishing these from the HBV/Bj/B1 subgenotype, the HBV/Ba/B2–B5 subgenotypes demonstrate evidence of intergenotypic recombination with HBV/C, in a genome part corresponding to the core promoter/precore/core (Cp/preC/C) genomic region (115). Clinically, HBV/Ba infection has been found in many Asian countries such as Taiwan to be associated with a higher risk of development of HCC in chronic HBV-infected subjects (116). By
210
Sarin and Kumar
contrast, in Japan, HCC has less commonly been associated with subgenotype Bj (117). In addition, the prevalence of HBeAg in persons infected with HBV/Bj has been found to be lower than that in persons infected with HBV/C or HBV/Ba (117). Although genotypes B and C are more prevalent in Asian countries, in India, genotypes D and A are more prevalent (118). A novel subgenotype, “B6,” of HBV/B in indigenous Arctic populations with chronic liver disease has been described (119). Thus, it has been suggested that HBV/B be considered to be a genotype present in two major forms: a nonrecombinant type (Bj/B1 and B6) and a recombinant type (Ba/B2–B5) (119). Except for genotype E and G, all HBV genotypes can be divided into subgenotypes. The absence of subgenotypes in HBV genotype E has been assumed to be the consequence of a recent genesis for genotype E. The case for HBV genotype G appears to be less clear. Genotype G was originally found in the United States, France, and Germany. Later, partial sequencing of HBV genes pointed to a high prevalence of HBV genotype G in Mexico. Nevertheless, the geographic origin of HBV genotype G remains unknown (120). 2.6.1. D OUBLE I NFECTIONS AND R ECOMBINANTS Double infections with two different HBV genotypes have been known since typing was done serologically. Subsequently, evidence of super infection with HBV isolates of the same or different genotype was described in chronic HBV patients. Additional observations came from patients treated with interferon, where after treatment and relapse, a switch of the genotype has been described (135). Using different methods for genotyping, several reports described high rates of double infection with two different HBV genotypes in all parts of the world. Using these methods double infections have been found in 4.4–17.5% (136). Even triple infections with HBV of genotypes A, B, and C have been described in 0.9% of HBV-infected intravenous drug users (137). Infection with HBV of genotype G seems to be associated very often with an infection of HBV genotype A (138). Japanese strain of HBV having a recombination between genotypes C and D have been reported (139). Recently, recombinant genotypes A and D have been identified from India (140).
3. SCREENING HIGH-RISK POPULATIONS TO IDENTIFY HBV-INFECTED PERSONS In developed countries such as the United States where most of the infants, children, and adolescents have been vaccinated against HBV, the risk of transmitting HBV in daycare centers or schools is
Natural History of Chronic Hepatitis B Infection
211
extremely low and HBsAg-positive children should not be isolated or prevented from participating in activities including sports. Table 2 displays AASLD recommendations for the population and high-risk groups that should be screened for HBV infection and immunized if seronegative (1). The tests used to screen persons for HBV should
Table 2 Groups at High Risk for HBV Infection Who Should Be Screened (From Reference 1) Individuals born in areas of high (>8%) and intermediate-prevalence rates (2–7%) for HBV including immigrants and adopted children# —South Asia (except Sri Lanka) —Africa —South Pacific Islands —Middle East (except Cyprus) —European Mediterranean: Greece, Italy, Malta, Portugal, and Spain —The Arctic (indigenous populations) —South America: Argentina, Bolivia, Brazil, Ecuador, Guyana, Suriname, Venezuela, and Amazon region of Colombia and Peru —Independent states of former Soviet Union —Eastern Europe, including Russia, except Hungary —Caribbean: Antigua and Barbuda, Dominica, Dominican Republic, Granada, Haiti, Jamaica, Puerto Rico, St Kitts and Nevis, St Lucia, St Vincent and Grenadines, Trinidad and Tobago, and Turks and Caicos Other high-risk groups recommended for screening —Household and sexual contacts of HBsAg-positive persons∗ —Persons who have ever injected drugs∗ —Persons with multiple sexual partners or history of sexually transmitted disease∗ —Men who have sex with men∗ —Inmates of correctional facilities∗ —Individuals with chronically elevated ALT or AST∗ —Individuals infected with HCV or HIV∗ —Patients undergoing renal dialysis∗ —All pregnant women # If HBsAg-positive persons are found in the first generation, subsequent generations should be tested. ∗ Those who are seronegative should receive hepatitis B vaccine.
212
Sarin and Kumar
include HBsAg and hepatitis B surface antibody (anti-HBs). Alternatively, hepatitis B core antibody (anti-HBc) can be utilized as long as those who test positive are further tested for both HBsAg and anti-HBs to differentiate infection from exposure. Some persons may test positive for anti-HBc but not HBsAg or anti-HBs. The finding of isolated anti-HBc can occur for a variety of reasons: (1). Anti-HBc may be an indicator of chronic HBV infection; in these persons, HBsAg had decreased to undetectable levels but HBV DNA often remains detectable, more so in the liver than in serum (Occult HBV infection). (2). Anti-HBc may be a marker of immunity after recovery from a prior infection. In these persons, anti-HBs had decreased to undetectable levels but anamnestic response can be observed after one dose of HBV vaccine (141). (3). Anti-HBc may be a false positive test result particularly in persons from low-prevalence areas with no risk factors for HBV infection. These individuals respond to hepatitis B vaccination similar to persons without any HBV seromarkers (142).
4. NATURAL HISTORY OF CHRONIC HBV INFECTION A number of phases of chronic HBV infection are recognized, reflecting the dynamic interaction between the virus and the human host immune system (143).
4.1. Phases of Chronic HBV Infection Following Vertical Transmission 4.1.1. I MMUNE -T OLERANT P HASE In patients with perinatally acquired HBV infection, the first phase (immune tolerance) is characterized by the absence of elevated transaminase levels despite evidence of active HBV replication (presence of HBeAg and HBV DNA in serum). During this phase, which may last 1–4 decades, spontaneous and treatment-induced HBeAg seroconversion is infrequent (<5% per year). Liver biopsy during immune tolerance often reveals an absence of inflammation and scarring. HBcAg is abundant in hepatocyte nuclei during this phase. A study from Taiwan followed 240 patients (54% men, mean age 27.6 years) who presented in this phase and found that only 5% progressed to cirrhosis and none to HCC during a follow-up period of 10.5 years (144). These findings indicate that prognosis is generally favorable for patients who are in the immune tolerant phase. However, recent data have shown that more than one-third of HBeAg-positive HBV-infected patients
Natural History of Chronic Hepatitis B Infection
213
with persistently normal ALT have significant fibrosis on liver biopsy (145). In patients with childhood- or adult-acquired HBV infection, the “immune tolerant” phase is short-lived or absent. 4.1.2. I MMUNE -R EACTIVE P HASE During the immune-reactive phase (immune clearance/HBeAgpositive chronic hepatitis), symptoms of liver disease may appear for the first time. Increased immune pressure on the virus during this phase leads to suppression of serum HBV DNA levels and accelerated clearance of HBeAg with seroconversion to anti-HBe. This phase is characterized by the presence of HBeAg, high or fluctuating serum HBV DNA levels, persistent or intermittent elevation in serum aminotransferases, and active inflammation on liver biopsy. The “flares” of aminotransferases are believed to be manifestations of immune-mediated lysis of infected hepatocytes secondary to increased T-cell responses to hepatitis B core antigen (HBcAg) and HBeAg. These flares may precede HBeAg seroconversion, but many flares only result in transient decreases in serum HBV DNA levels without loss of HBeAg and some flares may lead to hepatic decompensation. Generally, the flare subsides after a variable period of time, although the associated liver injury may not regress and fibrosis can result. Lobular hepatitis now becomes evident on histology and the histological changes may mimic acute hepatitis. However, the portal tracts tend to enlarge with fibrosis, and HBsAg can be demonstrated by specific stainings in hepatocytes, which is not seen in acute hepatitis B. HBcAg, which in the previous phase resided in the hepatocytes nucleus, is now frequently seen also in the cytoplasm. Histological changes can vary from mild hepatitis to cirrhosis. The duration of the “immune clearance” phase, and the frequency and severity of the flares, correlate with the risk of cirrhosis and HCC. Recurrent “flares” are more common in men and may explain why HBV-related cirrhosis and HCC are more common in men than in women. An important outcome of the “immune clearance” phase is HBeAg to anti-HBe seroconversion. Factors associated with higher rates of spontaneous HBeAg seroconversion include older age, higher aminotransferase levels, and HBV genotypes. High aminotransferase level is a surrogate marker for vigorous host immune response, accounting for its strong correlation with spontaneous as well as treatmentrelated HBeAg seroconversion. Studies from Asian countries, where genotypes B and C predominate, showed that genotype B is associated with a lower prevalence of HBeAg, HBeAg seroconversion at an earlier age, and more sustained virological and biochemical remission after HBeAg seroconversion (146, 147). Flares in aminotransferases were more typical in genotype C patients, suggesting that greater liver injury
214
Sarin and Kumar
at the time of seroconversion is also a feature of infection with this genotype (148). In a prospective cohort study, 1,158 Alaska Native persons were tested serially for HBeAg for a median of 20.5 years and were genotyped. Genotypes A, B, C, D, and F were identified. Genotype C persons initially HBeAg-positive were more likely than those with other genotypes to be positive on initial and final specimens and time to HBeAg clearance was longer (P < 0.001). Age at which 50% of persons cleared HBeAg was <20 years for those infected with genotypes A, B, D, and F and 47.8 years in genotype C (P < 0.001). After losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state (P < 0.001) (149). 4.1.3. L OW-R EPLICATIVE P HASE After destruction of the hepatocytes producing HBV, active replication of HBV decreases. In the serum, HBeAg disappears and anti-HBe starts to appear, ALT normalizes, and HBV DNA decreases. However, HBsAg is continuously produced by the liver cells containing integrated HBV genome. When the HBV genome starts to integrate within the hosts’ chromosomal DNA is unclear, but integration can be demonstrated readily at this stage. Because of the relatively lower HBV replication in the liver, hepatocytes are spared from attacks of the immune system, and the host once again becomes tolerant to HBV. The residual underlying pathology already present at the time of cessation of the HBV replication determines the outcome of the illness. If there is no cirrhosis caused by events during clearance phase, the previous liver injury may regress now. However, if cirrhotic changes are already present at the time of HBeAg seroconversion the cirrhosis remains and is likely to progress. Liver biopsy during this phase usually shows mild hepatitis and minimal fibrosis, but more severe liver damage including cirrhosis may be observed in patients who had accrued severe liver injury during the preceding “immune clearance” phase. HBcAg is generally not seen in the liver. This phase was referred to as the “healthy carrier” state in the past, but this is an erroneous label given that a significant proportion of patients may have high HBV DNA levels, hepatic fibrosis and the potential for further disease flares, and other complications such as HCC. Indeed, for patients with infection acquired at an early age, the majority of complications occur after HBeAg seroconversion. The so-called “inactive carriers” are rarely inactive and hence this term should preferably be abandoned. A better term would be “chronic HBV infection, with or without liver disease”; based on defined clinical, biochemical, and histological criteria (145). This relatively low-replicative phase may persist indefinitely, in which case the prognosis is generally favorable, especially if this state
Natural History of Chronic Hepatitis B Infection
215
is reached early. This is supported by a long-term follow-up study of HBsAg-positive healthy blood donors in northern Italy (150). No difference in survival was found between 296 HBsAg-positive blood donors and 157 uninfected controls over a 30-year period, and no episodes of hepatic decompensation were reported. Unfortunately, some patients in this phase have reactivation of HBV replication. Reactivation may occur spontaneously or as a result of immunosuppression. In one study of 283 Taiwanese patients followed for a median of 8.6 years after spontaneous HBeAg seroconversion, 67% had sustained remission, 4% had HBeAg reversion, and 24% had HBeAg-negative chronic hepatitis B. Cirrhosis developed in 8% and HCC in 2%, the risk being higher in those who had active hepatitis after HBeAg seroconversion (151). Recent data from India have shown that 13.8% of HBeAg-negative CHBV-infected patients with persistently normal ALT have significant fibrosis on liver biopsy (145). 4.1.4. R EACTIVATION P HASE The fourth phase (reactivation of HBV replication/HBeAg-negative chronic hepatitis B) is characterized by negative HBeAg, positive antiHBe, detectable HBV DNA, elevated aminotransferases, and continued necroinflammation. Whereas most patients reach this phase after a variable duration of nonreplicative phase, some progress directly from HBeAg-positive chronic hepatitis to HBeAg-negative chronic hepatitis. Patients in this phase are usually older and have more advanced liver disease because this represents a later phase in the course of chronic HBV infection. Serum HBV DNA levels are lower than in HBeAgpositive patients but may be high. The higher levels of serum HBV DNA result from a spontaneous mutation in the core or core promoter region of the viral genome. The precore mutation produces a stop codon in a region of the HBV genome that prevents the formation of HBeAg, whereas the basal core promoter mutation affects HBeAg transcription. These mutations either singly or in combination permit HBV replication in the absence of HBeAg. The hallmark of this phase is its fluctuating course. In a study of 164 anti-HBe-positive patients who were monitored at monthly intervals for a median period of 21 months, 64% had fluctuating alanine aminotransferase (ALT) levels, including 44% whose ALT levels were intermittently normal (152). Several investigators have attempted to define cutoff HBV DNA levels that would differentiate patients with HBeAg-negative chronic hepatitis from inactive carriers, but in view of the fluctuating course, serial testing is more reliable than a single test. A recent study found that reactivation of hepatitis B following HBeAg seroconversion correlated significantly with genotype C (P = 0.003), male sex (P = 0.03), alanine aminotransferase
216
Sarin and Kumar
levels >5 x upper normal limit during the HBeAg-positive phase (P = 0.02), and age at HBeAg seroconversion ≥40 years (P = 0.002) (153). HBeAg-negative chronic hepatitis B was originally reported in Mediterranean countries. It has now been reported in all parts of the world. The geographic variations in prevalence of HBeAg-negative chronic hepatitis B are related to the predominant HBV genotype in that region. Recent studies in Europe, Asia, and the United States have all reported an increased prevalence of HBeAg-negative chronic hepatitis and a decreased prevalence of HBeAg-positive chronic hepatitis (154); this may be related to increased awareness, decrease in new HBV infections, and aging of existing chronic HBV-infected subjects. Spontaneous HBsAg seroclearance has been reported to occur at the rate of 0.5–1% per year in patients with chronic HBV infection. HBsAg seroclearance is generally accompanied by undetectable serum HBV DNA, normalization of liver biochemistries, and improved liver histology. However, HCC has been reported in a small percent of patients, the risk being higher in those with cirrhosis, HCV coinfection, or older age at the time of HBsAg seroclearance (155).
4.2. Phases of Chronic HBV Infection Following Horizontal Transmission Horizontally acquired disease also evolves through a number of phases with active replication and hepatic necroinflammatory activity in the early months and years of chronic HBV infection. With time, replication often diminishes and host immune pressure results in HBeAg/anti-HBe seroconversion. This is followed by a quiescent phase of infection with lessened liver injury and evolution into a nonreplicative phase. Certain patients appear to suffer little morbidity after HBeAg seroconversion. For instance, studies of HBsAg-positive Italian patients in the inactive carrier state initially identified when they were rejected as blood donors showed that these individuals experienced no appreciable increase in liver-related morbidity over many years (150).
4.3. Predictors of Disease Progression in Chronic HBV Infection 4.3.1. C HRONIC HBV I NFECTION AND C IRRHOSIS The annual incidence of cirrhosis has been estimated to be 2–6% for HBeAg-positive and 8–10% for HBeAg-negative patients. The higher rate of cirrhosis among HBeAg-negative patients is related to older age and more advanced liver disease at presentation. Among HBeAgpositive patients, the rate of cirrhosis development is higher in those who remained HBeAg positive during follow-up. Other factors that
Natural History of Chronic Hepatitis B Infection
217
have been identified to be associated with progression to cirrhosis include significant alcohol intake, concurrent infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV), high levels of HBV replication, and HBV genotype (C>B). In a recent study from Taiwan, the 10-year cumulative probability of cirrhosis among chronic hepatitis B patients with HCV superinfection, HDV superinfection, and no superinfection was 48, 21, and 9%, respectively (156). Coinfection of HIV and HBV has also been shown to increase the risk of cirrhosis and liver-related mortality compared with HBV monoinfection. Patients who had HBeAg reversion had increased risk of cirrhosis compared with those who had sustained HBeAg seroconversion. In one study of 3,774 chronic HBsAg-positive patients aged 30–65 years, the adjusted relative risk of cirrhosis for patients with baseline serum HBV DNA >104 and >106 copies/mL was 2.3 (95% CI, 1.6–3.5) and 9.3 (95% CI, 6.5–13.1), respectively (157). Thus, persistent high levels of HBV replication (with accompanying hepatitis) increase the risk of cirrhosis, but the prognostic significance of a high serum HBV DNA level at a single time point in a young carrier (<30 years old) is unclear. Studies in Asia showed that genotype C is associated with HBeAg seroconversion at a later age and more active hepatitis than genotype B; these studies also found that genotype C is associated with a more rapid rate of progression to cirrhosis than genotype B (158, 159). 4.3.2. C HRONIC HBV I NFECTION AND HCC The incidence of HCC is higher in those with cirrhosis, as compared to those without cirrhosis. The annual incidence of HCC has been estimated to be <1% for HBV-infected subjects without cirrhosis, compared to 2–3% in those with cirrhosis (160). Other factors associated with development of HCC include coinfection with HCV (161), a family history of HCC (162, 163), significant alcohol intake (153), high levels of HBV replication (164), HBV genotype(C>B, D>A) (165–167), and core promoter mutations (168). Obesity, diabetes, and smoking may also contribute to the risk of HCC (169). Several lines of evidence support an association between HBV replication and the risk of HCC. In a prospective study of 11,893 Taiwanese men aged 30–65 years, followed for a mean of 8.5 years, the adjusted relative risk of HCC was six- to sevenfold higher among HBsAgpositive men who were HBeAg positive at entry than those who were HBeAg negative (170). Another study from Taiwan found that the risk of HCC increased with increasing baseline serum HBV DNA level. The adjusted odds ratio for patients with the highest quartile of HBV DNA level vs. those with the lowest was 7.26 (95% CI, 3.54–14.89) (171). Studies in Senegal and mainland China also confirmed an increased
218
Sarin and Kumar
risk of HCC among HBV-infected patients with high baseline serum HBV DNA levels (164). Unfortunately, none of these studies monitored serum HBV DNA and aminotransferase levels over time. The duration of high levels of HBV replication as well as the intensity and frequency of hepatitis activity may be more important than a high HBV DNA level on a random occasion in predicting the risk of HCC in individual patients. Several studies from Asia demonstrated that genotype C is associated with increased risk of HCC compared with genotype B (165, 166). This may be related to a longer duration of high levels of HBV replication and active hepatitis and a higher frequency of core promoter mutations. Core promoter mutations have been shown in many studies to be associated with increased risk of HCC and to precede HCC diagnosis (168). Core promoter mutations also have been found to be associated with more active hepatitis and are more frequently associated with genotype C than B (168). In addition, the most common core promoter mutations (A1762T, G1764A) result in corresponding changes in the overlapping X gene. The HBx protein is a potent transactivator and may activate host genes including oncogenes. HBV genotype D has been suggested to be predictive of the occurrence of HCC in young patients. In a study from India, genotype D was more prevalent in HCC patients < 40 years of age, as compared to incidentally detected asymptomatic HBsAg-positive subjects (63 vs. 44%, P = 0.06) (167). 4.3.3. HBV DNA L EVELS AND D ISEASE P ROGRESSION During the past few years, the key relationship between elevated and persistent viremia and disease outcomes (cirrhosis, HCC, and liver disease-related deaths) has been recognized. These data have shown that relatively low-level persistent viremia can increase an individual’s risk for these HBV-related outcomes. A study from Taiwan has clearly established a relationship between persistent HBV replication and the subsequent development of cirrhosis and HCC in patients with presumed early acquisition of HBV infection (172). The investigators in this prospective cohort study enrolled 3,653 chronically HBV-infected individuals, the majority of whom were HBeAg negative. Over a mean follow-up of 11.4 years without therapeutic intervention, the cumulative incidence of HCC was significantly related to baseline HBV DNA levels: 14.89% of those with baseline HBV DNA levels >1 million copies/mL (∼200,000 IU/mL) at entry developed HCC compared with only 1.30% of those with baseline HBV DNA levels < 300 copies/mL (∼60 IU/mL). The relationship between baseline HBV DNA levels and the development of HCC was constant in patients with an absence of cirrhosis and normal alanine aminotransferase (ALT) levels at baseline,
Natural History of Chronic Hepatitis B Infection
219
and this relationship persisted after adjusting for age, sex, alcohol use, and smoking status. Follow-up serum HBV DNA levels were available from some of the study participants. These values revealed that although a spontaneous reduction in HBV DNA levels during the course of the study diminished the risk for HCC, it did not eliminate it. The same group of investigators also correlated the development of cirrhosis with baseline HBV DNA levels (157). The researchers prospectively evaluated 3,582 individuals without clinical evidence of cirrhosis at entry and found that the incidence of cirrhosis began to increase when the baseline HBV DNA level was >10,000 copies/mL (∼2,000 IU/mL). The relative risk of cirrhosis development correlated with HBV DNA and was independent of HBeAg status and the ALT level. An unresolved issue is whether there is a threshold level of HBV DNA below which complications such as cirrhosis do not occur. Yuen and colleagues (173) prospectively assessed the complications associated with chronic HBV infection in Chinese patients over a 4-year period and correlated the occurrence of these complications with serum HBV DNA levels. However 28.9% of patients with complications had HBV DNA levels <200 copies/mL. 4.3.4. ALT L EVELS AND D ISEASE P ROGRESSION ALT level is commonly used as a biochemical marker of liver disease and has been important in defining which patients are candidates for therapy. The extent of liver cell necrosis and degree of elevated ALT level do not always correlate, and ALT measurements may fail to identify patients with necroinflammatory activity or fibrosis. In addition, the ALT activity may vary with body mass index, sex, abnormal lipid, and carbohydrate metabolism as well as the time of the day. According to a Korean study of 94,533 men and 47,522 women in the age range of 35–59 years, the relative risk for liver-related mortality was significantly higher in patients with ALT levels between 0.5 and 1x ULN compared to those with <0.5 x ULN (174), although this study did not test HBsAg and anti-HCV. Currently recommended and revised upper limit of normal ALT values are 30 IU/L for men and 19 IU/L for women. These values are almost half of the values traditionally accepted values of the upper limit of normal ALT. Elevated ALT has been considered to be associated with active liver disease on histology while normal ALT with inactive histology. Many initial studies had shown that among patients with HBV infection with normal ALT, about 50–90% of patients had either minimal changes or chronic persistent hepatitis on biopsy. Recently, however studies have described contrary findings also (145).
220
Sarin and Kumar
4.3.5. HBV DNA L EVELS IN PATIENTS WITH N ORMAL ALT Patients who are HBeAg positive with normal ALT (immunetolerance phase) have high levels of serum HBV DNA. Among patients who are HBeAg negative with normal ALT, it has traditionally been believed that they have low HBV DNA levels. However, in a recent study that investigated the correlation between serum ALT level and hepatitis B viral factors in HBeAg-negative patients with persistently normal serum ALT level (PNALT), it was found that 47.5% of patients with low-normal ALT (levels of less than 0.5x upper limit of normal) and 63.4% with high-normal ALT had serum HBV DNA level >104 copies/ml. Also compared with chronic HBV-infected subjects with low-normal ALT, those with high-normal ALT were older (41 vs. 37 years, P<0.001) (175). Studies from China have demonstrated that a significant proportion of patients with persistently normal ALT had elevated HBV DNA levels (145,176) (Table 3). Table 3 Histological and Virological Characteristics in Incidentally Detected Asymptomatic HBsAg-Positive Subjects with Persistently Normal ALT (PNALT) (Adapted from Reference 145) Patient Characteristic
HAI, median (range) >3, N (%) F score, median (range) Fibrosis stages [0/1/2/3/4] [%] Baseline HBVDNA (log cp/ml), N (%) <3 3–3.999 4–4.999 ≥5
HBeAg (+) PNALT [N=73]
HBeAg (–) PNALT [N=116]
5.0(1.0–11.0) 46(63) 1.0(0.0–4.0) 17.8/42.5/26.0/11.0/2.7
3(1–10) 23(39.7) 1(0–3) 39.7/46.6/8.6/5.2/0.0
5.23(2.78–9.27) 5(7.0%) 10(14.0%) 14(19.0%) 44(60.0%)
4.29(2.78–9.20) 29(25.0%) 23(20.0%) 23(20.0%) 41(35.0%)
4.3.6. H ISTOLOGY IN PATIENTS WITH N ORMAL ALT Elevated ALT has been considered to be associated with active liver disease on histology. Many initial studies had shown that among patients with chronic HBV infection with normal ALT, about 50–90%
Natural History of Chronic Hepatitis B Infection
221
of patients had either minimal changes or chronic persistent hepatitis on biopsy. Recent studies have, however, described higher prevalence of liver injury in such patients. In a recent analysis of chronic HBV patients, increasing age, higher ALT, higher grade of inflammation on biopsy, and HBeAg positivity predicted fibrosis: 18% of patients with PNALT had stage 2+ fibrosis and 34% had grade 2 or 3 inflammation. Overall, 37% of patients with PNALT had significant fibrosis or inflammation (177). A recent study from India found that 40.2 and 13.8% of HBeAg-positive and HBeAg-negative patients, respectively, with persistently normal ALT had significant fibrosis on histology (Tables 3 and 4) (145). Table 4 Histological Findings According to Baseline HBV DNA Levels Among HBeAg-Negative Patients with PNALT (Adapted from Reference 145) Group N
Baseline biopsy N (%) HAI [median (range)] HAI >3, N (%) F score [median (range)] Any fibrosis, N (%) Inactive liver disease [HAI <3, F ≤ 1], N (%) Active liver disease [HAI ≥3 and/or F ≥2], N (%)
HBVDNA < 105 copies/ml 75
HBV DNA < 3×103 copies/ml 65
HBV DNA < 104 copies/ml 52
29(38.7)
22(33.8)
9(17.3)
2.0(1–5)
2.0(1–5)
2.0(1–5)
6(20.7) 1.0(0.0–1.0)
6(27.3) 1.0(0.0–1.0)
3(33.3%) 1.0(0.0–1.0)
15(51.7) 23(79.3)
14(63.3) 16(72.7)
6(66.7%) 7(77.8%)
6(20.7)
6(27.2)
2(22.2)
Therefore, a considerable proportion of patients with normal or minimally elevated ALT are likely to have significant hepatic fibrosis. According to a large-scale study, there are differences in the cumulative risks of development of cirrhosis-related complications and HCC at 10 years of follow-up for patients with different ALT levels on presentation. Patients with ALT values near the upper range (0.5–1 x ULN)
222
Sarin and Kumar
have the same risk of development of complications as those with ALT 2–6 x ULN (173). 4.3.7. I NTERVENTIONS TO M ODIFY THE NATURAL H ISTORY OF C HRONIC HBV I NFECTION Accumulating evidence in the past 25 years showed that the risk of cirrhosis and HCC is higher in chronic HBV-infected subjects who undergo HBeAg seroconversion later in life, have persistent high levels of HBV replication, and long durations of active hepatitis. Thus, treatment that is effective in inducing sustained suppression of HBV replication may reduce the risk of cirrhosis and HCC. Long-term follow-up studies found that interferon therapy has a minimal effect on reducing the risk of cirrhosis, HCC, and liver-related mortality (178). However, a significant benefit has been observed among responders (178). The overall lack of benefit may be related to the low rate of sustained response after a single course of interferon therapy. The availability of oral antiviral therapy with minimal side effects has changed the paradigm of hepatitis B treatment. A study of patients who have received 3 years of lamivudine therapy found that necroinflammation as well as fibrosis was decreased, although maintenance of histologic benefit was mainly seen in patients who did not have evidence of lamivudine resistance (179). Lamivudine treatment has been associated with decreased risk of cirrhosis and major complications and improved survival. In a prospective, double-blind, randomized, controlled trial of lamivudine reported in 2004 (180), 651 Asian patients with compensated liver disease, who were positive for HBeAg or had serum HBV DNA >700,000 genome Eq./mL, with bridging fibrosis or cirrhosis on liver biopsy were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, a significant difference in disease progression as well as HCC was observed between the two groups despite a very high rate (49%) of lamivudine resistance. These data indicate that antiviral therapy can modify the natural history of chronic HBV infection. The results are likely to be better with newer antiviral agents such as adefovir and entecavir that have lower rates of drug resistance.
4.4. Natural History of HBV- and HCV-Coinfected Patients HBV and HCV interact with each other and affect immune responses. HCV infection can suppress HBV replication; patients with chronic hepatitis B who are coinfected with HCV have lower HBV DNA levels, decreased activity of HBV DNA polymerase, and decreased expression of HBsAg and hepatitis B core antigen in the liver. Furthermore,
Natural History of Chronic Hepatitis B Infection
223
patients with chronic HBV infection who become superinfected with HCV can undergo seroconversion of HBeAg and HBsAg to respective antibodies. The annual incidence of HBsAg seroconversion was found to be 2.08% in HCV-coinfected patients compared to 0.43% in patients with HBV monoinfection (181). HBV can reciprocally inhibit HCV replication as well. In one Italian study, coinfected patients had a rate of HCV RNA clearance of 71% compared to 14% with HCV monoinfection (182). HBV replication in coinfected individuals may result in more liver inflammation. Furthermore, coinfected patients have been demonstrated to have lower levels of both HBV DNA and HCV RNA than corresponding monoinfected controls, indicating that concurrent suppression of both viruses by the other virus can also occur (183). Overall, both viruses can inhibit each other simultaneously; either virus can play a dominant role; both viruses have the ability to induce seroconversion of the other; the chronology of infection has a role in determining the dominant virus; and HBV and HCV can alternate their dominance. However, the dominant effect appears to be HCV suppression of HBV (184). There are various immune profiles of dually infected patients with chronic hepatitis. One possibility is dually active HBV and HCV, in which patients have detectable serum HBV DNA and HCV RNA. These patients are at the highest risk of progression to cirrhosis and decompensated liver disease. Another possibility is active HCV infection (positive HCV RNA) in the setting of an inactive HBsAg carrier. Such patients behave similar to patients with HCV monoinfection and likely exhibit HCV viral suppression of HBV activity. Another possibility is active HBV infection in patients with inactive or prior HCV infection (HBV DNA positive/HBeAg positive/HCV RNA negative/anti-HCV positive). This immune profile is less common and indicates HBV suppression of HCV. Coinfected patients have higher rates of cirrhosis with decompensation. One cross-sectional study found higher rates of cirrhosis (44% vs. 21%) and decompensated liver disease (24% vs. 6%) in coinfected patients compared to patients with chronic HBV monoinfection (185). HBV replication in coinfected patients (detectable serum HBV DNA) has been correlated with higher rates of cirrhosis, Knodell score, piecemeal necrosis, and fibrosis (186). Coinfection with HBV and HCV has been shown in many case– control studies to correlate with an increased risk of developing HCC (187). A longitudinal study reported a rate of incidence of HCC (per100 person years) of 6.4 in dually infected patients, compared to 2.0 in HBV- and 3.7 in HCV-monoinfected patients, and a 45% cumulative
224
Sarin and Kumar
risk of developing HCC at 10 years in coinfected patients, compared with 16 and 28% in HBV- and HCV-monoinfected controls (188).
4.5. Natural History of Chronic Hepatitis B in HIV-Coinfected Patients The outcome of HBV infection depends on the strength and quality of the innate and adaptive humoral and cellular immune responses. HIV-infected individuals show a quantitative depletion of CD4 T cells but also an overall immune dysfunction including dysregulation of the cytokine network, a decrease of the functional capability of CD8 T cells and, at later stages, a significant reduction in their number. Even in most cases with an absent host defense, HBV replication in the liver is noncytopathic. In HIV-infected patients, host deficiencies are not “absent” even in the most advanced stages and are often aberrantly activated. In such cases, the quality of HIV-induced deregulation of a still active anti-HBV immune response may be crucial in determining the necroinflammation and fibrosis. Coinfection with HIV significantly modifies the natural history of HBV infection. In patients with HBV infection, HIV coinfection is associated with higher chronicity rate of acute hepatitis B, higher levels of HBV replication, a lower rate of spontaneous loss of HBeAg and/or HBsAg, and seroconversion to anti-HBe and anti-HBs, and a high rate of seroreversion after CD4 T-cell depletion in those with spontaneousor interferon-induced anti-HBe seroconversion (189). There are contradictory data on the activity of inflammatory liver disease in coinfected patients. Cohort studies from northern Europe and United States of homosexual men showed a significantly less severe necroinflammatory activity in HIV-coinfected patients (190, 191). In contrast, some studies performed in Californian and French cohorts that included injection drug users showed increased necroinflammatory activity in HIV seropositive subjects (192). There are also contradictory data on the impact of HIV on hepatitis B progression toward cirrhosis: some studies from northern Europe and United States performed in the pre-HAART era did not reveal an unfavorable impact of HIV coinfection on hepatitis B evolution (193), while three French studies (194–196) identified a more rapid progression toward cirrhosis in HIV-coinfected individuals. These discrepancies could be related to differences in the prevalence of infecting HBV genotypes and of mutant HBeAg-defective HBV strains or the degree of immune suppression or to the different prevalence of cofactors associated with liver injury (alcohol, HCV, HDV) in the various cohorts. A higher rate of decompensation has been observed in HIV/HBV-coinfected individuals with
Natural History of Chronic Hepatitis B Infection
225
cirrhosis (197). There is no data supporting an accelerated progression toward HCC in HIV/HBV-coinfected people, although there is a more severe presentation of hepatocellular carcinoma and a lower survival in HBsAg-positive patients with HIV infection (198). Individuals coinfected with HIV and HBV are at a greater risk of liver-related death than those infected by HIV or HBV alone (or not infected with either virus) (199). Natural history of HBV-related disease in HIV-infected patients can be modified due to the highly active antiretroviral therapy (HAART). HAART may either prevent or treat opportunistic infections and some opportunistic tumors, thus decreasing the incidence of AIDS and increasing life expectancy of HIV-infected patients. The prolonged survival of HIV-infected individuals allows a longer time for cirrhosis to develop and, therefore, since the introduction of HAART, the relative proportion of deaths attributable to liver disease has been rising. This increase is due partly to an absolute decrease of classical opportunistic infections and tumors, but possibly also to an absolute increase in liver-related deaths (200). HAART may have a major impact on HBV coinfection because of restoration of immune responses and decrease of aberrant activation and deregulation of the immune system. In addition, at least three antiretrovirals (lamivudine, tenofovir, and emtricitabine) are potent inhibitors of HBV replication. HAART may therefore influence the natural history of chronic hepatitis B as follows: (a) By preventing acute infection in patients using antiretrovirals with dual activity. However, use of lamivudine as an antiretroviral was not associated with a decreased incidence of acute hepatitis B in a large cohort of HIV-infected subjects (201). (b) By inhibiting HBV replication after the introduction of antiretrovirals with dual activity. Tenofovir, lamivudine, and emtricitabine are able to suppress HBV replication depending on immune status, despite the frequent persistence of residual replication. The prolonged suppression of HBV replication leads to histological improvement and induces a significant decrease or normalization of aminotransferase levels and prevents disease progression to cirrhosis and end-stage liver disease (202). However, anti-HBe and anti-HBs seroconversion have been observed in a minority of patients starting HAART regimens. (c) By reactivating HBV replication after withdrawal of antiretrovirals with dual activity or emergence of HBV-resistant strains. Withdrawal of antivirals with dual activity has been associated with reactivation of HBV infection and with flares of liver enzyme elevations and hepatic decompensation in patients with advanced liver disease (203). Similar phenomenon has been observed after the occurrence of HBV genome mutations that are associated with resistance to lamivudine (204).
226
Sarin and Kumar
(d) By restoring adaptive HBV-specific immune response and innate nonspecific immune response, and reducing aberrant activation of the immune system. Independent of the use of antivirals with dual activity, HAART may induce reconstitution of the adaptive immune response and this is a “double-edged sword” in patients infected with HBV: on one side, HBV seroconversion can occur leading to a better control of HBV replication with or without flares of necroinflammatory activity; on the other hand, flares of necroinflammatory activity have been reported without modification of HBV markers and of HBV replication levels (205). Additionally, the rapid phase inhibition of HIV replication that occurs when HAART is started has been associated with a transient increase of HBV replication. This association may be related to cessation of HIV-induced secretion of cytokines with antiviral activity and may trigger flares of necroinflammatory activity in the very early phases of HAART. Given the complex interactions between HAART and HBV coinfection, it is not so easy to establish if HAART has a beneficial or a negative effect on chronic hepatitis B. Thio and coworkers observed an increase of liver-related mortality in HBsAgpositive people living with HIV in the HAART era (96). They failed to observe a significant association between lamivudine use and a lower liver-related mortality because of lack of information in most patients. However, several direct and indirect data support a positive effect of HAART on the natural history of hepatitis B. In a recent analysis of data from the Italian ICONA cohort, the use of lamivudine as a part of the first HAART regimen in naive patients was independently associated with lower liver decompensation-related morbidity (206). Low CD4 T-cell count nadir value has been associated with higher liverrelated mortality in HBsAg-positive patients and severe cases of reactivation of hepatitis B related to immune restoration (206). Therefore, an earlier use of HAART for prevention of severe immune dysfunction and the inclusion of a drug with dual anti-HBV activity might slow down progression of chronic hepatitis B in HIV-infected patients.
Occult HBV in HIV-coinfected patients pose different kinds of problems. Reactivation of HBV infection following severe immune depletion and/or lamivudine withdrawal can occur in HIV-coinfected patients without HBsAg and with markers of past HBV infection. However, HBsAg seroreversion occurred in only one out of 98 subjects followed prospectively, at a rate of 0.23/100 patient-year (207).
4.6. Natural History of Occult HBV Infection The virological and clinical reactivation of occult HBV infection may occur in certain clinical situations. In fact, an occult HBV-infected patient who becomes immunocompromised may show a reactivation
Natural History of Chronic Hepatitis B Infection
227
of viral replication because of faulty immunological control, Once recovery is achieved and immune surveillance reconstituted, Tlymphocyte-mediated hepatocyte injury may lead to the development of hepatitis. The virological and clinical reactivation of occult HBV infection has been observed in several different clinical conditions including hematological malignancies, HIV infection, hematopoietic stem cell transplantation, and organ transplantation. Occult HBVinfected patients undergoing OLT may present reinfection of the new liver and occasionally this event may be followed by virological and clinical reactivation. The availability of new, potent immunosuppressive drugs (like anti-CD20, anti-CD52, and anti-TNF monoclonal antibodies) used in various clinical settings, have further increased the risk of HBV reactivation in occult HBV-infected individuals (189). The frequency of occult HBV reactivation is still unclear. In a recently reported study performed on 14 anti-HBs/anti-HBc-positive patients who underwent allogenic hematopoietic stem cell transplantation (190), 12 individuals experienced progressive and persistent disappearance of anti-HBs and 7 patients had HBsAg seroconversion. Of these last seven cases, only one developed symptomatic acute hepatitis and needed hospitalization. This suggests that occult HBV reactivation is quite a frequent event in immunocompromised patients, but since it is usually investigated only in the case of development of acute hepatitis, its recognition might be missed in most of the cases. Thus it seems prudent to monitor all patients undergoing immunosuppressive therapy very carefully for HBV serology and/or viremia and to continue this monitoring for months (or even years) after stopping treatment. In fact, early identification of a virological reactivation makes it possible to begin specific antiviral therapy early, which may prevent the occurrence of reactivation. Individuals who have recovered from self-limited acute hepatitis may persistently carry HBV genomes for decades without showing any clinical or biochemical sign of liver damage. However, when the liver tissue of these subjects examined, histological patterns of a mild necroinflammation have been revealed up to 30 years after the resolution of acute hepatitis (208–210). Occult HBV infection might accelerate the progression of chronic liver disease in HCV-infected individuals (211, 212). Several studies have suggested that occult HBV infection may also exert its negative influence on chronic hepatitis C in terms of a reduced response to IFN therapy (213). The mechanisms by which occult HBV may help HCV to resist IFN are unknown. Most cited reports have used conventional IFN therapy, whereas there are no reliable studies evaluating whether occult HBV infection may interfere with the response to PEG-IFN plus
228
Sarin and Kumar
Ribavirin (the present gold-standard therapy for the chronic hepatitis C treatment). Several reports indicate that occult HBV infection is associated with the progression of liver fibrosis and cirrhosis development in patients with cryptogenic liver disease (214, 215). Occult HBV infection has also been cited as a risk factor for HCC development (216).
5. SUMMARY AND FUTURE DIRECTIVES In recent years, there have been great advances in the understanding of the epidemiology and natural history of chronic hepatitis B virus infection. Key relationships have been discovered regarding HBV DNA and ALT and disease outcomes. The concept of the so-called “Inactive carrier” has not been found to be convincing and is gradually fading. However, many issues still remain unanswered. One key issue is the importance and natural history of various genotypes in varying geographical regions. Another crucial issue is whether earlier treatment of chronically infected individuals with active viral replication who do not have the current conventional indications for antiviral therapy (i.e., elevated aminotransferases and necroinflammatory damage on liver biopsy) will alter their natural history. Only long-term prospective studies can answer these questions, but as the benefits of effective viral suppression have become more apparent, it will be more difficult to perform placebo-controlled trials of HBV therapy. Acknowledgment We are thankful to Mrs Meena Bajaj for computer and graphic assistance.
REFERENCES 1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–539. 2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contribution of hepatitis B and hepatitis C virus infection to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529–538. 3. Lavanchy D, Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11: 97–107. 4. Kowdley KV. The cost of managing chronic hepatitis B infection: a global perspective. J Clin Gastroenterol 2004;38(10 suppl):S132–S133. 5. WHO. Hepatitis B vaccines. Wkly Epidemiol Rec 2004; 79: 255–263. 6. Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res 2007; 37: S9–S19. 7. Triki H, Said N, Ben Salah A, et al. Seroepidemiology of hepatitis B, C and delta viruses in Tunisia. Trans R Soc Trop Med Hyg 1997; 91: 11–14.
Natural History of Chronic Hepatitis B Infection
229
8. Tswana S, Chetsanga C, Nystrom L, Moyo S, Nzara M, Chieza L. A seroepidemiological cross-sectional study of hepatitis B virus in Zimbabwe. S Afr Med J 996; 86: 72–75. 9. Darwish MA, Faris R, Clemens JD, Rao MR, Edelman R. High seroprevalence of hepatitis A, B, C, and E viruses in residents in an Egyptian village in The Nile Delta: a pilot study. Am J Trop Med Hyg 1996; 54: 554–558. 10. Pellizzer G, Ble C, Zamperetti N et al. Serological survey of hepatitis B infection in Tanzania. Public Health 1994; 108: 427–431. 11. Ndumbe PM, Atchou G, Biwole M, Lobe V, Ayuk-Takem J. Infections among pygmies in the Eastern Province of Cameroon. Med Microbiol Immunol (Berl) 1993; 182: 281–284. 12. Kurbanov F, Tanaka Y, Fujiwara K et al. A new subtype (subgenotype) Ac (A3) of hepatitis B virus and recombination between genotypes A and E in Cameroon. J Gen Virol 2005; 86: 2047–2056. 13. Dumpis U, Holmes EC, Mendy M et al. Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis. J Hepatol 2001; 35: 99–104. 14. Centers for Disease Control and Prevention. Incidence of acute hepatitis B – United States, 1990–2002. MMWR 2004; 52: 1252–1254. 15. Gish RG, Gadano AC. Chronic hepatitis B: current epidemiology in the Americas and implications for management. J Viral Hepat 2006; 13, 787–798. 16. Kim WR, Benson JT, Therneau TM, Torgerson HA, Yawn BP, Melton LJ 3rd. Changing epidemiology of hepatitis B in a U.S. community. Hepatology 2004;39:811–816. 17. Kim WR, Ishitani MB, Dickson ER. Rising burden of hepatitis B in the United States: should the other virus be forgotten? Hepatology 2002;36;A-222. 18. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide survey. Gastroenterology 2003;125:444–451. 19. Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 2003;38:619–628. 20. Euler GL. The epidemiology of hepatitis B vaccination catch-up among AAPI children in the United States. Asian Am Pac Isl J Health 2001; 9: 154–161. 21. Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. Hepatology 2007 Oct;46(4):1034–1040. 22. Tanaka J. Hepatitis B epidemiology in Latin America. Vaccine 2000; 18 (Suppl. 1): S17–S19. 23. Fay OH. Hepatitis B in Latin America: epidemiological patterns and eradication strategy. The Latin American Regional Study Group. Vaccine 1990; 8 (Suppl.): S134–S139. 24. Gish RG, Gadano AC. Chronic hepatitis B: current epidemiology in the Americas and implications for management. J Viral Hepat 2006, 13, 787–798. 25. Viana S, Parana R, Moreira RC, Compri AP, Macedo V. High prevalence of hepatitis B virus and hepatitis D virus in the western Brazilian Amazon. Am J Trop Med Hyg 2005; 73: 808–814. 26. Ono-Nita SK, Carrilho FJ, Cardoso RA, Nita ME, Da Silva LC. Searching for chronic hepatitis B patients in a low prevalence area – role of racial origin. BMC Fam Pract 2004; 5: 7.
230
Sarin and Kumar
27. Fonseca JC, Simonetti SR, Schatzmayr HG, Castejon MJ, Cesario AL, Simonetti JP. Prevalence of infection with hepatitis delta virus (HDV) among carriers of hepatitis B surface antigen in Amazonas state, Brazil. Trans R Soc Trop Med Hyg 1988; 82: 469–471. 28. Gust ID. Control of hepatitis B in Australia: the case for alternative strategies. Med J Aust 1992; 156: 819–821. 29. Tawk H, Vickery K, Bisset L, Lo S, Selby W, Cossart Y, and Infection in Endoscopy Study Group. The current pattern of hepatitis B virus infection in Australia. J Viral Hepat 2005;13:206–215. 30. Dai ZC, Qi GM. Viral hepatitis in China: Seroepidemiological survey in Chinese population (Part one). Beijing Science and Technology Press; 1997: 39–58. 31. Jia JD, Zhuang H. A winning war against hepatitis B virus infection in China. Chin Med J (Engl) 2007 Dec 20;120(24):2157–2158. 32. Progress in preventing hepatitis B through universal infant vaccination: China, 1997–2006. Wkly Epidemiol Rec 2007 Jun 15;82(24):209–216. 33. Zhu X, Zhang XL, Wang LX. National EPI vaccination and hepatitis B coverage rate and the related factors: results from the 1999 national coverage survey. Chin J Vac Immun (Chin) 2000; 6: 1–5. 34. Lu L, Ma Y, Xie Z et al. A sampling survey on the epidemic status of hepatitis A, B, C among the pupils in the Yunnan province’s countryside. China Public Health 1998;14(11):647. 35. Jia ZY, Wu GZ, Su CA, Huang YY, Li YQ, Yang CM, Liu JD, Hu GW, Liu CB. An investigation on hepatitis B vaccination of newborns in four provincial capital cities and suburbs. Chin J VacImmun 1999; 5:258–261. 36. Li RC, Yang JY, Gong J, Li YP, Huang ZN, Fang KX, Xu ZY, Liu CB, Zhao K, Zhuang H. Efficacy of hepatitis B vaccination on hepatitis B prevention and on hepatocellular carcinoma. Zhonghua Liu Xing Bing Xue Za Zhi 2004 May;25(5):385–387. 37. Chen HL, Chang MW, Ni YH, Hsu HY, Lee PI, Lee CY, et al. Seroepidemiology of hepatitis B virus infection in children: Ten years of mass vaccination in Taiwan. J Am Med Assoc 1996;276:906–908. 38. Acharya SK, Madan K, Dattagupta S, Panda SK. Viral hepatitis in India. Natl Med J India 2006 Jul–Aug;19(4):203–217. 39. Singh H, Aggarwal R, Singh RL, Naik SR, Naik S. Frequency of infection by hepatitis B virus and its surface mutants in a northern Indian population. Indian J Gastroenterol 2003;22:132–137. 40. Indian Association for Study of the Liver (INSAL). Hepatitis B in India: Therapeutic options and prevention strategies – Consensus statement. Indian J Gastroenterol. 2000;19: C4–C66. 41. Lodha R, Jain Y, Anand K, Kabra SK, Pandav CS. Hepatitis B in India. A review of disease epidemiology. Indian Pediatr 2001; 38: 349–371. 42. Murhekar MV, Murhekar KM, Arankalle VA, Sehgal SC. Epidemiology of hepatitis B infection among the Nicobarese – a mongoloid tribe of the Andaman and Nicobar Islands, India. Epidemiol Infect 2002;128:465–471. 43. Biswas D, Borkakoty BJ, Mahanta J, Jampa L, Deouri LC. Hyperendemic foci of hepatitis B infection in Arunachal Pradesh, India. J Assoc Physicians India. 2007;55:701–704.
Natural History of Chronic Hepatitis B Infection
231
44. Tandon BN, Irshad M, Raju M, Mathur GP, Rao MN. Prevalence of HBsAg and anti-HBs in children and strategy suggested for immunisation in India. Indian J Med Res 1991;93:337–339. 45. Sobeslavsky O. Prevalence of markers of hepatitis B virus infection in various countries: A WHO collaborative study. Bull World Health Organ 1980;58: 621–628. 46. Thakur V, Kazim SN, Guptan RC, Malhotra V, Sarin SK. Molecular epidemiology and transmission of hepatitis B virus in close family contacts of HBV-related chronic liver disease patients. J Med Virol 2003;70:520–528. 47. Anand K, Pandav CS, Kapoor SK, Undergraduate Study Team. Injection use in a village in north India. Natl Med J India 2001;14:143–144. 48. Qirbi N, Hall AJ. Epidemiology of hepatitis B virus infection in the Middle East. East Mediterr Health J 2001 Nov; 7(6): 1034–1045. 49. FitzSimons D, Van Damme P. Prevention and control of hepatitis B in central and eastern Europe and the newly independent states, Siofok, Hungary, 6–9 October 1996. Vaccine 1997;15(15):1595–1597. 50. Da Villa G. Rationale for infant and adolescent vaccination programs in Italy. Vaccine 2000;18:S31–S34. 51. Yim HJ, Lok AS. Natural history of chronic hepatitis B infection: what we knew in 1981 and what we know in 2005. Hepatology 2006;43:S173–S181. 52. Shepard CW, Finelli L, Fiore AE, Bell BP. Epidemiology of Hepatitis B and Hepatitis B Virus Infection in United States Children. Pediatr Infect Dis J 2005;24:755–760. 53. Bai H, Zhang L, Ma L, Dou XG, Feng GH, Zhao GZ. Relationship of hepatitis B virus infection of placental barrier and hepatitis B virus intra-uterine transmission mechanism. World J Gastroenterol 2007; 13(26):3625–3630. 54. Liu CJ, Lo SC, Kao JH, et al. Transmission of occult hepatitis B virus by transfusion to adult and pediatric recipients in Taiwan. J Hepatol 2006;44:39–46. 55. Wang JT, Lee CZ, Chen PJ, Wang TH, Chen DS. Transfusion-transmitted HBV infection in an endemic area: the necessity of more sensitive screening for HBV carriers. Transfusion 2002;42:1592–1597. 56. Liu CJ, Lo SC, Kao JH, et al. Transmission of occult hepatitis B virus by transfusion to adult and pediatric recipients in Taiwan. J Hepatol 2006;44:39–46. 57. Allain JP. Occult hepatitis B virus infection: implications in transfusion. Vox Sang 2004;86:83–91. 58. Zou S, Dodd RY, Stramer SL, Strong M. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med 2004;351:751–759. 59. Burdick RA, Bragg-Gresham JL, Woods JD et al. Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: the DOPPS. Kidney Int 2003; 63: 2222–2229. 60. Fehr T, Ambuhl PM. Chronic hepatitis virus infections in patients on renal replacement therapy. Nephrol Dial Transplant 2004; 19: 1049–1053. 61. Wyatt HV. Injections and AIDS. Tropical Doctor 1986; 16, 97–98. 62. Kane A, Lloyd J, Zaffran M, Simonsen L, Kane M. Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses through unsafe injections in the developing world: model-based regional estimates. Bull World Health Organ 1999; 77, 801–807.
232
Sarin and Kumar
63. Douvin C, Simon D, Zinelabidine H, Wirquin V, Perlemuter L, Dhumeaux D. An outbreak of hepatitis B in an endocrinology unit traced to a capillary-blood sampling device. N Engl J Med 1990;322:57–58. 64. Sukriti, Pati NT, Sethi A, Agrawal K, Agrawal K, Kumar GT, Kaanan AT, Sarin SK. Low Levels Of Awareness, Vaccine Coverage And Need For Boosters Among Health Care Workers In Tertiary Care Hospitals In India. J Gastro Hep 2008; 23(11):1710–15. 65. Bell DM, Shapiro CN, Ciesielski CA, Chamberland ME. Preventing blood borne pathogen transmission from health-care workers to patients. The CDC perspective. Surg Clin North Am 1995; 75: 1189–1203. 66. Tokars JI, Bell DM, Culver DH, Marcus R, Mendelson MH, Sloan EP, Farber BF, Fligner D, Chamberland ME, McKibben PS, et al. Percutaneous injuries during surgical procedures. JAMA 1992; 267, 2899–2904. 67. Beltrami EM, Williams IT, Shapiro CN, Chamberland ME. Risk and management of blood-borne infections in health care workers. Clin Microbiol Rev 2000;13: 385–407. 68. Makary MA, Al-Attar A, Holzmueller CG, Sexton JB, Syin D, Gilson MM, Sulkowski MS, Pronovost PJ. Needlestick injuries among surgeons in training. N Engl J Med 2007 ;356(26):2693–2699. 69. Corden S, Ballard AL, Ijaz S, Barbara JAJ, Gilbert N, Gilson RJC, Boxall EH, Tedder RS. HBV DNA levels and transmission of hepatitis B by health care workers. J Clin Virol 2003; 27: 52–58. 70. Hasselhorn HM, Hofmann F. Transmission of HBV, HCV and HIV by infectious medical personnel – presentation of an overview. Chirurg 2000; 71: 389–395. 71. Bell DM, Shapiro CN, Culver DH, Martone WJ, Curran JW, Hughes JM. Risk of hepatitis B and human immunodeficiency virus transmission to a patient from an infected surgeon due to percutaneous injury during an invasive procedure: estimates based on a model. Infect Agents Dis 1992;1:263–269. 72. Ross RS, Viazov S, Roggendorf M. Risk of hepatitis C transmission from infected medical staff to patients. Model-based calculations for surgical settings. Arch Intern Med 2000;160:2313–2316. 73. Davis JP. Experience with hepatitis A and B vaccines. Am J Med 2005; 118 Suppl 10A:7S–15S. 74. GAVI. Meeting of the Proto-Board, Seattle, Washington, 12–13 July, 1999. GAVI/99.01. 75. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336: 1855–1859. 76. Ni YH, Chang MH, Huang LM, Chen HL, Hsu HY, Chiu TY, et al. Hepatitis B virus infection in children and adolescent in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001; 135:796–800. 77. Chen HL, Chang CJ, Kong MS, Huang FC, Lee HC, Lin CC, et al. Fulminant hepatic failure in children in endemic areas of hepatitis B virus infection: 15 years after universal hepatitis B vaccination. Hepatology 2004;39:58–63. 78. Poovorawan Y, Theamboonlers A, Vimolket T, Sinlaparatsamee S, Chaiear K, Siraprapasiri T, et al. Impact of hepatitis B immunization as part of EPI. Vaccine 2001;19:943–949. 79. Andre F. Hepatitis B epidemiology in Asia, the Middle East and Africa. Vaccine 2000;18(suppl 1):20–22.
Natural History of Chronic Hepatitis B Infection
233
80. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004;38(10 suppl): S158–168. 81. Chotard J, Inskip HM, Hall AJ, Loik F, Mendy M, Whittle H, et al. The Gambian hepatitis intervention study: follow-up of a cohort of children vaccinated against hepatitis B. J Infect Dis 1992;166: 764–768. 82. Tsebe JV, Burnett RJ, Hlungwani NP, Sibara MM, Venter PA, Mphahlele MJ. The first 5 years of universal hepatitis B vaccination in South Africa: evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine .2001;19: 3919–3926. 83. Al-Faleh FZ, Al-Jeffri M, Ramai S, Al-Rashed R, Arif M, Rezeig M, et al. Seroepidemiology of hepatitis B virus infection in Saudi children 8 years after mass hepatitis B vaccination program. J Infect 1999;38: 167–170. 84. Da Villa G. Rationale for infant and adolescent vaccination programs in Italy. Vaccine. 2000;18:S31–S34. 85. Bonanni P, Colombai R, Gasparini R, Nostro AL, Tiscione E, Tomei A, et al. Impact of routine infant and adolescent hepatitis B vaccination in Tuscany, Central Italy. Pediatr Infect Dis J 1999;18:677–682. 86. Gatcheva N, Vladimirova N, Kourtchatova A. Implementing universalvaccination programs: Bulgaria. Vaccine 1995;13:S82–S83. 87. Centers for Disease Control and Prevention (CDC). Acute hepatitis B among children and adolescents: United States, 1990–2002. MMWR Morb Mortal Wkly Rep 2004;53:1015–1018. 88. Harpaz R, McMahon BJ, Margolis HS, et al. Elimination of new chronic hepatitis B infections: results of the Alaska immunization program. J Infect Dis 2000;181:413–418. 89. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV. Global epidemiology of hepatitis B virus. J Clin Gastroenterol. 2004;38(10 suppl): S158–S168. 90. Alter MJ. Epidemiology of hepatitis B in Europe and worldwide. J Hepatol 2003;39 Suppl 1:S64–S69. 91. Fortuin M, Karthigesu V, Allison L, et al. Breakthrough infections and identification of a novel variant in Gambian children immunized with hepatitis B vaccine. J Infect Dis 1994;169:1374–1376. 92. Hsu HY, Chang MH, Ni YH, Chen HL. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut 2004;53(10):1499–1503. 93. Atanasova MV, Haydouchka IA, Zlatev SP, Stoilova YD, Iliev YT, Mateva NG: Prevalence of antibodies against hepatitis C virus and hepatitis B coinfection in healthy population in Bulgaria. A seroepidemiological study. Minerva Gastroenterol Dietol 2004;50:89–96. 94. Gaeta GB, Stornaiuolo G, Precone DF, Lobello S, Chiaramonte M, Stroffolini T, Colucci G, Rizzetto M. Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter Italian study. J Hepatol 2003; 39:1036–1041. 95. Torbenson M, Kannangai R, Astemborski J, et al. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology 2004;39:51–57. 96. Thio CL. Hepatitis B in the human immunodeficiency virus infected patient: epidemiology, natural history, and treatment. Semin Liver Dis 2003;23:125–136.
234
Sarin and Kumar
97. Tsui JI, French AL, Seaberg EC, Augenbraun M, Nowicki M, Peters M, et al. Prevalence and long-term effects of occult hepatitis B virus infection in HIVinfected women. Clin Infect Dis 2007;45:736–740. 98. Rodriguez-Torres M, Gonzalez-Garcia J, Brau N, Sola R, Moreno S, Rockstroh J, et al. Occult hepatitis B virus infection in the setting of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection: clinically relevant or a diagnostic problem? J Med Virol 2007;79:694–700. 99. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002;2: 479–486. 100. Ramia S, Sharara AI, El-Zaatari M, Ramlawi F, Mahfoud Z. Occult hepatitis B virus infection in Lebanese patients with chronic hepatitis C liver disease. Eur J Clin Microbiol Infect Dis. 2007 Dec 11 (Epub ahead of print) 101. Chemin I, Zoulim F, Merle P, Arkhis A, Chevallier M, Kay A, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol 2001;34:447–454. 102. Kumar GT, Kazim SN, Kumar M, Hissar S, Chauhan R, Basir SF, Sarin SK. HBV genotypes and HBsAg mutations in family contacts of HBV infected patients with occult HBV infection. J Gastro Hepatol 2009; 24(4): 588–598. 103. Toyoda H, Hayashi K, Murakami Y, Honda T, Katano Y, Nakano I, et al. Prevalence and clinical implications of occult hepatitis B viral infection in hemophilia patients in Japan. J Med Virol 2004;73:195–199. 104. Kanbay M, Gur G, Akcay A, Selcuk H, Yilmaz U, Arslan H, et al. Is hepatitis C virus positivity a contributing factor to occult hepatitis B virus infection in hemodialysis patients? Digest Diseases Sci 2006; 51(11): 1962–1966. 105. Nunez M, Rios P, Perez-Olmeda M, Soriano V. Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients. AIDS 2002;16:2099–2101. 106. Hofer M, Joller-Jemelka HI, Grob PJ, Luthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis 1998;17:6–13. 107. Minuk GY, Sun DF, Uhanova J, Zhang M, Caouette S, Nicolle LE, et al. Occult hepatitis B virus infection in a North American community-based population. J Hepatol 2005;42:480–485. 108. Miyakava Y, Mizokami M.Classifying hepatitis B virus Genotypes. Intervirology 2003;46:329–338. 109. Norder H, Courouc´e A-M, Coursaget P, Echevarria JM, Leef S-D, Mushahwar IK, Robertson BH, Locarnini S, Magnius LO. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004; 47: 289–309. 110. Sugauchi F, Kumada H, Acharya SA, Shrestha SM, Gamutan MT, Khan M, Gish RG, Tanaka Y, Kato T, Orito E, Ueda R, Miyakawa Y, Mizokami M. Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. J Gen Virol 2004; 85: 811–820. 111. Banerjee A, Kurbanov F, Datta S, Chandra PK, Tanaka Y, Mizokami M, Chakravarty R. Phylogenetic relatedness and genetic diversity of hepatitis B virus isolates in Eastern India. J Med Virol 2006; 78: 1164–1174.
Natural History of Chronic Hepatitis B Infection
235
112. Kimbi GC, Kramvis A, Kew MC. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol 2004; 85: 1211–1220. 113. Sugauchi F, Orito E, Ichida T, et al. Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene. J Virol 2002; 76:5985–5992. 114. Sakamoto T, Tanaka Y, Orito E, et al. Novel subtypes (subgenotypes) of hepatitis B virus genotypes B and C among chronic liver disease patients in the Philippines. J Gen Virol 2006; 87:1873–1882. 115. Sugauchi F, Orito E, Ichida T, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. Gastroenterology 2003; 124:925–932. 116. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000; 118: 554–559. 117. Orito E, Ichida T, Sakugawa H, et al. Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology 2001; 34:590–594. 118. Chauhan R, Kazim SN, Bhattacharjee J, Sakhuja P, Sarin SK. Basal core promoter, precore region mutations of HBV and their association with e antigen, genotype, and severity of liver disease in patients with chronic hepatitis B in India. J Med Virol 2006 Aug;78(8):1047–1054. 119. Sakamoto T, Tanaka Y, Simonetti J, Osiowy C, Borresen ML, Koch A, Kurbanov F, Sugiyama M, Minuk GY, McMahon BJ, Joh T, Mizokami M. Classification of hepatitis B virus genotype B into 2 major types based on characterization of a novel subgenotype in Arctic indigenous populations. J Infect Dis 2007 Nov 15;196(10):1487–1492. 120. Lindh M. HBV genotype G-an odd genotype of unknown origin. J Clin Virol 2005; 34: 315–316. 121. Kramvis A, Weitzmann L, Owiredu WK, Kew MC. Analysis of the complete genome of subgroup A’ hepatitis B virus isolates from South Africa. J Gen Virol 2002; 83: 835–839. 122. Kurbanov F, Tanaka Y, Fujiwara K, Sugauchi F, Mbanya D, Zekeng L, Ndembi N, Ngansop C, Kaptue L, Miura T, Ido E, Hayami M, Ichimura H, Mizokami M. A new subtype (subgenotype) Ac (A3) of hepatitis B virus and recombination between genotypes A and E in Cameroon. J Gen Virol 2005; 86: 2047–2056. 123. Makuwa M, Souquiere S, Telfer P, Apetrei C, Vray M, Bedjabaga I, MouingaOndeme A, Onanga R, Marx PA, Kazanji M, Roques P, Simon F. Identifi cation of hepatitis B virus subgenotype A3 in rural Gabon. J Med Virol 2006; 78: 1175–1184. 124. Olinger CM, Venard V, Njayou M, Oyefolu AO, Maiga I, Kemp AJ, Omilabu SA, le Faou A, Muller CP. Phylogenetic analysis of the precore/core gene of hepatitis B virus genotypes E and A in West Africa: new subtypes, mixed infections and recombinations. J Gen Virol 2006; 87: 1163–1173. 125. Nagasaki F, Niitsuma H, Cervantes JG, Chiba M, Hong S, Ojima T, Ueno Y, Bondoc E, Kobayashi K, Ishii M, Shimosegawa T. Analysis of the entire nucleotide sequence of hepatitis B virus genotype B in the Philippines reveals a new subgenotype of genotype B. J Gen Virol 2006; 87: 1175–1180.
236
Sarin and Kumar
126. Sakamoto T, Tanaka Y, Orito E, Co J, Clavio J, Sugauchi F, Ito K, Ozasa A, Quino A, Ueda R, Sollano J, Mizokami M. Novel subtypes (subgenotypes) of hepatitis B virus genotypes B and C among chronic liver disease patients in the Philippines. J Gen Virol 2006; 87: 1873–1182. 127. Chan HL, Tsui SK, Tse CH, Ng EY, Au TC, Yuen L, Bartholomeusz A, Leung KS, Lee KH, Locarnini S, Sung JJ. Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C. J Infect Dis 2005; 191: 2022–2032. 128. Sugauchi F, Mizokami M, Orito E, Ohno T, Kato H, Suzuki S, Kimura Y, Ueda R, Butterworth LA, Cooksley WG. A novel variant genotype C of hepatitis B virus identified in isolates from Australian Aborigines: complete genome sequence and phylogenetic relatedness. J Gen Virol 2001; 82: 883–892. 129. Kato H, Fujiwara K, Gish RG, Sakugawa H, Yoshizawa H, Sugauchi F, Orito E, Ueda R, Tanaka Y, Kato T, Miyakawa Y, Mizokami M. Classifying genotype F of hepatitis B virus into F1 and F2 subtypes. World J Gastroenterol 2005; 11: 6295–6304. 130. Norder H, Arauz-Ruiz P, Blitz L, Pujol FH, Echevarria JM, Magnius LO. The T (1858) variant predisposing to the precore stop mutation correlates with one of two major genotype F hepatitis B virus clades. J Gen Virol 2003; 84: 2083–2087. 131. Naumann H, Schaefer S, Yoshida CF, Gaspar AM, Repp R, Gerlich WH. Identification of a new hepatitis B virus (HBV) genotype from Brazil that expresses HBV surface antigen subtype adw4. J Gen Virol 1993; 74 (Pt 8): 1627–1632. 132. Devesa M, Rodriguez C, Leon G, Liprandi F, Pujol FH. Clade analysis and surface antigen polymorphism of hepatitis B virus American genotypes. J Med Virol 2004; 72: 377–384. 133. Huy TT, Ushijima H, Sata T, Abe K. Genomic characterization of HBV genotype F in Bolivia: genotype F subgenotypes correlate with geographic distribution and T (1858) variant. Arch Virol 2006; 151: 589–597. 134. Devesa M, Loureiro CL, Rivas Y, Monsalve F, Cardona N, Duarte MC, Poblete F, Gutierrez MF, Botto C, Pujol FH. Subgenotype diversity of hepatitis B virus American genotype F in Amerindians from Venezuela and the general population of Colombia. J Med Virol 2008 Jan;80(1):20–26. 135. Hannoun C, Krogsgaard K, Horal P, Lindh M, and Group, tIT. Genotype Mixtures of Hepatitis B Virus in Patients Treated with Interferon. J Infect Dis 2002; 186: 752–759. 136. Shaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J Gastroenterol 2007; 13(1): 14–21. 137. Chen BF, Kao JH, Liu CJ, Chen DS, Chen PJ. Genotypic dominance and novel recombinations in HBV genotype B and C coinfected intravenous drug users. J Med Virol 2004; 73: 13–22. 138. Kato H, Orito E, Gish RG, Bzowej N, Newsom M, Sugauchi F, Suzuki S, Ueda R, Miyakawa Y, Mizokami M. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology 2002; 35: 922–929. 139. Yano Y, Truong BX, Seo Y, Kato H, Miki A, Tanaka Y, Mizokami M, Kagawa A, Miyazaki H, Kasuga M, Azuma T, Hayashi Y. Japanese case of hepatitis B virus genotypes C/D hybrid. Hepatol Res 2007;37(12):1095–1099. 140. Chauhan R, Kazim SN, Kumar M, Bhattacharjee J, Krishnamoorthy N, Sarin SK. Identification and characteristization of genotype A and D recombinant HBV from Indian Chronic HBV Isolates World J Gastro 2008; 14: 6228–6236.
Natural History of Chronic Hepatitis B Infection
237
141. Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology 1988;8:766–770. 142. McMahon BJ, Parkinson AJ. Clinical significance and management when antibody to hepatitis B core antigen is the sole marker for HBV infection. Viral Hep Rev 2000;6:229–236. 143. Yim HJ, Lok AS. Natural history of chronic hepatitis B infection: what we knew in 1981 and what we know in 2005. Hepatology 2006;43:S173–S181. 144. Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004;116:829–834. 145. Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virological And Histological Features Of Chronic Hepatitis B Virus Infected Asymptomatic Patients With Persistently Normal ALT. Gastroenterology 2008;134:1376–1384. 146. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol 2004;72:363–369. 147. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology 2002;122:1756–1762. 148. Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B. J Hepatol 2005;43:411–417. 149. Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball MM, Cagle HH, Negus SE, McMahon BJ. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007 Nov;133(5):1452–1457. 150. Manno M, Camma C, Schepis F, Bassi F, Gelmini R, Giannini F, et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology 2004;127:756–763. 151. Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002;35:1522–1527. 152. Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha–interferon treated and untreated patients: a long term cohort study. J Hepatol 2002; 36:263–270. 153. Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007;133(5):1458–1465. 154. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg negative chronic hepatitis B and associated precore and core promoter variants. J Viral Hepatol 2002;9:52–61. 155. Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002;123:1084–1089. 156. Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 2004;126:1024–1029.
238
Sarin and Kumar
157. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678–686. 158. Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology 2001;33:218–223. 159. Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19–26. 160. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127 (Suppl): S35–S50. 161. Benvegnu L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004;53:744–749. 162. Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000;92:1159–1164. 163. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155: 323–331. 164. Tang B, Kruger WD, Chen G, Shen F, Lin WY, Mboup S, et al. Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers. J Med Virol 2004;72:35–40. 165. Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005;97:265–272. 166. Chan HL, Tse CH, Mo F, Koh J, Wong VW, Wong GL, Lam Chan S, Yeo W, Sung JJ, Mok TS. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 2008 Jan 10;26(2):177–182. 167. Thakur V, Guptan RC, Kazim SN, Malhotra V, Sarin SK. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol 2002;17(2):165–170. 168. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003;124:327–334. 169. Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the US Cancer 2004;101:1009–1017. 170. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Taiwan CommunityBased Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168–174. 171. Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005;97:265–272. 172. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73.
Natural History of Chronic Hepatitis B Infection
239
173. Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54:1610–1614. 174. Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004; 328:983–988. 175. Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, Chen DS, Kao JH. Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology 2007 May;45(5):1193–1198. 176. Li J, Zhao GM, Zhu LM, Li Y, Xin SJ. Liver pathological changes and clinical features of patients with chronic hepatitis B virus infection in their immune tolerant phase and non-active status. Zhonghua Gan Zang Bing Za Zhi 2007 May;15(5):326–329. 177. Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol 2007 Sep 24; Epub ahead of print PMID: 17928090. 178. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29:971–975. 179. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105–117. 180. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521–1531. 181. Ruggiero G, Capasso M, Indolfi P, Casale F, et al.: Dual or single hepatitis B and C virus infections in childhood cancer survivors: long-term follow-up and effect of interferon treatment. Blood. 1999;p 94:4046–4052 182. Pontisso P, Gerotto M, Ruvoletto MG, Fattovich G, Chemello L, Tisminetzky S, Baralle F, Alberti A. Hepatitis C genotypes in patients with dual hepatitis B and C virus infection. J Med Virol 1996; 48:157–160. 183. Jardi R, Rodriguez F, Buti M, Costa X, Cotrina M, Galimany R, Esteban R, Guardia J. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology 2001; 34:404–410. 184. Liaw YF: Concurrent hepatitis B and C virus infection: Is hepatitis C virus stronger? J Gastroenterol Hepatol 2001; 16:597–598. 185. Fong TL, Di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology 1991; 14:64–67. 186. Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F, Tran van Nhieu J, Seigneurin JM, Buffet C, Dhumeaux D. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol 1998; 28:27–33. 187. Mohamed Ael S, al Karawi MA, Mesa GA. Dual infection with hepatitis C and B viruses: clinical and histological study in Saudi patients. Hepatogastroenterology 1997; 44:1404–1406. 188. Chiaramonte M, Stroffolini T, Vian A, Stazi MA, Floreani A, Lorenzoni U, Lobello S, Farinati F, Naccarato R. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 1999; 85:2132–2137.
240
Sarin and Kumar
189. Sulkowski MS. Viral hepatitis and HIV coinfection. J Hepatol 2008;48(2): 353–367. 190. Mills CT, Lee E, Perillo R. Relationship between histology, aminotransferase levels and viral replication in chronic hepatitis B. Gastroenterology 1990;99: 519–524. 191. Rector W, Govindarajan S, Horsburgh C, Penley K, Cohn D, Judson F. Hepatic inflammation, hepatitis B replication, and cellular immune function in homosexual males with chronic hepatitis B and antibody to HIV. Am J Gastroenterol 1988;83:262–266. 192. Housset C, Pol S, Carnot F, Dubois F, Nalpas B, Housset B, et al. Interactions between human immunodeficiency virus-1, hepatitis delta and hepatitis B virus infection in 260 chronic carriers of hepatitis B virus. Hepatology 1992;15: 578–583. 193. Gilson R, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M, et al. Interaction between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS 1997;11: 597–606. 194. Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999;29:1306–1310. 195. Di Martino V, Thevenot T, Colin J. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology 2002;123:1812–1822. 196. Housset C, Pol S, Carnot F, Dubois F, Nalpas B, Housset B, et al. Interactions between human immunodeficiency virus-1, hepatitis delta and hepatitis B virus infection in 260 chronic carriers of hepatitis B virus. Hepatology 1992;15: 578–583. 197. Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS 2004;18:2039–2046. 198. Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004;18: 2285–2293. 199. Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS 2004; 18: 2039–2046. 200. Rosenthal E, Poiree M, Pradier C, Perronne C, Salmon-Ceron D, Geffray L, et al. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17:1803–1809. 201. Kellermann SE, Hanson DL, McNaghten AD, Fleming PL. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human imunodeficiency virus-infected subjects. J Infect Dis 2003;188:571–577. 202. Benhamou Y. Antiretroviral therapy and HIV/hepatitis B virus coinfection. Clin Infect Dis 2004;38:S98–S103. 203. Fang CT, Chen PJ, Chen MY, Hung CC, Chang SC, Chang AL, et al. Dynamics of plasma hepatitis B virus levels after highly active antiretroviral therapy in patients with HIV infection. J Hepatol 2003;39:1028–1035. 204. Bruno R, Sacchi P, Malfitano A, Filice G. YMDD-mutant HBV strain as a cause of liver failure in an HIV-infected patient. Gastroenterology. 2001;121: 1027–1028.
Natural History of Chronic Hepatitis B Infection
241
205. Drake A, Mijch A, Sasadeusz J. Immune reconstitution hepatitis in HIV and hepatitis B co-infection, despite lamivudine therapy as a part of HAART. Clin Infect Dis 2004;39:129–132. 206. Puoti M, Cozzi-Lepri A, Ancarani F, Bruno R, Ambu S, Ferraro T, et al. The management of hepatitis B virus/HIV-1 co-infected patients starting their first HAART regimen. Treating two infections at the price of one drug? Antiviral Ther 2004;9:811–817. 207. Piroth L, Binquet C, Vergne M, Minello A, Livry C, Bour JB, et al. The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients. J Hepatol 2002;36:681–686. 208. Raimondo G, Pollicino T, Cacciola. Occult hepatitis B virus infection. J Hepatol 2007 Jan;46(1):160–170. 209. Onozawa M, Hashino S, Izumiyama K, Kahata K, Chuma M, Mori A, et al. Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection. Transplantation 2005;79: 616–619. 210. Yuki N, Nagaoka T, Yamashiro M, Mochizuki K, Kaneko A, Yamamoto K, et al. Long-term histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology (Baltimore, MD) 2003;37:1172–1179. 211. Squadrito G, Pollicino T, Cacciola I, Caccamo G, Villari D, La Masa T, et al. Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients. Cancer 2006;106:1326–1330. 212. Kazemi-Shirazi L, Petermann D, Muller C. Hepatitis B virus DNA in sera and liver tissue of HBsAg negative patients with chronic hepatitis C. J Hepatol 2000;33:785–790. 213. Sagnelli E, Coppola N, Scolastico C, Mogavero AR, Stanzione M, Filippini P, et al. Isolated anti-HBc in chronic hepatitis C predicts a poor response to interferon treatment. J Med Virol 2001;65:681–687. 214. Chemin I, Zoulim F, Merle P, Arkhis A, Chevallier M, Kay A, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol 2001;34:447–454. 215. Berasain C, Betes M, Panizo A, Ruiz J, Herrero JI, Civeira MP, et al. Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology. Gut 2000;47:429–443. 216. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004;127:S56–S61.
Current Treatment of Chronic Hepatitis B Walid S. Ayoub, MD and Emmet B. Keeffe, MD CONTENTS I NTRODUCTION NATURAL H ISTORY I NDICATIONS FOR T REATMENT A PPROVED D RUGS FOR T REATMENT OF C HRONIC H EPATITIS B D RUGS IN D EVELOPMENT FOR T REATMENT OF C HRONIC H EPATITIS B N EW T REATMENT S TRATEGIES ROADMAP C ONCEPT FOR ON -T REATMENT M ANAGEMENT C ONCLUSION R EFERENCES
Key Principles
• The natural history of HBV infection can be divided into four phases: immune tolerance, immune clearance (HBeAg-positive chronic hepatitis B), nonreplicative (inactive HBsAg carrier), and reactivation (HBeAg-negative chronic hepatitis B). • Patients with chronic hepatitis B should receive treatment when alanine aminotransferase (ALT) levels are elevated (>19 U/L for
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 8, C Humana Press, a part of Springer Science+Business Media, LLC 2009
243
244
•
•
•
•
Ayoub and Keeffe
women and >30 U/L for men) and serum HBV DNA levels are ≥20,000 IU/mL (HBeAg-positive disease) or ≥2,000 IU/mL (HBeAg-negative disease). The preferred treatment of chronic hepatitis B in 2008 includes adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir. Standard interferon alfa-2b has been replaced by peginterferon alfa-2a, and lamivudine is not a preferred first-line drug due to high rates of resistance. With use of the oral agents, serum HBV DNA should be less than 2000 IU/mL or undetectable 24 weeks after the initiation of therapy for maximal efficacy and the lowest rate of antiviral drug resistance (“roadmap” concept). The rates of genotypic resistance with long-term therapy are high with lamivudine (65–70% at 4–5 years), intermediate with telbivudine (22% in HBeAg-positive and 9% in HBeAg-negative patients at year 2), lower with adefovir (29% at 5 years of therapy), and lowest with entecavir in nucleoside-na¨ıve patients (∼1% at year 4) but higher in lamivudine-resistant patients (∼40% at year 4). Interferon and peginterferon therapy have not been associated with the development of antiviral drug resistance. Potential future therapies for chronic hepatitis B include clevudine and peginterferon alfa-2b. There is an evolving role for combination therapy primarily to reduce the rate of resistance with longterm therapy and manage resistance when it occurs.
1. INTRODUCTION Despite the advances in the diagnosis and treatment of viral hepatitis, chronic infection with hepatitis B virus (HBV) continues to have a major worldwide impact. As many as 2 billion persons have been infected with HBV worldwide, and 350 million people are chronically infected, including at least 1.25 million individuals living in the United States (1, 2). In addition, the prevalence of chronic hepatitis B (CHB) in the United States has been underestimated, considering the lack of inclusion of the prison population with their high infection rate in epidemiological studies and the continuous influx of immigrants from endemic areas with high rates of HBV infection. Individuals with chronic HBV infection are at an increased risk of dying prematurely from the development of hepatocellular carcinoma (HCC) or cirrhosis (3). Therefore, diagnosis and treatment of CHB in its early stages is imperative to potentially prevent such complications. In addition, the degree of HBV replication as assessed by serum HBV DNA levels is associated with the risk of development of HCC (Fig. 1) (4).
Current Treatment of Chronic Hepatitis B
245
Fig. 1. HBV viral load level correlates with the risk of development of hepatocellular carcinoma (adapted from Chen CJ et al. (4)).
Compared to only two available therapies for the management of CHB in the 1990s, i.e., interferon alfa-2b and lamivudine, there are now five additional agents that have been approved by the United States Food and Drug Administration (FDA) over the last decade: adefovir dipivoxil, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir. The future management of CHB appears to be even more promising based on a number of additional drugs in development and newer treatment strategies.
2. NATURAL HISTORY An individual’s age and time of infection have a strong impact on the course of acute HBV infection. Infection at birth or in early childhood results in the development of chronic HBV infection in more than 90% of individuals. In contrast, infection in adulthood is most often selflimited, with more than 95% clearing the virus (5). The hallmark of acute HBV infection is the presence of detectable hepatitis B surface antigen (HBsAg), IgM antibody to hepatitis B core antigen (anti-HBc), and hepatitis B e antigen (HBeAg). Once chronicity is established, patients infected at birth or early in life typically enter into an initial immune tolerance phase, which is characterized by high levels of viral replication (elevated HBV DNA levels and presence of HBeAg) but normal alanine aminotransferase (ALT) levels (Table 1). This phase is usually short-lived or absent when infection occurs in adults and long-lived when infection occurs in infancy or early childhood. Although a liver biopsy is not usually
246
Ayoub and Keeffe Table 1 Phases of Chronic HBV Infection
Definitions Immune tolerance phase
Immune clearance phase (HBeAgpositive CHB) Inactive HBsAg carrier state
Reactivation phase (HBeAgnegative CHB)
Diagnostic Criteria HBsAg positive >6 months HBeAg positive, anti-HBe negative HBV DNA > 20,000 IU/mL Normal ALT HBsAg positive > 6 months HBeAg positive, anti-HBe negative HBV DNA > 20,000 IU/mL Elevated or fluctuating ALT levels HBsAg positive > 6 months HBeAg negative, anti-HBe positive HBV DNA undetectable or less than 2,000 IU/mL Normal ALT levels HBsAg positive > 6 months HBeAg negative, anti-HBe positive HBV > 2,000 IU/ml Fluctuating ALT levels
Biopsy Normal or minor nonspecific changes Active necroinflammation, with or without fibrosis Absence of significant hepatitis
Active necroinflammation, with or without fibrosis
pursued in this stage in practice, studies have shown the presence of minimal or absent necroinflammation and fibrosis on histological examination (5–7). The immune clearance phase follows the immune tolerance phase and is characterized by clearance of infected hepatocytes, resulting in elevated or fluctuating ALT levels and persistently high HBV DNA levels. Necroinflammation with various degrees of fibrosis is the hallmark of this stage on liver biopsy. Repetitive hepatitis flare and prolonged duration of this phase can lead to advanced fibrosis or cirrhosis. During this phase, patients seroconvert and develop antibodies to HBeAg (antiHBe) at an annual rate of 5–15% without therapy but can be accelerated by initiation of antiviral therapy (6, 7). Seroconversion from HBeAg to anti-HBe signals the transition to the nonreplicative phase of infection, and patients in this stage are referred to as inactive HBsAg carriers (8). Normal ALT levels, undetectable or low levels of serum HBV DNA, and the presence of antiHBe are the hallmarks of this phase. In addition, liver biopsy reveals either resolution or minimal lingering necroinflammation, with vari-
Current Treatment of Chronic Hepatitis B
247
able amounts of fibrosis that may have developed during the immune clearance phase. Inactive carriers, particularly older subjects, may spontaneously lose HBsAg and seroconvert to hepatitis B surface antibody (anti-HBs). However, small amounts of serum HBV DNA can often be detected using sensitive, real-time polymerase chain reaction techniques (9). Reactivation of HBV infection may occur in a subgroup of patients despite HBeAg seroconversion. Reactivation usually occurs close to the time of HBeAg loss or can occur many years later, with the finding of high levels of serum HBV DNA and significant disease on liver biopsy (8, 10, 11). Emergence of the precore or double-core promoter mutants of HBV is responsible for such reactivation (9, 11). This phenomenon was first recognized in the Mediterranean area (9); however, it is becoming more commonly recognized in the United States. Chu and colleagues (12) reported a prevalence rate of 27% and 44% for the precore and the core promoter variants, respectively, in a survey of patients in the United States. Patients with HBeAg-negative CHB tend to have more severe liver disease than patients with HBeAgpositive CHB. Serum ALT levels may remain normal and serum HBV DNA undetectable for many years before later detection. Many patients with HBeAg-negative CHB are erroneously labeled as inactive carriers due to intermittently low or normal ALT levels and undetectable HBV DNA. However, frequent monitoring of HBV DNA and ALT can easily detect fluctuation in viremia level in such a group of patients, leading to early detection and intervention prior to the development of progressive liver disease (13). A serum HBV DNA level greater than 2000 IU/mL should raise the suspicion for HBeAg-negative CHB rather than an inactive carrier state (14). Therefore, it is not surprising that significant necroinflammatory changes and fibrosis are present in more than 50% of patients. The majority of the patients with HBeAg-negative CHB have a poor long-term prognosis since the diagnosis of CHB is made late in the course of the disease, with 25–50% having cirrhosis at the time of diagnosis (8, 9, 15).
3. INDICATIONS FOR TREATMENT The goals of antiviral treatment are to achieve maximal viral suppression, reduce progression to cirrhosis, and decrease the risk of developing HCC. The presence of elevated ALT and serum HBV DNA levels is an indication for treatment of patients in both the immune clearance phase and the reactivation phase. The target goals of treatment of patients with HBeAg-positive CHB are loss of HBeAg and/or seroconversion to anti-HBe, normalization of ALT levels, and maximal
248
Ayoub and Keeffe
suppression of HBV DNA to undetectable or low levels. If these goals can be achieved, improvement of liver histology, reduction in disease progression, and decrease in incidence of HCC are likely (17). Recent data from a Korean-based population revealed the presence of higher risk of liver-related mortality with ALT levels greater than 20 U/L for females and 30 U/L for males (18). Those findings have led to the proposal that a lower threshold for an elevated serum ALT be used when considering who should be treated (8, 19). Standard practice guidelines (8, 19) recommend initiation of treatment in patients with HBeAg-positive CHB when serum HBV DNA is at least 20,000 IU/mL (∼100,000 copies/mL) and ALT levels are either elevated above normal (8) or greater than two times the upper limits of normal (ULN) (19). A liver biopsy should be considered in patients with ALT less than two times the ULN, as approximately 20% of these individuals if over age 35–40 years will have significant hepatic fibrosis (8). Active necroinflammatory activity on a liver biopsy is an indication for treatment regardless of the level of serum HBV DNA. Patients with HBV DNA levels over the threshold for treatment and high ALT levels can be monitored for 3–6 months to assess for the development of HBeAg seroconversion, or started right away on therapy. However, if such patients have high serum bilirubin levels or signs of liver decompensation, prompt initiation of therapy is warranted. The goals of treatment patients with HBeAg-negative CHB are to achieve maximal viral suppression and normalization of ALT levels. Initiation of treatment is indicated at a lower HBV DNA threshold compared to patients with HBeAg-positive CHB (8). Approximately 50% of patients with HBeAg-negative CHB and HBV DNA levels less than 100,000 copies/ml have significant inflammation on liver biopsy (14). In addition, the course of HBeAg-negative CHB is marked by fluctuation of ALT levels. Therefore, any ALT elevation in the setting of HBV DNA greater than 2,000 IU/ml (∼10,000 copies/ml) is an indication to initiate therapy. A liver biopsy is recommended in patients with normal ALT levels to assess for the presence of necroinflammation. If active hepatitis is found on liver biopsy, treatment is indicated. While antiviral therapy can be discontinued after treatment for an additional 6–12 months after seroconversion in patients with HBeAgpositive CHB, long-term therapy is recommended for HBeAg-negative CHB, as relapse is common if therapy is stopped (8, 19). Patients with a positive or negative HBeAg, low HBV DNA levels, and a normal ALT level do not warrant treatment. Such patients need to be monitored every 3 months for 1 year after initial diagnosis and then every 6–12 months thereafter.
Current Treatment of Chronic Hepatitis B
249
4. APPROVED DRUGS FOR TREATMENT OF CHRONIC HEPATITIS B Patients with CHB can be treated with two classes of drugs: immunomodulatory agents (interferon and peginterferon) and antiviral agents (nucleoside and nucleotide analogues). Each class of drugs has its own advantages and limitations. Interferons may not be tolerated based on significant side effects and poor tolerability, while the efficacy of antiviral agents is limited by the emergence of resistance over time. There are seven drugs currently approved by the FDA for the treatment of CHB: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. While all of the approved agents can be used as first-line therapy for CHB, lamivudine is not recommended as a first-line agent secondary to a high rate of antiviral drug resistance of 65–70% after 5 years of therapy (8, 19). In addition, telbivudine is recommended only in patients who achieved undetectable viral load by week 24 of therapy, based on an overall rate of resistance of 22% in patients with HBeAg-positive and 9% in patients with HBeAg-negative disease. However, studies have shown that achieving an undetectable level of HBV viremia by week 24 is associated with a very low rate of resistance and continued efficacy at week 96 (20).
4.1. Peginterferon Alfa-2a Standard interferon alfa-2b has been replaced in routine practice with peginterferon alfa-2a for the treatment of chronic hepatitis B. Rather than the daily or thrice weekly injection schedule of interferon alfa2b, peginterferon alfa-2a is given weekly due to its longer half-life. It also has comparable, if not better, efficacy than interferon alfa-2b (8, 19). Standard interferon alfa-2b therapy is associated with 37% loss of serum HBV DNA, 18% HBeAg seroconversion rate, and 80–90% durability of response in HBeAg-positive individuals (8). Standard interferon therapy in patients with HBeAg-negative CHB results in 60–70% loss of serum HBV DNA, 48% histological improvement, and 20–30% durability of response (21). Treatment with peginterferon alfa-2a for 48 weeks results in 25% loss of HBV DNA, 27% HBeAg seroconversion, and a higher seroconversion rate of 32% at week 72. No added benefit has been reported in HBeAg-positive and HBeAg-negative CHB with the addition of lamivudine to peginterferon monotherapy (22, 23). Unlike oral antiviral therapy where genotype does not predict the response to therapy, genotype has been noted to be associated with the response to therapy with peginterferon: genotype A responds more favorably than genotype D and genotype B better than genotype C in
250
Ayoub and Keeffe
some but not all studies (8, 22). Patients with CHB genotype A or B are optimal candidates for peginterferon therapy if they are young, lack comorbidities, have HBV DNA levels less than 109 copies/mL, and ALT levels at least 2–3 times the upper limit of normal (24). Fixed duration of therapy and lack of antiviral resistance are advantages of peginterferon therapy compared with oral antiviral therapy. However, the need for injections and presence of significant side effects has limited the use of peginterferon therapy in the United States.
4.2. Lamivudine Lamivudine was the first licensed oral agent for the treatment of CHB. It has similar efficacy to interferon-based therapy. Like other oral antiviral agents, it has a lower durability of response in HBeAgpositive patients (50–80%) and even lower durability in HBeAgnegative patients (20–25%) (8, 21). Treatment is typically for 1 year but is extended until HBeAg seroconversion occurs. It is further continued for an additional 6 months to enhance the durability of response in HBeAg-positive patients. In addition, prolonged treatment has been associated with decreased rate of disease progression and lowering the incidence of HCC in individuals with advanced fibrosis or cirrhosis (17). However, prolonged use of lamivudine is associated with the development of the YMDD mutation at a rate of ∼20% per year, increasing to approximately 70% by year 4 of therapy. Therefore, lamivudine is no longer recommended as a first-line agent for the treatment of CHB (8, 19). Patients who develop lamivudine resistance were historically switched to adefovir or entecavir (8, 19). However, the risk of subsequent adefovir resistance is increased after switching from lamivudine to adefovir therapy, and thus adefovir should be added to continue lamivudine therapy, particularly in cirrhotic patients to also avoid a flare of hepatitis B (8, 19, 25). In addition, lamivudine can be successfully used to treat patients who developed adefovir mutation (26).
4.3. Adefovir Dipivoxil Adefovir dipivoxil is a nucleotide analogue approved for the treatment of CHB at a dose of 10 mg daily. Higher doses have been associated with significant nephrotoxicity. One year of therapy results in a 12% HBeAg seroconversion rate in patients with HBeAg-positive CHB. Adefovir results in a 53% and 63% rate of histological improvement in HBeAg-positive and HBeAg-negative patients, respectively, when compared with placebo (27, 28). HBeAg seroconversion marks the end of therapy in HBeAg-positive patients, while patients with
Current Treatment of Chronic Hepatitis B
251
HBeAg-negative CHB are treated long-term. Once HBeAg seroconversion occurs with adefovir therapy, it is sustained in 91% of patients. Recent studies have demonstrated the continuous beneficial effect of adefovir, i.e., improvement in fibrosis, ALT normalization, and viral suppression with prolonged duration of therapy up to 4–5 years (29, 30). Resistance to adefovir develops at a slower rate than resistance to lamivudine. Rates of resistance are 0%, 3%, 18%, and 29% after 1, 2, 4, and 5 years of therapy (29). Elevated serum HBV DNA levels after 48 weeks of adefovir therapy correlate with the emergence of resistance (31).
4.4. Entecavir Entecavir is the most potent licensed nucleoside analogue, which results in a 6.98 log10 copies/mL decrease of HBV DNA levels in HBeAg-positive patients at a dose of 0.5 mg daily. It is more potent when compared to lamivudine in achieving better rates of histological improvement (72% vs. 62%), normalization of ALT (78% vs. 70%), and viral suppression of HBV DNA to less than 400 copies/mL (69% vs. 38%). However, the rate of HBeAg seroconversion was comparable to lamivudine after 1 year of therapy (32, 33). Entecavir was also found to be superior to lamivudine in HBeAg-negative CHB patients in regard to histological improvement (70% vs. 61%) and viral suppression (91% vs. 73%) (33). Maintenance of the virologic response has been documented in long-term follow-up studies extending up to 96 weeks (34). Low resistance rate (<1%) has been observed in treatmentna¨ıve patients after 4 years of therapy. However, patients with lamivudine resistance have a higher rate of development of resistance. They also require a higher dose of entecavir (1 mg daily). Resistance in this population has been reported as 1%, 10%, 27%, and 39% at 1, 2, 3, and 4 years, respectively (35, 36).
4.5. Telbivudine Telbivudine is a nucleoside analogue of thymidine. It is a potent inhibitor of HBV DNA polymerase. Telbivudine was found to be superior to lamivudine in a phase III trial (GLOBE trial) in HBeAg-positive CHB patients, with a HBeAg seroconversion rate of 22% and HBV DNA undetectability (<300 copies/mL) of 60% after 1 year of therapy (37). The GLOBE trial, a randomized phase III study, provided 2 years follow-up data on patients with HBeAg-negative CHB and HBeAgpositive CHB, confirming superiority of telbivudine over lamivudine (38). Genotypic resistance to telbivudine at 1 year and 2 years is 4.4% and 21.6%, respectively, in HBeAg-positive patients and 2.7% and
252
Ayoub and Keeffe
8.6%, respectively, in HBeAg-negative patients (38). Secondary analysis of the GLOBE data demonstrated the pivotal role of week 24 level of serum HBV DNA. Patients with undetectable HBV DNA at week 24 achieved better outcomes after 1 and 2 years of therapy in terms of HBeAg seroconversion, ALT normalization, and a lower rate of antiviral drug resistance (20). Telbivudine also achieved superiority to adefovir in terms of early viral suppression at week 24 in HBeAg-positive patients with CHB who were initially treated with telbivudine or switched from adefovir to telbivudine (39). The early virologic suppression correlated with better rates of HBeAg seroconversion, ALT normalization, and undetectable HBV DNA.
4.6. Tenofovir Tenofovir is a nucleotide analogue structurally related to adefovir. It has been in widespread use for the treatment of human immunodeficiency virus (HIV) infection and just gained FDA approval for the treatment of CHB. Results from a phase III study in HBeAg-positive patients comparing tenofovir to adefovir showed superiority of tenofovir in achieving combined viral suppression (<400 copies/mL) and histological improvement (67% vs. 12%) at 48 weeks. In addition, tenofovir therapy was associated with higher rates of HBsAg loss (3.2% vs. 0%) and HBV DNA <400 copies/mL (76% vs. 13%) when compared to adefovir therapy (40, 41). Similar results were found in another phase III study of patients with HBeAg-negative CHB who were treated with tenofovir vs. adefovir, with regard to better combined viral suppression, improved inflammatory score (71% vs. 49%), and better viral suppression to <400 copies/ml (93% vs. 63%) (41).
5. DRUGS IN DEVELOPMENT FOR TREATMENT OF CHRONIC HEPATITIS B Many drugs are currently in different stages of development for the treatment of CHB, including emtricitabine and clevudine.
6. NEW TREATMENT STRATEGIES 6.1. Combination Therapy Combination therapy with peginterferon and lamivudine was not superior to peginterferon alone in both HBeAg-positive and HBeAgnegative CHB (22, 23). The combination of peginterferon with other nucleoside/nucleotide analogues might be more beneficial. The addition
Current Treatment of Chronic Hepatitis B
253
of adefovir to peginterferon results in better early virologic suppression at week 24 than peginterferon alone (71% vs. 41%) (42). In addition, combination therapy of adefovir and peginterferon for 48 weeks results in a marked decrease from baseline of serum HBV DNA and intrahepatic covalently closed circular DNA, which are closely related with reduced HBsAg (43). Switching from lamivudine to adefovir in lamivudine-resistant cases is associated with higher rate of emergence of adefovir resistance (44), while combination therapy resulted in lower rate of development of adefovir resistance (45). The timing of addition of adefovir to lamivudine in the case of the presence of YMDD mutation is also paramount. Patients who have clinical evidence of lamivudine resistance (HBV DNA >106 copies/mL and elevated ALT) at the time of addition of adefovir achieved worse control of viral replication than patients who had only genotypic expression of lamivudine resistance (46). Therefore, the addition of adefovir to lamivudine therapy should be pursued as soon as the genotypic resistance is detected. The cross-resistance for lamivudine and telbivudine at codon 204 makes the combination or switching therapy between lamivudine and telbivudine not desirable, even though a multicenter, randomized, phase III trial of HBeAg-negative and HBeAg-positive patients with persistent HBV viremia who were treated with lamivudine vs. switching to telbivudine showed improvement of HBV DNA suppression at week 24 (80% vs. 56%, p<0.001) (47). It will be interesting to see in the follow-up results of this study whether cross-resistance became a major limiting factor. The combination of nucleosides and nucleotides appears to be beneficial. The in vitro addition of tenofovir to lamivudine, emtricitabine, telbivudine, or entecavir appears to be beneficial (48). However, more issues need to be addressed such as resistance profile of the agents, prior therapies, and drug–drug interactions before clinically embarking on such an approach (49).
7. ROADMAP CONCEPT FOR ON-TREATMENT MANAGEMENT Current treatment guidelines do not offer recommendations regarding on-treatment monitoring. A panel of international experts recently recommended a “roadmap” approach with on-treatment monitoring of patients with CHB (50). The roadmap approach recommends making management decisions based on stratification of the patients according to week 12 and 24 serum HBV DNA levels (Fig. 2). Patients with <1 log10 IU/mL reduction of serum HBV DNA from baseline at week
254
Ayoub and Keeffe
Fig. 2. The roadmap concept for on-treatment management of CHB (51).
12 are classified as primary treatment failures. It is also important to assess for patient compliance with therapy prior to labeling the patients as primary treatment failures. The addition of a more potent drug is recommended in the primary treatment failure. Patients are then further stratified at week 24 based on their virologic response: complete (HBV DNA <60 IU/mL), partial (HBV DNA 60 to less than 2000 IU/mL), or inadequate (HBV DNA >2000 IU/mL). The expert panel also recommended continuous monitoring for virologic breakthrough on therapy every 3–6 months. While the proposed roadmap applies generally to HBeAg-positive and HBeAg-negative patients, relapse is common in HBeAg-negative patients once therapy is discontinued, regardless of the HBV DNA negativity period while on therapy (51).
8. CONCLUSION CHB is a global health concern with a significant economic burden from acute and chronic infection. However, HBV infection is a vaccinepreventable disease, and broader vaccine recommendations have the potential to markedly reduce infection with this virus. The primary goal of treatment of CHB is to prevent the progression to cirrhosis, liver failure, and HCC. Treatment strategies of CHB continue to evolve with the introduction of new drugs and lower threshold for initiation of therapy. This more aggressive approach to treatment has the potential to interrupt the inevitable progression of CHB to cirrhosis or HCC. The proposed active on-treatment monitoring strategy will help guide clinicians
Current Treatment of Chronic Hepatitis B
255
in assessing response to therapy and make adjustments when needed to optimize the outcome of therapy with the lowest rate of resistance.
REFERENCES 1. Hepatitis B fact sheet. World Health Organization. (Accessed 9/17/07, at http://www.who.int/mediacentre/factsheets/fs204/en/index.html.) 2. Ganem D, Prince AM. Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 2004;350:1118–29. 3. Lok ASF. Navigating the maze of hepatitis B treatments. Gastroenterology 2007;132:1586–94. 4. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73. 5. Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 2006;43:S173–81. 6. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000 – summary of a workshop. Gastroenterology 2001;120:1828–53. 7. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47–58. 8. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol 2006;4:936–62. 9. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis 2006;26:130–41. 10. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617–24. 11. Hadziyannis S. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment. Viral Hepatitis Rev 1995;1:7–36. 12. Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 2003;38:619–28. 13. Papatheodoridis GV, Hadziyannis SJ. Diagnosis and management of pre-core mutant chronic hepatitis B. J Viral Hepat 2001;8:311–21. 14. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002;36:1408–15. 15. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 2005;42:121–9. 16. Lin CL, Liao Ly, Liu CJ, et al. Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology 2007;45:1193–8. 17. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521–31. 18. Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004;328:983. 19. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–39.
256
Ayoub and Keeffe
20. Di Bisceglie A, Lai C, Gaines E, et al. Telbivudine GLOBE trial: maximal early HBV suppression is predictive of optimal two-year efficacy in nucleoside-treated hepatitis B patients. Hepatology 2006;44:230A–1A. 21. Lok AS. The maze of treatments for hepatitis B. N Engl J Med 2005;352:2743–6. 22. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682–95. 23. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206–17. 24. Perrillo RP. Therapy of hepatitis B – viral suppression or eradication? Hepatology 2006;43:S182–93. 25. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419 26. Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003;125:292–7. 27. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348: 808–16. 28. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800. 29. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673–81. 30. Hadziyannis SJ TN, Chang TT, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B (results after 5 years of therapy) [Abstract]. Hepatology 2005;42: 754A. 31. Locarnini S, Qi W, Arterburn S, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) [Abstract]. Hepatology 2005;42:17A. 32. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–10. 33. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011–20. 34. Shouval D, Akarca U, Hatzis G. Continued virologic and biochemical improvement through 96 weeks of entecavir treatment in HBeAg-chronic hepatitis B patients (study ETV-027) [Abstract]. J Hepatol 2006;130:S21–2. 35. Colonno RJ, Rose R, Baldick CJ, et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology 2006;44:1656–65. 36. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437–44. 37. Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129:528–36.
Current Treatment of Chronic Hepatitis B
257
38. Lai CL, Gane E, Hsu C, et al. Two-year results from GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LdT) vs lamivudine [Abstract]. Hepatology 2006;44:222A. 39. Bzowej N, Chan H, Lai C, et al. A randomized trial of telbivudine (LdT) vs. adefovir for HBeAg-positive chronic hepatitis B: final week 52 results [Abstract]. Hepatology 2006;44:563A. 40. Heathcote EJ, Ed Gane E, DeMan R, et al. A randomized, double-blind, comparison of tenofovir df (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): Study GS-US-174-0103 [Abstract]. Hepatology 2007;46:861A. 41. Marcellin P, Buti M, Krastev Z, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB): Study GS-US-174-012 [Abstract]. Hepatology 2007;46:80A. 42. Piccolo P, Lenci I, Di Paolo D, et al. Peginterferon alpha-2a plus adefovir vs. peginterferon alpha-2a for 48 weeks in HBeAg-negative chronic hepatitis B: preliminary 24 week results of the PEG FOR B randomized multicenter trial [Abstract]. J Hepatol 2007;46:S26. 43. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 2006;44:675–84. 44. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44:283–90. 45. Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switchingto adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 2007;45:307–13. 46. Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005;42:1414–9. 47. Safadi R, Xie Q, Chen Y, et al. A randomized trial of switching to telbivudine versus continued lamivudine in adults with chronic HBV: results of primary analysis at week 24 [Abstract]. J Hepatol 2007;46:S196–7. 48. Zhu Y, Delaney W, Curtis M, Miller MD, Borroto-Esada K. Anti-HBV activity of in vitro combinations of tenofovir with nucleoside analogs [Abstract]. Hepatology 2006;44:253A. 49. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45:1056–75. 50. Keeffe EB, Zeuzem S, Koff RS, et al. Report of an international workshop: Roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 2007;5:890–7. 51. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004;11:432–8.
Management of Patients Co-Infected with Chronic Hepatitis B (CHB) and the Human Immunodeficiency Virus (HIV) Edward Doo, MD and Marc Ghany, MD CONTENTS I NTRODUCTION E PIDEMIOLOGY NATURAL H ISTORY M ANAGEMENT R EFERENCES
Key Principles
• Certain populations with CHB present additional clinical complexities. These include populations co-infected with the human immunodeficiency virus (HIV) chronic hepatiti B (CHB). • CHB does not appear to affect the progression of HIV infection; conversely, HIV infection does adversely influence several aspects of the natural history of CHB. • Current guidelines recommend that all HIV positive patients should be tested for the hepatitis B surface antigen (HBsAg), and
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 9, C Humana Press, a part of Springer Science+Business Media, LLC 2009
259
260
Doo and Ghany
that all HIV positive individuals who are seronegative for markers of HBV infection undergo vaccination. • The decision to treat CHB infection in HIV-infected individuals must be based on careful consideration of the need for antiretroviral therapy, the severity of liver disease, and potential adverse effects. • Liver transplantation is a feasible option for those with coinfection and advanced liver disease.
1. INTRODUCTION Despite recent improvements in therapy, the management of chronic hepatitis B virus (HBV) infection remains challenging. Certain populations with chronic HBV infection present additional clinical complexities. One such population comprises those co-infected with human immunodeficiency virus 1 (HIV-1). This chapter will address the major issues relevant to the management of the HBV/HIV co-infected individuals. Important differences in the natural history and therapy will be discussed and suggested approaches to management based on the available data and guidelines are offered.
2. EPIDEMIOLOGY Approximately 2 billion people worldwide have been exposed to HBV with an estimated 370 million people with chronic infection (1). Forty million people are estimated to be infected with HIV worldwide (2). Reports have suggested that 5–10% of persons with HIV infection are co-infected with HBV (3, 4). However, the prevalence varies depending on the route of transmission, with the highest rates of coinfection occurring in men who have sex with men (9–17%), intermediate in injection drug users (7–10%), and lowest in heterosexuals (4– 6%) (1). Co-infection with HBV/HIV is common because of the similar modes and routes of transmission of the two viruses. Both are bloodborne viruses that are transmitted through sexual contact, the sharing of needles through illicit drug use, or acquired at birth from mother to child. Eight hepatitis B viral genotypes have been identified that have a variable geographical distribution (5). Individual genotypes differ by a genome nucleotide sequence divergence of greater than 8%. Among co-infected patients, the distribution of HBV genotypes mirrors the local genotype distribution (6–8). Though not routinely determined in
Management of Patients Co-Infected with Chronic Hepatitis B
261
the management of chronic HBV infection, recent studies have suggested a role for HBV genotypes in the natural history of liver disease and outcome of interferon therapy. Genotype A was shown to have a better response to nucleoside or nucleotide (nucleos(t)ide) agents in HBV/HIV co-infection (6), although in the HBV mono-infected population response to nucleos(t)ide analogues was shown to be independent of genotype (9). HBV genotype G has been associated with more rapid liver fibrosis progression in co-infected patients (10). Further studies in the mono- and co-infected population will be needed in order to better clarify the role of HBV genotypes in clinical practice.
3. NATURAL HISTORY 3.1. Influence of HBV on Outcome of HIV Disease The effect of HBV infection on the natural history of HIV infection has been evaluated in several large cohorts (3, 4). Analysis of 9,802 HIV positive patients (9% of whom were HBsAg positive) from 72 European centers found a negligible influence of HBV on the progression of HIV disease (4). The presence of HBV did not appear to affect the HIV virological or immunologic response to highly active anti-retroviral therapy (HAART), the frequency of improvements in CD4+ counts, or time to achieve an undetectable HIV RNA in serum. These studies also reported no effect of HBV on the progression of HIV infection to clinical AIDS (3, 4).
3.2. Influence of HIV on Outcome of HBV Disease In contrast, HIV infection does appear to influence several aspects of the natural history of HBV infection. Markers of HBV replication are significantly higher in co-infected patients including higher HBV DNA levels and a higher prevalence of hepatitis B e antigen (HBeAg) positivity (11, 12). Paradoxically, serum ALT levels are lower, perhaps due to the HIV-induced immunosuppression (12). Immune reconstitution associated with Highly Active Anti-Retroviral Therapy (HAART) may be associated with hepatitis reactivation and ALT flares. The risk of liver-related death is higher among HBV/HIV co-infected persons than among those infected with either virus alone (4, 13–15). Finally, spontaneous resolution of HBV infection indicated by loss of HBsAg occurs far less commonly in co-infected patients as opposed to HBV mono-infected patients (16). Acute HBV infection resolves in the majority of HIV negative adults with less than 10% developing chronic infection. However clearance rates of HBV are significantly reduced in persons with HIV
262
Doo and Ghany
co-infection, with 21% developing chronic infection in one study (11). The higher chronicity rate is felt to be due to the impaired cellular immunity associated with HIV infection. Studies during the pre-HAART era suggested that HIV infection did not influence the rate of fibrosis progression in patients with CHB perhaps due to a variety of confounding factors, such as alcohol use, hepatitis delta co-infection, and degree of immunosuppression (3, 13, 16, 17). However, more recent studies have suggested that progression to cirrhosis is more rapid in HBV/HIV co-infected persons particularly those with a CD4+ count below 200 mm3 (12, 18). Further corroborating the untoward effect of HIV on HBV related liver disease, several prospective cohort studies have reported an increased rate of liverrelated complications and death in HBV/HIV co-infected persons (4, 14, 19). The advent of HAART for HIV infection has greatly diminished mortality from HIV infection and consequently, liver disease as a cause of morbidity and mortality has become more prominent. In the Multi Center AIDS Cohort Study, death in HBV/HIV co-infected persons was 14-fold higher compared to patients with either HBV or HIV infection alone (14). Similar findings have been reported from other HIV cohorts (4, 19). Notably, liver-related mortality was significantly increased in those with lower CD4+ counts (14). Interestingly, despite the accelerated progression of liver fibrosis in co-infected patients, an increased prevalence of hepatocellular carcinoma has not been observed (20). HBV reactivation in patients with resolved infection (HBsAg negative, anti-HBc positive with or without anti-HBs) is uncommon in the absence of immunosuppression or chemotherapy; however, it has been reported in HBV/HIV co-infection (18). This is most likely due to the persistence of covalently closed circular HBV DNA (cccDNA), which serves as the template for viral transcription and resides in the nucleus of hepatocytes.
3.3. Elevated Serum ALT Levels During HAART Therapy in HBV/HIV Co-infection The development of serum ALT flares on HAART therapy in HBV/HIV–co-infected patients may be related to a number of diagnostic possibilities. Initiation of HAART therapy can be associated with immune reconstitution with resulting ALT flares due to enhanced cytotoxic T-cell recognition of HBV infected hepatocytes. Serum ALT flares while on a stable HAART regimen can be associated with the development of HBV viral resistance to the anti-HBV components of the HAART: or could represent immunoclearance of HBV with the
Management of Patients Co-Infected with Chronic Hepatitis B
263
concomitant loss of HBeAg, superinfection with hepatitis delta or hepatotoxicity due to HAART therapy. Serum ALT flares in the setting of discontinuation of HAART therapy may represent reactivation of a previously suppressed HBV infection by the anti-HBV component. Significant ALT flares on HAART should warrant further evaluation.
4. MANAGEMENT 4.1. Prevention Given the increased morbidity and mortality from liver disease in HIV infection, several guidelines recommend that all HIV positive patients should be tested for HBsAg particularly since effective vaccines for the prevention of HBV exist (21). Since 1991, universal vaccination against hepatitis B for children was implemented in the United States with coverage rates equivalent to other standard childhood vaccines. The Advisory Committee on Immunization Practices, the Department of Health and Human Services (DHHS), and American Association for the Study of Liver Diseases (AASLD) all recommended vaccination of HIV positive individuals who are seronegative for markers of HBV infection (22). Primary vaccine response exceeded 90% in HIV uninfected individuals who completed three or more doses of hepatitis B vaccine but was reduced in HIV positive individuals (23). In HIV patients without an initial hepatitis B surface antibody response to vaccination, additional cycles of HBV vaccine appeared to improve acquisition of immunity (24). The use of a double dose regimen has been shown to improve response rates to HBV vaccination (25). In one study, the use of a double dose regimen was associated with a 58% rate of anti-HBs positivity in previous vaccine failures (25). Postvaccination testing is recommended in HBV- and HIV-susceptible individuals to confirm a primary vaccine response.
4.2. Therapy 4.2.1. G OALS The goals of therapy are to stop progression of liver disease and to prevent the development of cirrhosis and hepatocellular carcinoma. Many unanswered questions remain regarding who to treat, when to treat, how long to treat, and when to stop. 4.2.2. W HO AND W HEN TO T REAT HBV The decision to treat CHB in HIV-infected individuals must be based on careful consideration of the need for antiretroviral therapy for HIV
264
Doo and Ghany
infection, the severity of liver disease, and the likelihood of response to anti-HBV agents and potential adverse events. In general, the indications for treatment of HBV infection in the setting of HIV infection are the same as those for HBV mono-infected persons as recommended by the AASLD, the European AIDS Clinical Society (EACS) on the Treatment of HBV and HCV in HIV co-infected patients and the DHHS guidelines on the management of adults and adolescents with HIV infection (21, 26, 27). Hepatitis B e antigen positive patients with a serum HBV DNA level >20,000 IU/ml and elevated serum ALT levels greater than 2 x ULN are candidates for treatment. HBeAg positive patients with normal ALT levels should be monitored without HBV therapy if HAART therapy is not indicated. The HBV DNA level for treatment in HBeAg negative patients is lower with a threshold of >2,000 IU/ml. Whether a liver biopsy is necessary before initiating therapy in HBV HIV coinfected patients is an unsettled issue. Given the association between HBV DNA level and outcome of CHB coupled with the rapidity by which liver histology can progress in chronic HBV infection, there has been a notable shift in clinical practice toward performing fewer liver biopsies in patients with chronic HBV infection and instead basing therapy on HBV DNA and serum ALT levels. Performing a liver biopsy remains a reasonable consideration in individuals with mildly elevated (<1–2 × ULN) or fluctuating ALT levels in the process of gathering data to determine initiation of treatment. Decompensated patients are best managed at liver transplant centers. 4.2.3. T REATMENT M EDICATIONS Currently, six drugs are licensed for the treatment of chronic HBV. Two are formulations of interferon that require injection as the route of delivery. The other agents are all oral nucleos(t)ide analogues that target the viral reverse transcriptase and include lamivudine, adefovir, entecavir, and telbivudine. Additionally, two nucleos(t)ide analogues licensed for HIV therapy, tenofovir and emtricitabine, have known activity against HBV. Potency, side effects, and resistance profiles vary among the different agents and are essential to consider when selecting agent(s).
4.3. Interferon Two interferon preparations have been approved for the treatment of chronic HBV infection, standard interferon alfa-2b and pegylated interferon alfa-2a. Very few studies have been conducted in the co-infected population and most reported a lower response rate as determined by the loss of HBeAg and a higher rate of HBV reactivation as assessed
Management of Patients Co-Infected with Chronic Hepatitis B
265
by the reappearance of HBeAg when compared to mono-HBV infected patients (18).
4.4. Lamivudine Lamivudine was the first nucleoside analogue approved for chronic HBV and also has activity against HIV. Therapy with lamivudine in HBV/HIV co-infected persons resulted in a mean reduction in HBV viral levels of 2.7–3 log10 copies/ml and undetectable HBV DNA in 40% by PCR assay (lower limit of detection 400 copies/ml) after 1 year of therapy (28). HBeAg seroconversion rates ranged from 11 to 17% which were comparable to that reported for HBV mono-infected subjects at 16–21% (29, 30). Resistance to lamivudine occurred at a rate of 14–24% after 1 year of treatment and >70% after 5 years of therapy in HBV mono-infected persons (29–31). Unfortunately, lamivudine resistance developed more rapidly in HBV/HIV co-infected persons. Emtricitabine and telbivudine have similar antiviral effects as lamivudine and develop similar patterns of HBV polymerase genotypic resistance (32).
4.5. Adefovir Adefovir is an acyclic phosphonate nucleotide analogue with activity against HBV but not against HIV at the approved dose of 10 mg. Adefovir is effective at suppressing HBV DNA and is associated with a median reduction in HBV DNA level of 3.5–3.7 log10 copies/ml after 48 weeks of therapy (33, 34). However, a high rate of primary nonresponse (20–50%) has been reported indicating inadequate viral suppression (35). Rates of resistance to adefovir were 2% at 2 years and 29% after 5 years of therapy in HBV mono-infected persons (36). Adefovir is active against lamivudine-resistant mutants. In one study, 35 HBV/HIV co-infected persons with lamivudine resistance received adefovir 10 mg daily (37). The median reduction in HBV DNA levels reported at 48, 96, and 144 weeks were 4.7, 5.5, and 5.9 log10 copies/ml (37). For the management of lamivudine resistance, adding adefovir to lamivudine is preferred to switching to adefovir because of a lower rate of developing adefovir resistance (38–40).
4.6. Entecavir Entecavir is a carbocyclic analogue of 2-deoxyguanosine with potent activity against HBV and a high genetic barrier to the development of resistance in HBV mono-infected individuals (41, 42). In treatment of na¨ıve HBV mono-infected patients, entecavir 0.5 mg daily for 48 weeks was associated with a 6.9 log10 copies/ml reduction in HBV DNA level and 67% tested HBV DNA negative using an assay with a lower limit of
266
Doo and Ghany
detection of 300 copies/ml (42). No genotypic resistance was reported at 48 weeks. In extended use, entecavir continued to demonstrate a low rate of resistance, 1.2% at 5 years (43). For management of lamivudine resistance, the recommended dose of entecavir is 1.0 mg daily. However, even at twice the na¨ıve patient dose, the efficacy is reduced in mono-infected patients with lamivudineresistant HBV raising the development of entecavir resistance as an issue in this population. After 5 years of therapy in lamivudine-resistant chronic HBV patients, 51% developed evidence of genotypic resistance (43). This is because pre-existence of lamivudine-resistant mutations resulted in an increase in the rate of entecavir resistance. In one randomized study of entecavir in HBV/HIV co-infected patients with lamivudine resistance, the mean reduction of HBV DNA was 3.66 log10 copies/ml and only 8% of patients developed undetectable HBV after 1 year of therapy (44). Entecavir was initially believed not to have activity against HIV and was therefore an ideal therapeutic choice for HBV/HIV co-infected individuals who did not require HAART. However, recent reports demonstrated that entecavir has anti-viral activity against HIV and selects for the M184V HIV mutation (45). Thus, entecavir monotherapy for HBV in co-infected individuals should be not be used unless combined with HAART therapy.
4.7. Tenofovir Tenofovir is an acyclic nucleotide analogue with activity against both HBV and HIV. It has been approved for use in HIV and more recently for HBV infection. Tenofovir exhibited more potent anti-HBV activity than adefovir in both HBV mono- and HBV/HIV co-infected persons (46, 47). This was demonstrated in a small randomized trial comparing tenofovir 300 mg daily to adefovir 10 mg daily, where 94% of subjects had lamivudine resistance (48). The trial was terminated early after the primary non-inferiority endpoint was met. The mean reduction in HBV DNA was 4.4 log10 copies/ml with tenofovir and 3.2 copies/ml with adefovir. Similar results were reported in a retrospective analysis of the efficacy of tenofovir in HBV/HIV co-infected persons (49). No resistance has been reported as yet with tenofovir.
4.8. Which Regimen to Use? Selection of an appropriate regimen will depend on whether the patient only warrants treatment for just CHB alone, just the HIV infection alone, or both infections simultaneously, Table 1.
Management of Patients Co-Infected with Chronic Hepatitis B
267
Table 1 Summary Of Therapeutic Guidelines For The Management of HBV–HIV Co-Infection Clinical scenario
DHHS panel (50) EACS (21)
AASLD guidelines (26)
Treat HBV
•
• Pegylated interferon alfa-2a • Adefovir
•
Pegylated interferon alfa-2a Adefovir
•
Pegylated interferon alfa-2a
•
Telbivudine with adefovir add-on if HBV DNA positive at 24 weeks Adefovir and telbivudine combination therapy Early HAART initiation with tenofovir and lamivudine or emtricitabine HAART including • Tenofovir and tenofovir and lamivudine or lamivudine or emtricitabine emtricitabine
•
•
Treat HIV
Lamivudine resistance present
•
HAART • including tenofovir and lamivudine or emtricitabine •
Add on/replace with tenofovir
• Add-on tenofovir or adefovir
4.9. Patients Who Do Not Require Treatment for HIV Agents that have dual activity against HBV and HIV should not be used as monotherapy to treat HBV in the absence or HAART because of the risk of developing HIV resistance which may limit future HIV therapeutic options. In HBeAg positive patients with low viral load and high serum ALT levels or genotype A and who have preserved CD4 counts (>500 mm3 ) consideration can be given to using pegylated interferon alfa-2a. The limitation of pegIFN is its poor tolerability and lower efficacy in the HIV setting. Moreover, the drug is contraindicated
268
Doo and Ghany
in decompensated cirrhosis. The only nucleos(t)ide analogue without HIV activity is adefovir. However, given its relatively low potency and increased rate of resistance over time, monotherapy with adefovir is not advised. Because of the risk for HIV drug resistance, the use of emtricitabine, lamivudine, tenofovir, or entecavir without a full combination antiretroviral regimen should be avoided. Recent DHHS guidelines recommended initiating HAART therapy if HBV treatment alone is necessary (50).
4.10. Patients Who Require Therapy for HIV and HBV HAART therapy that includes two dual acting drugs against HBV are suitable options for treating co-infected patients. The best choice is to combine a nucleoside and a nucleotide analogue that do not share cross-resistance. Thus, tenofovir plus either emtricitabine or lamivudine would be considered as first-line options. The use of tenofovir, lamivudine, or emtricitabine as the only anti-HBV agent should be avoided because of the risk of developing HBV resistance. Entecavir could be substituted for either emtricitabine or lamivudine. If patients need to change their anti-HIV regimen because of treatment failure or side effects, the anti-HBV component should be continued even if it is not part of the new regimen. A degree of caution should be exercised when stopping HBV therapy as it has been associated with reactivation of HBV and ALT flares.
4.11. Patients Who Require Treatment for HIV but not HBV If treatment is indicated for the HIV infection in co-infected individuals, then the ability to avoid treatment of the HBV infection becomes problematic as most antiretroviral regimens contain agents with activity against HBV. In this situation, the preferred HAART backbone should include tenofovir in combination with either lamivudine or emtricitabine in order to treat the HBV infection concomitantly (50).
4.12. When to Stop Therapy? Durable treatment endpoints in HBV/HIV co-infected persons have not been well studied. HBV DNA levels should be monitored every 3–6 months to detect emergence of virological breakthrough heralding drug resistance. The durability of HBeAg and HBsAg loss or seroconversion has not been reported in HBV/HIV co-infected persons. Since in most circumstances therapy for HIV will be necessarily long term, there is little need to discontinue anti-HBV therapy even if these serological endpoints are achieved.
Management of Patients Co-Infected with Chronic Hepatitis B
269
4.13. Management of End-Stage Liver Disease in Co-Infection The development of signs and symptoms of abdominal ascites, hepatic encephalopathy, and gastrointestinal varices heralds the progression to decompensated liver disease. The treatment and management of these complications in co-infected individuals is identical to the management of end-stage liver disease caused by other chronic liver conditions (51). 4.13.1. L IVER T RANSPLANTATION Liver transplantation has been evaluated as a medical option for coinfected patients who progress to end-stage liver disease. Prior to the advent of HAART therapy, the presence of HIV infection was considered a contraindication for liver transplantation. However, HAART therapy has altered the natural history of HIV infection such that liver disease is among the leading causes of mortality in co-infected patients. As such, liver transplantation has been assessed as a therapeutic option in end-stage co-infected individuals. In general, HBV/HIV co-infected patients who are highly selected candidates appeared to have comparable survival as those who are HIV mono-infected 2 years after transplantation. However, the number of co-infected patients reported in these studies was small and thus rendering it difficult to generalize their findings (52, 53). Improved management of the complexities associated with the medical management after liver transplantation has required heightened attention to drug–drug interactions, infections, and rejection episodes (51).
REFERENCES 1. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44(1 Suppl):S6–9. 2. http://www.unaids.org/wad2004/report pdf.html Accessed March 2008. 3. Zhou J, Dore GJ, Zhang F, Lim PL, Chen YM. Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database. J Gastroenterol Hepatol 2007;22(9):1510–8. 4. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. Aids 2005;19(6):593–601. 5. Norder H, Courouce AM, Coursaget P, et al. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004;47(6):289–309. 6. Jain MK, Comanor L, White C, et al. Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response. J Viral Hepat 2007;14(3):176–82.
270
Doo and Ghany
7. Ramos B, Nunez M, Martin-Carbonero L, et al. Hepatitis B virus genotypes and lamivudine resistance mutations in HIV/hepatitis B virus-coinfected patients. J Acquir Immune Defic Syndr 2007;44(5):557–61. 8. Quarleri J, Moretti F, Bouzas MB, et al. Hepatitis B virus genotype distribution and its lamivudine-resistant mutants in HIV-coinfected patients with chronic and occult hepatitis B. AIDS Res Hum Retroviruses 2007;23(4):525–31. 9. Westland C, Delaney Wt, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology 2003;125(1):107–16. 10. Lo Re V, 3rd, Frank I, Gross R, et al. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr 2007;44(3):315–20. 11. Hadler SC, Judson FN, O’Malley PM, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163(3):454–9. 12. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999;29(4):1306–10. 13. Gilson RJ, Hawkins AE, Beecham MR, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. Aids 1997;11(5):597–606. 14. Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360(9349):1921–6. 15. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166(15):1632–41. 16. Krogsgaard K, Lindhardt BO, Nielson JO, et al. The influence of HTLV-III infection on the natural history of hepatitis B virus infection in male homosexual HBsAg carriers. Hepatology 1987;7(1):37–41. 17. Bodsworth N, Donovan B, Nightingale BN. The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J Infect Dis 1989;160(4):577–82. 18. Di Martino V, Thevenot T, Colin JF, et al. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology 2002;123(6):1812–22. 19. Sheng WH, Chen MY, Hsieh SM, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clin Infect Dis 2004;38(10):1471–7. 20. Puoti M, Torti C, Bruno R, Filice G, Carosi G. Natural history of chronic hepatitis B in co-infected patients. J Hepatol 2006;44(1 Suppl):S65–70. 21. Rockstroh JK, Bhagani S, Benhamou Y, et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 2008;9(2):82–8. 22. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1–33; quiz CE1-4.
Management of Patients Co-Infected with Chronic Hepatitis B
271
23. Bruguera M, Cremades M, Salinas R, Costa J, Grau M, Sans J. Impaired response to recombinant hepatitis B vaccine in HIV-infected persons. J Clin Gastroenterol 1992;14(1):27–30. 24. Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine 2000;18(13):1161–5. 25. de Vries-Sluijs TE, Hansen BE, van Doornum GJ, et al. A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients. J Infect Dis 2008;197(2):292–4. 26. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45(2):507–39. 27. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 28. Dore GJ, Cooper DA, Barrett C, Goh LE, Thakrar B, Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B viruscoinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis 1999;180(3):607–13. 29. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341(17):1256–63. 30. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339(2):61–8. 31. Chang TT, Lai CL, Chien RN, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol 2004;19(11):1276–82. 32. Thio CL, Locarnini S. Treatment of HIV/HBV coinfection: clinical and virologic issues. AIDS Rev 2007;9(1):40–53. 33. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348(9):800–7. 34. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348(9): 808–16. 35. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44(2):283–90. 36. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131(6):1743–51. 37. Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001;358(9283):718–23. 38. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 2006;43(6):1385–91. 39. Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology 2007;133(5):1445–51. 40. Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 2007;45(2):307–13. 41. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354(10):1011–20.
272
Doo and Ghany
42. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354(10):1001–10. 43. Tenney DJ. PKA, Rose, RE, Baldick CJ, Eggers BJ, et al. Entecavir at Five Years Shows Long-Term Maintenance of High Genetic Barrier to Hepatitis B Virus Resistance. Hepatology International 2008. 44. Pessoa M, Gazzard B, Huang A, et al. Entecavir in HIV/HBV co-infected patients: safety and efficacy in a phase II study (ETV-0389). Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections 2005:109. 45. McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir – effects on HIV-1 replication and resistance. N Engl J Med 2007;356(25):2614–21. 46. van Bommel F, Zollner B, Sarrazin C, et al. Tenofovir for patients with lamivudineresistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 2006;44(2):318–25. 47. Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, et al. A Randomized Doubleblind, Comparison of Tenofovir (TDF) versus Adefovir (ADV) for the Treatment of HBeAg positive chronic Hepatitis B (CHB): Study GS-US-174-0103. Hepatology 2007;46(4):861A. 48. Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006;44(5):1110–6. 49. Benhamou Y, Fleury H, Trimoulet P, et al. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology 2006;43(3): 548–55. 50. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 51. Bonacini M. Diagnosis and management of cirrhosis in coinfected patients. J Acquir Immune Defic Syndr 2007;45 Suppl 2:S38–46; discussion S66–7. 52. Mindikoglu AL, Regev A, Magder LS. Impact of human immunodeficiency virus on survival after liver transplantation: analysis of United Network for Organ Sharing database. Transplantation 2008;85(3):359–68. 53. Norris S, Taylor C, Muiesan P, et al. Outcomes of liver transplantation in HIVinfected individuals: the impact of HCV and HBV infection. Liver Transpl 2004;10(10):1271–8.
Management of Antiviral Resistance in Chronic Hepatitis B Edward Doo, MD and Marc Ghany, MD CONTENTS I NTRODUCTION W HY D OES A NTIVIRAL R ESISTANCE D EVELOP ? N OMENCLATURE OF A NTIVIRAL D RUG R ESISTANCE R ATES OF R ESISTANCE TO A PPROVED AGENTS C LINICAL C ONSEQUENCES OF A NTIVIRAL R ESISTANCE M ANAGEMENT OF A NTIVIRAL R ESISTANCE P REVENTION OF A NTIVIRAL R ESISTANCE R EFERENCES
Key Principles
• Antiviral resistance in HBV infection is becoming an increasingly encountered clinical problem. • Characterizing and standardizing definitions of antiviral resistance is of paramount importance in defining a framework within which efficacy may be judged. • The different classes of antiviral agents have varying risks of resistance. The development of resistant mutations may limit future treatment options due to cross-resistance to other antiviral agents.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 10, C Humana Press, a part of Springer Science+Business Media, LLC 2009
273
274
Doo and Ghany
• Management strategies include early detection, add-on therapy, and salvage or rescue therapy based on cross-resistant profile of the mutations present.
1. INTRODUCTION Almost one-third of the world’s population has been exposed to hepatitis B virus (HBV) and it is estimated that there are 370 million chronic HBV carriers (1). When unrecognized or if left untreated, 40% of individuals will be at risk for developing significant liver disease including cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). Thus, chronic hepatitis B is a considerable global public health issue. The availability of oral nucleos(t)ide analogue treatment has revolutionized the management of chronic HBV infection. The advantages of oral nucleos(t)ide analogues include their ease of administration, high antiviral efficacy, and a favorable side effect profile. These characteristics represent a major advancement over interferon therapy, which required the use of injection as the route of administration and was associated with many side effects. The development of drug resistance is a major problem associated with the administration of nucleos(t)ide agents. The current challenge is how to best use these agents, whether singly, in combination, or sequentially in order to minimize the development of viral resistance. This chapter will review antiviral resistance of chronic hepatitis B therapy in terms of nomenclature, rates of occurrence, and management.
2. WHY DOES ANTIVIRAL RESISTANCE DEVELOP? Several viral, host, and drug factors that contribute to the development of nucleos(t)ide resistance have been identified (2, 3). The viral polymerase is the target of nucleos(t)ide analogue therapy. The absence of proofreading function in the viral polymerase results in a relatively high mutation rate of 10–4 to 10–5 mutations per base per cycle. This high mutation rate coupled with a high replication rate of 1012 to 1013 virions per day means that all possible mutations can be generated daily for every nucleotide site within the viral genome. In general, most viral mutations are not tolerated and viral variants replicate less well compared to wild-type virus. Therefore, wild-type virus is the predominant viral population in the absence of selective pressure such as nucleos(t)ide treatment. Another important factor is the relationship between the potency of an antiviral agent and its ability to induce selection pressure on the virus. A drug with low antiviral potency does not exert significant
Management of Antiviral Resistance in Chronic Hepatitis B
275
pressure upon the virus, and the chance of developing drug resistance is low. Similarly, a potent drug with rapid and complete suppression of viral replication allows little opportunity for the emergence of resistant virus, as mutagenesis is replication dependent. An agent exerting modest antiviral activity directed at a single target site would potentially lead to the highest probability of selecting for drug-resistant virus. Several other characteristics of the antiviral agent are important. These include the structure of the antiviral agent and the genetic barrier to resistance. The genetic barrier to resistance refers to the number of mutations that the virus must accumulate to restore replication fitness in order to circumvent the effect of the antiviral agent. The higher the genetic barrier of a therapeutic agent, the less likely is the chance of developing resistance. Regarding the host, the immune status of the patient is one important factor determining the development of viral resistance. Immune suppression, whether acquired primarily or secondarily, indirectly affects the rate of viral replication and the level of circulating virus. Obesity is another factor that can affect drug concentrations in the setting of fixed dosing by altering volumes of distribution; and patient nonadherence can affect steady-state drug levels, all of which are important in the development of drug resistance. Since many of these agents are prodrugs or require phosphorylation for their function, the activity of host cellular enzymes is also an important determinant of antiviral drug resistance.
3. NOMENCLATURE OF ANTIVIRAL DRUG RESISTANCE Characterizing and standardizing definitions of antiviral resistance has been a major effort of investigators in the field of viral hepatitis B. Standardized definitions acceptable by all investigators allow for more equitable comparisons among antiviral agents in different studies and provide a framework upon which efficacy can be judged. At a National Institutes of Health Workshop on the Management of Chronic HBV: 2006, a panel of experts proposed a consensus opinion of standardized definitions of response to treatment (4, 5).
3.1. Primary Antiviral Treatment Failure (or Primary Non-Response) Primary non-response is defined as the inability of a nucleos(t)ide analogue to reduce serum HBV DNA by ≥1 log10 IU/ml after the initial 6 months of therapy (4, 5). This definition was chosen because it exceeded the variability of the HBV DNA assays and reflected a true virological response, but not a clinical one. Potency of the antiviral
276
Doo and Ghany
agent is probably the most important factor contributing to primary nonresponse. Monitoring of primary non-response is important because a high residual viral level after 1 year of treatment is associated with a high rate of antiviral resistance (6).
3.2. Secondary Antiviral Treatment Failure (or Virological Breakthrough) Virological breakthrough is defined as a consistent increase in serum HBV DNA by ≥1 log10 IU/ml above nadir while on treatment, after achieving an initial virological response in patients who are compliant with their medication (4, 5). Virological breakthrough is usually the result of drug resistance. Virological breakthrough may occur with or without a concomitant rise in serum alanine aminotransferase (ALT) level.
3.3. Biochemical Breakthrough Biochemical breakthrough is defined as elevation in serum ALT level during treatment in a patient who has achieved initial normalization (4, 5). Biochemical breakthrough may occur concomitantly with viral breakthrough and in some cases may be accompanied by a hepatitis flare (defined as an ALT level >5X upper limit of normal) and clinical decompensation (7, 8).
3.4. Genotypic Resistance Genotypic resistance is defined as the presence of mutations within the HBV polymerase that have been demonstrated to decrease susceptibility to treatment (4, 5). Primary drug-resistant mutations cause an amino acid substitution that results in reduced susceptibility to an antiviral agent. A secondary or compensatory mutation results in amino acid substitutions that restore functional defects in viral polymerase activity associated with primary drug resistance.
3.5. Phenotypic Resistance Phenotypic resistance refers to the in vitro confirmation that the genotypic mutation decreases susceptibility to treatment and is the gold standard to confirm antiviral resistance (4, 5).
3.6. Recognition of Antiviral Resistance Detection of antiviral resistance requires the implementation of an adequate monitoring schedule while on therapy. There are no firm recommendations on what constitutes an appropriate monitoring
Management of Antiviral Resistance in Chronic Hepatitis B
277
schedule but a reasonable approach would be to monitor the serum ALT and HBV DNA every 3 months while on treatment. Virological breakthrough is typically the first manifestation of antiviral resistance (Fig. 1). Therefore HBV DNA levels should be monitored in all patients receiving nucleos(t)ide analogues to document an initial virological response and to monitor for virological breakthrough during treatment in those who had an initial virological response. It is important to exclude non-compliance in patients with virological breakthrough and this should be considered before ordering expensive tests to confirm the presence of drug-resistant mutants. Investigation into the specific resistant mutations should be performed if testing is available so as to confirm genotypic resistance and to help direct the selection of salvage therapy. The development of viral breakthrough is more often than not followed by biochemical breakthrough, which may occasionally rise to the level of a hepatitis flare.
4. RATES OF RESISTANCE TO APPROVED AGENTS 4.1. L-Nucleosides Currently, lamivudine and telbivudine are the only L-nucleosides approved for treatment of chronic HBV infection in the United States. Other L-nucleoside agents with antiviral activity against HBV include emtricitabine and clevudine. These compounds have a similar Rates of Genotypic Resistance in Nucleos(t)ide Naïve Subjects
80 71
70
65
Percent
60 49
50
38
40 30
29 24
22 18
20
11
10 0
3 0
0 Lamivudine
Adefovir Year 1
Year 2
0
1 <1 1.2
Entecavir Year 3
4
0
Telbivudine Year 4
Tenofovir
Year 5
Fig. 1. The rates of genotypic resistance for nucleos(t)ide analogues over time.
278
Doo and Ghany
molecular structure and target site of action, and as a result, similar patterns of antiviral-resistant mutations. Primary mutations conferring resistance to L-nucleosides occur in the YMDD motif of the reverse transcriptase, which is located in the catalytic site for viral polymerase (9). The specific primary mutations conferring resistance to lamivudine are the rtM204V/I substitutions and for telbivudine, only the rtM204I substitution (9, 10). In vitro studies have shown that these mutations result in a >1000-fold decreased susceptibility of the viral polymerase for lamivudine and reduced functional capacity of the viral polymerase (9). As a result, compensatory secondary mutations including rtV173L, rtL180M, and rtL80I that restore the viral polymerase function to near wild-type levels are almost always associated with the primary resistance mutations (11). The primary lamivudine-resistant mutations are cross-resistant with other agents in the L-nucleoside class. Therefore, other L-nucleoside agents have significantly reduced activity against the lamivudine-resistant mutant virus and should not be used as salvage therapy (12). In clinical trials, the rate of resistance to lamivudine is relatively high with 14%–24% developing genotypic resistance at 1 year and >70% at 5 years (7, 13, 14). Telbivudine is associated with a lower rate of resistance compared to lamivudine at 1 year, 12%, but the rate almost doubles at two years to 22%, suggesting that the development of resistance may be a significant problem with longer duration of therapy.
4.2. Acyclic Phosphonates Adefovir and more recently tenofovir are acyclic phosphonates approved for therapy of HBV. Tenofovir has been shown to have superior antiviral activity against HBV compared to adefovir (15). Mutations that confer resistance to adefovir reside outside of the YMDD motif and result in only a modest increase (two- to ninefold) in the EC50. Nevertheless, virological breakthrough occurs with this subtle change in the binding of adefovir to the mutant HBV polymerase (16). The primary adefovir-resistant mutations are the rtA181T and rtN236T substitutions in the viral polymerase (16). The adefovir-resistant mutations are partially cross-resistant with tenofovir but are sensitive to the L-nucleoside and cyclopentane class of agents. The one exception being the rtA181T mutation, which has been shown to result in primary lamivudine resistance in the absence of the rtM204V/I mutations. Accordingly, lamivudine should not be used as salvage therapy for adefovir resistance if this mutation is present (17). Long-term follow-up results of registration studies indicated the rate of genotypic resistance to adefovir was 2% at 2 years but increased to
Management of Antiviral Resistance in Chronic Hepatitis B
279
29% at 5 years in HBeAg-negative and 20% at a median of 235 weeks in HBeAg-positive subjects (18–20). No resistance to tenofovir has been reported at 1 year of use.
4.3. Cyclopentane Group Entecavir is a carbocyclic analogue of 2-deoxyguanosine with potent activity against HBV. Entecavir acts at three stages in the viral life cycle by inhibiting priming as well as inhibiting synthesis of both negative and positive strands. Entecavir has a high genetic barrier to resistance, which means that the virus must accumulate several mutations before virological breakthrough is observed. Two patterns of mutations have been reported (21). One pattern includes rtI169T + rtL180M + rtM204V + rtM250V and the other rtL180M + rtT184G + rtS202I, and rtM204V (21). Both patterns of mutations encompass the primary lamivudine-resistant mutation, rtM204I/V. In the absence of the primary lamivudine-resistant mutation, the entecavir-associated resistant mutations results in only a modest change in EC50 (<10-fold) as opposed to over a 1000-fold susceptibility in the presence of the lamivudineresistant mutant (21). Entecavir is associated with a low rate of antiviral resistance in nucleoside-na¨ıve patients, 0% at 1 year and 1.2% at 5 years (22). In lamivudine-experienced patients with rtM204V/I ± rtL180M mutations, the rate of entecavir resistance is significantly increased from 1% at 1 year to 51% at 5 years (23). Therefore, careful consideration should be given to other therapeutic options before selecting entecavir as salvage therapy for lamivudine resistance. The entecavir-resistant mutations have been shown to be responsive to adefovir and tenofovir (24).
5. CLINICAL CONSEQUENCES OF ANTIVIRAL RESISTANCE The development of antiviral resistance is usually associated with loss of initial virological, biochemical, and histological response. In a long-term follow-up study of patients treated with lamivudine 100 mg daily, liver biopsies were performed at baseline, 1, and 3 years (25). Histological improvement was observed more frequently in patients without lamivudine resistance, 77% versus 44%, and histological worsening was less common, 15% versus 5%, compared to patients with lamivudine resistance (25). Patients with resistance for >2 years were least likely to demonstrate histological improvement (36%). An important randomized placebo-controlled study of lamivudine to prevent disease
280
Doo and Ghany
progression in patients with bridging fibrosis or cirrhosis showed that resistance diminished the therapeutic benefits of lamivudine (26). In this study, half of the patients developed lamivudine resistance. Although benefit was observed among treated patients who developed lamivudine resistance when compared to placebo, the benefit was clearly less relative to lamivudine-treated patients without resistance (26). Hepatitis flares and hepatic decompensation may occur following the development of antiviral-resistant mutants. In a study of almost 1000 HBeAg-positive patients with compensated liver disease who received lamivudine for a median of 4 years, the risk of hepatitis flares increased with the duration of lamivudine resistance such that 80% patients who had lamivudine-resistant mutants for >4 years would have experienced at least one hepatitis flare (7). The risk of hepatic decompensation was extremely low in this cohort, less than 1%, except for the group who had lamivudine resistance for more than 4 years. The generally favorable short-term clinical outcome of this cohort may be related to their young age (mean 32 years old) and the fact that only 10% had cirrhosis at the onset of treatment. Development of antiviral resistance may limit future treatment options due to mutations that confer cross-resistance to other antiviral agents. For example, development of lamivudine-resistant mutation rtM204V/I is associated with cross-resistance to other L-nucleoside analogues, such as telbivudine and emtricitabine, as well as entecavir. The presence of the rtM204V/I mutation effectively eliminates these drugs as rescue agents for these patients (12).
6. MANAGEMENT OF ANTIVIRAL RESISTANCE Several important concepts of management of antiviral resistance have emerged in recent years. The earlier therapy is altered after detecting the emergence of virological breakthrough, the better the long-term virological and biochemical outcome. Additionally, the strategy of addon therapy appears to be a better approach as opposed to switching therapy with regard to preventing subsequent multi-drug resistance. Salvage therapy should be implemented immediately in patients with cirrhosis to prevent the possibility of hepatitis flares and subsequent hepatic decompensation. Finally, the choice of rescue therapy for a patient with drug-resistant HBV should be based on the cross-resistant profile of the mutations present, the potency of available agents against these mutations, and the presence of co-morbid conditions such as renal insufficiency (Table 1).
Management of Antiviral Resistance in Chronic Hepatitis B
281
Table 1 General Principles of Management • Obtain pre-treatment HBV DNA level • Assess on-treatment virological response profile • Document previous antiviral therapy if any • Know potency and resistance profile of antiviral drugs • Know of cross-resistance profile of drug • Assess severity of underlying liver disease • Address Co-morbid medical conditions e.g. renal disease • ? Perform resistance testing
In a study to assess whether the timing of administration of rescue therapy influenced outcome, adefovir was initiated either at the time of detection of genotypic resistance without biochemical breakthrough or at the time of genotypic and clinical breakthrough in patients treated with lamivudine (27). At 2 years, the virological response was 100% in patients treated at the time of genotypic resistance only but 78% in those with both genotypic and clinical breakthrough, suggesting that early implementation of rescue therapy was associated with a more favorable clinical outcome (27). Several studies have demonstrated that when adefovir was used to manage lamivudine resistance, the strategy of add-on was superior to switching in terms of preventing future adefovir resistance (28, 29). In a retrospective analysis of 588 patients with lamivudine resistance, 303 were switched to adefovir and 285 had adefovir added in combination with lamivudine (29). The rates of virological response were similar in both the switched and combination groups after 3 years of therapy (71% versus 78%, respectively). However, the rate of virological breakthrough (30% versus 6%, respectively) and the genotypic resistance to adefovir (16% versus 0%) were significantly higher in the group switched to adefovir monotherapy as opposed to adefovir add-on therapy respectively, underscoring the benefit of combination therapy in preventing the development of multi-drug resistance (29).
6.1. Options for Management of Antiviral Resistance Data on management options for patients with lamivudine resistance are evolving and are available from clinical trials and in vitro testing. Therapeutic options include adding adefovir, switching to drugs with
282
Doo and Ghany
high potency and genetic barriers to resistance such as entecavir or tenofovir or the combination of tenofovir plus emtricitabine (off label use) (3). Rates of undetectable HBV DNA by PCR in HBeAg-positive patients treated with adefovir 10 mg daily as add-on therapy or who were switched to entecavir 1.0 mg daily or tenofovir 300 mg daily were reported as 35%, 21%, and 91%, respectively (30–32). Although these results are not directly comparable because of different baseline characteristics, the 1-year rate of resistance to adefovir add-on or switching to entecavir or tenofovir were 0%, 1% and 0%, respectively (30–32). These data would support all of these strategies at least in the short term but longer term data are necessary before one strategy can be recommended over the other. Of concern is recently released 5-year data on rates of genotypic resistance to entecavir in lamivudine-resistant patients, indicating that 51% developed resistance (23). Lamivudine-resistant HBeAg-negative patients showed better virological responses compared to HBeAg-positive patients as was the case in the treatment of na¨ıve patients (28, 29). In one study, 67% and 69% of patients treated with switching or add-on adefovir therapy, respectively, achieved a virological response, but add-on therapy was associated with a lower rate of subsequent adefovir resistance (29). Currently, only case reports are available on the use of entecavir or tenofovir as salvage therapy in HBeAg-negative chronic hepatitis B and therefore no evidence-based recommendations can be made about these agents. Figures 2 and 3 illustrate virologic responses and resistance rates encountered with rescue therapy of lamivudine resistant HBeAg positive and negative patients. For the management of adefovir resistance, evidence is based on small case reports and in vitro testing (33). These reports suggested that management should be based on the pattern of adefovir-resistant mutations present (16, 34). For patients with the rtN236T mutation, options include switching to or adding entecavir; adding lamivudine; or switching to tenofovir; or switching to the combination of tenofovir plus emtricitabine (off-label use). For the scenario where the rtA181T mutation has developed, options are fewer and include switching to or adding entecavir; or switching to tenofovir; or switching to the combination of tenofovir plus emtricitabine (off-label use). Lamivudine should not be used in this setting due to cross-resistance to the rtA181T mutation. Data on the management of entecavir resistance are based largely from case reports and in vitro phenotypic testing. On the basis of this limited evidence, two approaches are available: to switch or add adefovir; or switch to or add tenofovir monotherapy; or switch to tenofovir plus emtricitabine (off-label) (24, 35).
Management of Antiviral Resistance in Chronic Hepatitis B
283
Outcome of Rescue Therapy in HBeAg (+) Patients with Lamivudine Resistance
100 90 80 70 60 50 40 30 20 10 0
(b) Rate of Resistance
91
40
35 26
Percent Resistance
HBV DNA by PCR
(a) Virologic Response
19
Switch to ADV
Add ADV Year 1
Switch to ETV Switch to TDF Year 2
45 40 35 30 25 20 15 10 5 0
39 27 15 11 0
1
0
Switch to ADV
Add ADV
Year 1
Year 3
Year 2
0
Switch to ETV Switch to TDF Year 3
Year 4
Fig. 2. Outcomes of rescue therapy for lamivudine resistance in HBeAgpositive patients. (a) Virological response: percent HBV DNA undetectable by PCR assay. (b) Rates of resistance over time either with switching or add-on strategy.
Outcome of Rescue Therapy in HBeAg (–) Patients with Lamivudine Resistance
90 80 70 60 50 40 30 20 10 0
(b) Rate of Resistance 79
66
67
69
64
Switch to ADV Year 1
Add ADV Year 2
Year 3
Percent Resistance
HBV DNA (-) by PCR
(a) Virologic Response 10 9 8 7 6 5 4 3 2 1 0
9
2 0
0
Switch to ADV Year 1
0 Add on ADV
Year 2
Year 3
Fig. 3. Outcomes of rescue therapy for lamivudine resistance in HBeAgnegative patients. (a) Virological response: percent HBV DNA undetectable by PCR assay. (b) Rates of resistance over time either with switching or addon strategy.
There is limited information on the management of resistance to telbivudine; however, the recommendations would be similar to those for lamivudine resistance based upon the similarities of these two compounds. Scant data are available on the management of multi-drug resistance (36). Every precaution should be taken to prevent this clinical scenario from occurring. Peginterferon may have a role in carefully selected cases and expert advice should be sought in managing these patients.
284
Doo and Ghany
7. PREVENTION OF ANTIVIRAL RESISTANCE The prevention of antiviral resistance is a major goal of future management strategies. This should begin with proper patient selection and judicious use of antiviral agents. One should avoid futile/inappropriate antiviral therapy. An antiviral agent with the highest potency and high genetic barrier to resistance should be selected especially in HBeAgpositive patients with high viral loads to prevent the emergence of drugresistant mutants. Whether initiating therapy with combination therapy will achieve the goal of minimizing the development of antiviral resistance is currently an unanswered question. Since all available antiviral agents have the same target of action, the utility of this approach would have to be proven in clinical trials. Certainly, the 5-year data for entecavir in the treatment of na¨ıve patients would not support this approach. Other unanswered questions include what agents to combine and could one agent be withdrawn after HBV DNA is fully suppressed. It is important to avoid sequential monotherapy, which can lead to multi-drug resistance and avoid use of agents with similar cross-resistance profiles. Monitoring the antiviral response is crucial for the early detection of virological breakthrough, thus permitting early intervention with the prospect of better outcomes. Finally, reinforcement of compliance with a prescribed regimen is of paramount importance.
REFERENCES 1. http://www.who.int/mediacentre/factsheets/fs204/en/index.html Accessed August 2008. 2. Fung SK, Lok AS. Management of hepatitis B patients with antiviral resistance. Antivir Ther 2004;9:1013–26. 3. Locarnini S, Hatzakis A, Heathcote J, Keeffe EB, Liang TJ, Mutimer D, Pawlotsky JM, Zoulim F. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther 2004;9:679–93. 4. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45:1056–75. 5. Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007;46:254–65. 6. Locarnini S QX, Arterburn S, Snow A, Brosgart CL, Currie G, et al. Incidence and predictors of emergence of Adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) J Hepatol 2005;42:17. 7. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA, Gardner SD, Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125: 1714–22.
Management of Antiviral Resistance in Chronic Hepatitis B
285
8. Fung SK, Andreone P, Han SH, Rajender Reddy K, Regev A, Keeffe EB, Hussain M, Cursaro C, Richtmyer P, Marrero JA, Lok AS. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol 2005;43:937–43. 9. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, Brown N, Condreay LD. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998;27:1670–7. 10. Standring DNP, A., Chapron C, van Doorn L, Belanger B, et al. Resistance determination in patients experiencing virologic breakthrough following Telbivudine or Lamivudine therapy in the international GLOBE trial. Gastroenterology 2007. 11. Delaney WEt, Yang H, Westland CE, Das K, Arnold E, Gibbs CS, Miller MD, Xiong S. The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J Virol 2003;77: 11833–41. 12. Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WEt. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudineresistant HBV. Antivir Ther 2005;10:625–33. 13. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341: 1256–63. 14. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339: 61–8. 15. Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, et al. A randomized, double-blind, Comparison of Tenofovir (TDF) versus Adefovir Dipivoxil (ADV) for the treatment of HBeAg positive CHronic Hepatitis B (CHB). Hepatology 2007;46:861A. 16. Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, Brosgart C, Colledge D, Edwards R, Ayres A, Bartholomeusz A, Locarnini S. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003;125:292–7. 17. Villet S, Pichoud C, Billioud G, Barraud L, Durantel S, Trepo C, Zoulim F. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol 2008;48:747–55. 18. Yang H, Westland CE, Delaney WEt, Heathcote EJ, Ho V, Fry J, Brosgart C, Gibbs CS, Miller MD, Xiong S. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks. Hepatology 2002;36: 464–73. 19. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Brosgart CL, Borroto-Esoda K, Arterburn S, Chuck SL. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131:1743–51. 20. Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008;48:750–8.
286
Doo and Ghany
21. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P, Ayres A, Bartholomeusz A, Sievert W, Thompson G, Warner N, Locarnini S, Colonno RJ. Clinical emergence of entecavirresistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother 2004;48:3498–507. 22. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–10. 23. Squibb. B-M. Baraclude (Entecavir) Data continue to demonstrate low incidence of resistance through five years of treatment in Nucleoside-Naive Chronic Hepatitis B Patients. Press Release. March 24, 2008. 24. Leemans WF, Niesters HG, van der Eijk AA, Janssen HL, Schalm SW, de Man RA. Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir. Eur J Gastroenterol Hepatol 2008;20:773–7. 25. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105–17. 26. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351: 1521–31. 27. Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005;42:1414–9. 28. Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switchingto adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 2007;45:307–13. 29. Lapertico P, Marzano A, Levero M, Santantonio T, Di Marco V, et al. Adefovir and lamivudine combination therapy is superior to adefovir monotherapy for lamivudine resistant patients with HBeAg negative chronic hepatitis B. Hepatology 2006;44:693A. 30. Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df D, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004;126:91–101. 31. Sherman M, Yurdaydin C, Simsek H, Silva M, Liaw YF, Rustgi VK, Sette H, Tsai N, Tenney DJ, Vaughan J, Kreter B, Hindes R. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 2008;48: 99–108. 32. Van Bommel F, De Man RA, Erhardt A, Huppe D, Stein K, et al. First multicenter evaluation of the efficacy of tenofovir in nucleoside analogue experienced patients with HBV monoinfection. Hepatology 2007;46:270A. 33. Brunelle MN, Jacquard AC, Pichoud C, Durantel D, Carrouee-Durantel S, Villeneuve JP, Trepo C, Zoulim F. Susceptibility to antivirals of a human HBV
Management of Antiviral Resistance in Chronic Hepatitis B
287
strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology 2005;41:1391–8. 34. Villeneuve JP, Durantel D, Durantel S, Westland C, Xiong S, Brosgart CL, Gibbs CS, Parvaz P, Werle B, Trepo C, Zoulim F. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol 2003;39: 1085–9. 35. Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo C, Zoulim F. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol 2007;46:531–8. 36. Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 2006;44:703–12.
Herbal and Non-Traditional Therapies for Viral Hepatitis Veronika Gagovic and Paul Kwo CONTENTS E CONOMICS OF C OMPLIMENTARY A LTERNATIVE M EDICINE B URDEN OF V IRAL H EPATITIS S ELECTED H ERBAL T HERAPIES A NTIOXIDANTS AND D IETARY S UPPLEMENTS D ISCUSSION R EFERENCES Key Principles
• Complementary alternative therapy is a growing market, estimated at $180 billion annually, with at least one-third of liver patients acknowledging their use. • Patients infected with hepatitis B and C account for the wide use of herbal and non-traditional therapies for viral hepatitis. • Silymarin is most commonly used for patients with liver disease. In hepatitis C patients, two small trials showed a benefit in the reduction of liver enzymes, without affecting the hepatitis C viral load. Other trials have demonstrated no difference in aminotransferase levels and no reported trial has noted an effect on viral clearance rates with silymarin administration. • In hepatitis B patients, silymarin showed potential benefit in some trials, but these results could not be reproduced. As such,
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 11, C Humana Press, a part of Springer Science+Business Media, LLC 2009
289
290
•
•
•
•
• •
•
•
• • •
Gagovic and Kwo
silymarin, while safe, cannot be recommended for patients with hepatitis B or C. Glycyrrhizin, the active constituent of glycyrrhiza, has showed some benefits in the treatment of those with chronic hepatitis C, with a reduction in aminotransferase levels noted in some trials. The side effect profile including hypokalemia and fluid retention approaching 20% of patients who receive this supplement cautions against its use. Small trials using Phyllanthus amarus have suggested a higher clearance rate of serum HBsAg when given in combination with interferon. There is insufficient data to routinely recommend its use. TJ-9 (Xiao-Chai-Hutang/Sho-Saiko-To) showed benefit in patients with chronic HBV with increased HBeAg seroconversion, as well as an improved survival rate in those with non-HBsAg-related cirrhosis at 5 years. Unfortunately, side effects including liver injury, autoimmune hepatitis, hypokalemia, and hypertension prohibit routine use of this medicine. St. John’s wort (Hypericum perforatum) showed no efficacy in decreasing viral levels in chronic hepatitis C patients. Significant side effects associated with this medication suggest against its use in patients with liver disease. Plantago Asiatic has shown preliminary promising results, suggesting suppression of hepatitis B DNA levels. More studies are required to recommend its use. Herbal Medicine 861 showed promising initial results in patients with hepatitis B, reducing the level of liver fibrosis at the 6-month posttreatment interval. More studies will be required to verify this promising result. CH 100 showed initial promise in decreasing ALT levels in patients with chronic hepatitis C, but these results were not verified by other studies. More data will be required for it to be recommended in patients with liver disease. Liv 52 initially showed benefit in non-alcohol-related cirrhosis. However, in alcohol-related cirrhosis, a randomized, placebocontrolled trial showed increased mortality among the Child Class C patients, leading to the immediate withdrawal of the supplement from the United States. The antioxidant N-acetyl cysteine (NAC) failed to show a benefit in patients with acute hepatitis A and B. S-Adenosylmethionine use in patients with liver disease has also failed to show a consistent benefit. Vitamin E may show benefit in those with chronic HBV infection though additional studies are required.
Herbal and Non-Traditional Therapies for Viral Hepatitis
291
1. ECONOMICS OF COMPLIMENTARY ALTERNATIVE MEDICINE Acute and chronic liver disease due to viral hepatitis is an important cause of morbidity and mortality throughout the world. Over the past two decades, there has been rapid development of specific antiviral therapies in developing countries where chronic liver disease due to viral hepatitis may be prevalent at rates equal to or greater than that seen in developed countries. These therapies have been tested in rigorous randomized trials with objective endpoints. However, cost and limited resources have limited access to these therapies in many parts of the world including continents where specific therapies are available. As an example, anti-viral therapy for chronic hepatitis C (HCV) with pegylated interferon and ribavirin may cost more than $25,000 (US) per year for treatment, and even oral therapies for chronic hepatitis B (CHB) such as lamivudine, adefovir, entecavir, and telbivudine are associated with costs from $2000 to $9000 (US) per year. In addition, these therapies are often administered for greater than 1 year and can be associated with resistance and other side effects. Finally, not all patients with chronic viral hepatitis are candidates for these therapies. As an alternative to these specific antiviral therapies, herbal and nontraditional therapies for viral hepatitis, which have been used worldwide for thousands of years, remain the backbone of treatment in many parts of the world. They are widely used in countries with access to traditional antiviral agents as well as countries without the resources to provide widespread access to traditional antiviral agents. There are multiple reasons for the widespread use of these agents including lower cost, the perception that these “natural agents” are safer than traditional medicines, and fewer restrictions as these herbal therapies may not require a physician visit or a prescription. However, these agents have rarely been evaluated in a fashion similar to approved antiviral therapies, rather relying on uncontrolled data with subjective endpoints. Moreover, many herbal and non-traditional therapies for viral hepatitis are not single agents but rather combinations of various herbs or other compounds, without stringent guidelines, thus making assessment of efficacy difficult. The complementary alternative medicine (CAM) industry is a growing market among the population in the United States and is currently estimated at $180 billion. Approximately one in six adults taking prescription drugs is currently using CAM (1). Liver disease patients report the use of CAM from 30 to 64%, with silymarin noted as the most commonly used agent by this group (2–6).
292
Gagovic and Kwo
2. BURDEN OF VIRAL HEPATITIS The two diseases responsible for the majority of chronic viral hepatitis worldwide are hepatitis B and hepatitis C. Hepatitis B represents a major concern to public health and of two billion individuals who have been infected worldwide, there are an estimated 400 million persons worldwide who are chronically infected with HBV. Sub-Saharan Africa, the Pacific Islands, and particularly Asia represent most of the HBV disease burden due to the vertical transmission of the disease. Many countries in these continents lack resources to provide traditional medicines for viral hepatitis (7). Hepatitis C chronically infects an estimated 170 million persons worldwide. There are an estimated 2.7 million people in the United States who have active HCV infection with higher prevalence rates in Europe and Asia (8). Just 15% of patients with acute hepatitis C infection achieve clearance, leaving the large worldwide reservoir in approximately 85% of acutely infected individuals (9). It is these two large reservoirs of patients that account for the wide use of herbal and nontraditional therapies for viral hepatitis. In this chapter, we will review the most commonly used herbal and non-traditional therapies and the data that support their efficacy as well as noting potential toxicities of this class of therapies.
3. SELECTED HERBAL THERAPIES 3.1. Silymarin Silymarin or milk thistle has been used medicinally for over 2000 years, most commonly for the treatment of liver and gallbladder disorders. There is one specific medical indication, that being therapy for Amanita phalloides poisoning (10). Silymarin is an extract of Silybum marianum (milk thistle) found commonly throughout Europe, Asia, and North America and typically comprises at least 70% of milk thistle. Highly purified extracts of this plant have been available since the 1960s (11,12). Silymarin has been reported to be composed of the flavonolignans silybin, silycristin, silydianin, and isosilybin (a diastereomer of silybin) (13). Silybilin is the major active constituent of silymarin and represents 80–90% of its composition, while the rest is undefined19 . Proposed mechanisms of action of silymarin are believed to be through antioxidant properties as can be seen in iron overload and other states with increased oxidative stress (14) and through anti-fibrotic properties (15). Additionally, silymarin is thought to act via anti-inflammatory properties through inhibition of cytokine production by the Kupffer cells (16).
Herbal and Non-Traditional Therapies for Viral Hepatitis
293
3.1.1. S ILYMARIN U SE IN H EPATITIS C There is limited data supporting silymarin as a beneficial treatment for HCV infection. A recent Cochrane database review focused on the use of silymarin in patients with alcoholic and viral causes of liver disease (10). Of the 1833 initial references, exclusion criteria reduced the set to 26 references of 13 randomized controlled trials. In this review a potentially beneficial effect of silymarin on alcoholic liver disease was observed, although this finding could not be supported by two highquality trials. Additionally, the benefit was not observed in a subgroup analysis including patients with HCV infection. Overall, the review concluded that there is insufficient evidence to recommend or refute the use of milk thistle in patients with liver disease of any etiology including HCV, emphasizing the need for more randomized clinical trials (10). A second Cochrane hepatobiliary systematic review of randomized trials evaluating medicinal herbs for chronic HCV yielded similar results for silymarin (17). In only one placebo-controlled trial was silymarin noted to improve AST and ␥-glutamyl transpeptidase (GGTP) levels compared to placebo, although there were no effects on the viral load. In small pilot studies, silymarin showed a possible decrease in ALT levels in patient with chronic HCV without impacting HCV RNA levels (11). Other trials have demonstrated no difference in aminotransferase levels and most importantly, no reported trial has noted an effect on viral clearance rates with silymarin administration (18).
3.1.2. S ILYMARIN U SE IN H EPATITIS B Currently, no randomized controlled trials have evaluated the efficacy of silymarin in those with CHB. In a review focusing on silymarin in acute viral hepatitis, promising results were noted in a cohort of patients acute hepatitis B (19). In this study, HBV patients treated with silymarin had a shorter hospitalization (23 vs 30 days) and improved liverassociated chemistries as compared to patients with supportive care. However, other studies have not been able to demonstrate a similar benefit in those with acute HBV infection (20). Magnulio et al. (21) did not find a difference in the seroconversion rate in HBV-positive patients treated with silymarin, though they did show an improvement in liver tests, most notably for bilirubin and aminotransferase levels in the silymarin group. While these studies have shown that silymarin does not appear to have any hepatotoxic concerns in acute and chronic viral hepatitis, the current evidence demonstrates that there is no definite indication for using silymarin in either hepatitis B or C viral infection.
294
Gagovic and Kwo
3.2. Glycyrrhizin Glycyrrhiza glabra (lichorice root) originates in the Middle East and Mediterranean and in the past has been used for numerous medical purposes, including peptic ulcer disease and as an expectorant. Glycyrrhizin, the active part of glycyrrhiza, is a conjugate of glucuronic acid and glycyrrhetinic acid (22). There are several proposed mechanisms to explain its potential benefit including antioxidant properties, tumor necrosis factor inhibition, and endogenous interferon production (23). In the treatment of HCV with glycyrrhizin, some trials have demonstrated a decrease in aminotransferase levels (23). Two well-designed studies with glycyrrhizin in 226 patients with chronic HCV failed to show viral clearance in any of the patients. In one study, patients received either ursodeoxycholic acid plus intravenous glycyrrhizin or glycyrrhizin alone. Patients who received the combination therapy showed improvement of liver enzyme levels. Another large non-randomized trial observed a significantly lower prevalence of cirrhosis (21% vs 35%) and HCC (12% vs 25%) in patients treated with Stronger Neo-Minophagen C (SNMC), a derivation of glycyrrhizin, cysteine, and glyceine routinely used for active chronic hepatitis in Japan (24). Trials with glycyrrhizin in CHB have shown improvement in aminotransferase levels in patients receiving glycyrrhizin. In addition to lacking sufficient detail with respect to nature of liver disease or hepatitis B viral (HBV) DNA levels, none of the trials using glycyrrhizin have reported a benefit with reduction in HBV DNA level (22–24). Importantly, patients who consider the use of glycyrrhizin should be counseled regarding the side effects of fluid retention and hypokalemia, which are seen in up to 20% of patients receiving glycyrrhizin (22). Generally, beneficial effects of glycyrrhizin cease after the cessation of the administration of the medication and in trials that showed benefit in chronic viral hepatitis, it was related to the reduction of aminotransferase levels. There are no studies to our knowledge that assess the addition of glycyrrhizin for patients receiving interferon therapy. However, the side effect profile of this herbal therapy limits its recommendation for routine use in liver disease and patients who take glycyrrhizin should be cautioned regarding the side effects.
3.3. Phyllanthus amarus P. amarus is a herb, which is a part of Indian ayurvedic medicine. P. amarus has been used to treat diabetes, kidney and urinary problems, diarrhea, and viral hepatitis and has thus far been limited to chronic hepatitis B. The proposed mechanism of action is believed to act through
Herbal and Non-Traditional Therapies for Viral Hepatitis
295
the inhibition of polymerase activity, mRNA transcription, and replication (18). A systematic review by Liu et al. of 22 trials noted that most were of small sample size and less than ideal methodological quality. In patients using this supplement, nausea, decreased appetite, and stomach ache were reported with no serious side effects found (25). Five trials were assessed to be of adequate methodological quality. The results of four placebo-controlled trials showed that Phyllanthus herb vs placebo had an effect on clearance of serum HBsAg. The beneficial effect of Phyllanthus was mainly from an Indian trial, which was not repeated in a later trial by the same author (26). Additionally, in the trial by Liu et al, beneficial effects were noted when patients used interferon in combination with the P. amarus with improved clearance of HBsAg noted, as compared to interferon alone (25). No other supplements or herbal therapies for treatment of CHB have been assessed in this manner. Although using Phyllanthus for the treatment of patients with CHB is an attractive option, randomized controlled trials need to be conducted to confirm this effect and as such, this herb cannot be routinely recommended for use alone in the treatment of CHB.
3.4. TJ-9 (Xiao-Chai-Hutang/Sho-Saiko-To) This herbal supplement has been a part of the traditional Japanese Kampo system and the herbal medicine Sho-saiko-to (TJ-9) is an officially approved prescription drug in Japan, widely administered in Japan to patients with chronic liver disease. TJ-9 consists of a dried mixture of seven herbs including roots of scutellaria, glycyrrhiza, bupleurum, ginseng, pinella tuber, jujube fruit, and the ginger rhizome (27). In animal and cell culture models, TJ-9 has showed benefit by preventing collagen production in cultured stellate cells, as well as inhibiting lipid peroxidation in liver mitochondrial membranes (28). In investigating the mechanism by which TJ-9 activates stellate cells, Kakumu et al. showed that TJ-9 enhanced in vitro production of interferon-␥ and production of antibodies to hepatitis B core and hepatitis B e antigens by peripheral blood mononuclear cells from patients with chronic hepatitis B (28). Similar to many of the herbal therapies, there are limited studies in humans, though one study treated 116 patients with chronic hepatitis with TJ-9. Liver chemistries improved significantly after administration of TJ-9, and in patients with CHB, hepatitis B e antigen (HBeAg) seroconversion was observed with no significant side effects noted (29). Another randomized prospective study in patients with cirrhosis due to CHB or HCV noted an improved survival rate in those with nonHBsAg-related cirrhosis at 5 years (30). However, side effects including
296
Gagovic and Kwo
liver injury, autoimmune hepatitis, hypokalemia, and hypertension have been noted, raising concerns regarding the use of this herb, particularly in those with cirrhosis (28–32). At this time, there is insufficient evidence in human studies to recommend the use of this drug though future studies might be desirable in those with HBV-related liver disease.
3.5. St. John’s Wort Hypericin is a natural derivative of the common St. John’s wort plant, H. perforatum. Previous reviews suggested there may be benefit from the use of St. John’s wort in depression, but a Cochrane database review from 2005 contradicted previous reviews from 1995 and 2000 and concluded that in the treatment of mild-to-moderate depression, the data were inconsistent and did not support its use as an antidepressant (33). Regarding the use of St. John’s wort in viral hepatitis, in a phase one trial, Jacobson et al. tested the effect of hypericin in patients with chronic HCV infection. In this study, hypericin demonstrated no detectable benefit as defined by change in HCV RNA levels and caused considerable phototoxicity at the doses studied (34). The side effect profile of St. John’s wort also includes solid organ rejection, as well as a number of other potentially significant interactions with other medications, making its use hazardous as an herbal supplement, and this supplement should be avoided in those with chronic liver disease (35, 36).
3.6. Plantago Asiatic This Chinese herb’s active component, aucibin, was systematically studied for its potent liver-protective activities using experimental systems of hepatic damage. In animal studies, this plant was found to suppress the HBV replication and in humans, suppression of HBV DNA levels was also noted with the anti-viral effect ceasing after the herb was stopped (37). While encouraging, more trials need to be completed to assess its effect and safety profile in humans.
3.7. Herbal Medicine 861 Herbal medicine 861 is a mixture of 10 extract herbs, including Salvia miltiorrhiza, Astragalus membranaceous, and Spatholobus suberectus. In patients with hepatitis B, three controlled trials showed a reduction in the level of liver fibrosis 6 month post treatment. All patients remained hepatitis B surface antigen (HBsAg)-positive (11). In vitro studies of this herbal supplement showed a possible reduction in the expression of ␣-smooth muscle actin mRNA in liver cells. Since the cell proliferation and high levels of ␣-SMA are associated
Herbal and Non-Traditional Therapies for Viral Hepatitis
297
with liver fibrosis, HM 861 may be useful in the treatment of those with chronic liver disease with advanced fibrosis and no significant side effects have been reported (20, 38). However, more trials will need to be performed to verify these promising results.
3.8. CH-100 CH-100 is a herbal formulation of 19 known ingredients that may work by reducing TNF-␣ production by lymphocytes (38). This Chinese herbal medication was associated with a significant reduction in alanine aminotransferase (ALT) levels over a 6-month study period with four individuals normalizing their ALT levels on treatment in those with chronic HCV infection, though there was no significant effect on the clearance of serum HCV RNA (38). Similar to many herbal preparations, larger studies with better endpoints will be required to assess whether the reduction in ALT levels noted in these small studies can be reproduced and to allow collection of better safety data in those with viral hepatitis.
3.9. Liv 52 Liv 52 is an Indian supplement that has been marketed specifically for the treatment of liver diseases. The extract was reported to improve serum liver chemistry values in rats with toxic liver damage and in humans with acute viral hepatitis (39). In one trial patients with non-alcoholic-related cirrhosis, patients treated with Liv 52 for 6 months had significantly better Child-Pugh score, decreased ascites, and decreased serum ALT and AST levels compared to those who received placebo (39). However, in another randomized, placebo-controlled trial for over 2 years in 188 patients with alcohol-related cirrhosis, Liv 52 did not affect the survival rate of Child-Pugh Class A and B patients but increased mortality among Child Class C patients. This led to the drug being withdrawn from the US market (18).
4. ANTIOXIDANTS AND DIETARY SUPPLEMENTS Multiple studies have demonstrated that in both acute and chronic viral hepatitis, there may exist high levels of oxidative stress that can be associated with reduced levels of some important antioxidants. In addition, the amount of reactive oxygen species (ROS) found in healthy human livers is significantly lower than values found in livers infected by HBV or HCV (40). This provides a theoretical rationale for the use of antioxidants in those with chronic viral hepatitis. In a trial by
298
Gagovic and Kwo
von Herbay et al., high-dose vitamin E was found to improve aminotransferase levels in hepatitis C-infected patients refractory to interferon treatment. The ALT and AST improvement was transient and after the cessation of vitamin E, liver tests returned to their previous levels (41). Andreone et al. evaluated vitamin E supplementation as therapy for CHB in a pilot study including 32 patients (42). Patients were randomly allocated to receive vitamin E at the dose of 300 mg twice daily. At the end of the study period, ALT normalization was observed in 47% patients in vitamin E group and only in 6% of the controls; HBV DNA was cleared in 53% patients in the vitamin E group and 18% in the control group, respectively. These preliminary results suggest that additional trials should be done to establish the beneficial effect of vitamin E in chronic viral hepatitis patients, particularly in those with hepatitis B.
4.1. N-Acetyl Cysteine (NAC) N-Acetyl cysteine (NAC) is well known as an effective antidote in acetaminophen hepatotoxicity by repleting glutathione stores. In vitro studies demonstrated that NAC administration to HBV-producing cell lines resulted in the reduction of HBV DNA levels (43). However, when NAC was administered to patients with acute viral hepatitis A and B, no effect on aminotransferase levels or bilirubin levels was seen, suggesting little effect in the setting of acute viral hepatitis (44). The role of NAC in acute liver failure due to viral hepatitis is an area currently undergoing study.
4.2. S-Adenosylmethionine (SAM) S-Adenosylmethionine deficiency may be seen in alcoholic liver disease (ALD) as well as in experimental models of hepatotoxicity and may potentiate liver damage by furthering mitochondrial damage (45). The studies on the benefit of this supplement on mortality in patients with liver disease have not shown a consistent benefit and thus more studies will be required to be able to recommend this supplement (18). 4.2.1. ACUPUNCTURE This method of Chinese traditional treatment requires mention due to its high prevalence among liver patients with as many as 18% of patients with chronic hepatitis receiving acupuncture therapy (46). The transmission of hepatitis B and C is a concern in this method of treatment though the use of universal precautions should minimize this risk (47).
Herbal and Non-Traditional Therapies for Viral Hepatitis
299
5. DISCUSSION As noted in the previous review of the peer-reviewed medical literature, none of the herbal/CAM supplements can be recommended for both safe and effective use in patients with acute or chronic viral liver disease. Only silymarin appears to have sufficient data available to have minimal safety concerns, though efficacy data in viral hepatitis remain limited. Tables 1 and 2 summarize common herbal supplements for chronic viral hepatitis, with available data regarding their benefits and risks. One major issue that stands out for most herbal therapies is the lack of randomized controlled trials supporting their use, as the herbal/CAM industry is not required to conduct such efficacy trials to get their products to market. Manufacturers of herbal/CAM have noted that it would be difficult to recover the high research costs required of a randomized controlled trial, because herbal products can be patented less easily than newly synthesized drugs (48). Other issues of concern with research conducted by the CAM industry include lack of randomization, lack of standardization and quality control of the herbal drugs, use of varying dosages, small patient numbers, lack of placebo, and the wide variation in the time during which the herbal preparations were used. Furthermore, even published research in this clinical area must be interpreted with caution as some have noted that certain countries, including China are known to publish only positive results (49). Moreover, it is well known from clinical trial literature that methodologically less rigorous trials may demonstrate larger treatment effects than those conducted with better rigor. As such, the potential beneficial effects of
Table 1 Common Herbal Supplements for Chronic Viral Hepatitis Plant
Dose/ potency
Number of tablets
Administration
Price
Manufacturer
Silymarin
200 mg/ 80% 500 mg/ 12%
240
1–3 tablets daily
$43
Nature Purest
$14.60
Douglas Laboratories
P. amarus
250 mg
60
$10
St. John’s wort
990 mcg
90
1–2 tablets between meals 1 tablet with meals 1 tablet with meals
Douglas Laboratories Blackmores
Glycyrrhizin
60
$40
300
Gagovic and Kwo Table 2 Summary of Common Herbal/CAM
Herbal/CAM
Efficacy in HCV Efficacy in HBV
Safety concerns/side effects
Simylarin Glycyrrhizin
No clear benefit Transaminase decrease None
No hepatotoxic effects Fluid retention, hypokalemia Stomach ache, nausea
Phyllanthus amarus
TJ-9
None
No clear benefit Transaminase decrease Possible improved viral clearance when used with interferon Possible benefit in HBeAg
St. John’s wort None
None
Plantago Asiatic HM861
None
None
None
Possibly in liver fibrosis None
CH100 Liv 52
Transaminase decrease None
None
Liver injury, autoimmune hepatitis, hypokalemia, and hypertension Solid organ rejection, phototoxicity Insufficient data on side effect profile Insufficient data on side effect profile Insufficient data on side effect profile Increased mortality in patients with Child Class C patients
herbal medications can be magnified and the lay public may be influenced into their use without recognizing the limitations of trial designs (50–52). Still, there is no denying of the widespread appeal that surrounds the CAM industry and clinicians should question patients specifically about their use as the majority of patients will not volunteer their use of herbal supplements (53). Patients perceive that herbal/CAM preparations are natural and therefore possess an inherent safety profile not present in prescription medicines available for chronic viral hepatitis as well as the relative cost factor. In fact, herbal/CAM preparations often are concoctions of various extracts, many of which are unidentified, thus limiting the safety evaluation (54). In China, 50% of clinical trials of Chinese medicinal herbs report adverse effects and one possible explanation is that Chinese practitioners perceive herbs as free of side effects (55).
Herbal and Non-Traditional Therapies for Viral Hepatitis
301
While not as well known to the lay public, it is well known by practicing clinicians that the use of herbal remedies can pose serious health risks. Besides the direct risks of adverse effects and drug interactions, there is an indirect risk that a herbal remedy without demonstrated efficacy may compromise, delay, or replace an effective form of conventional treatment. There are reports of liver toxicity and other serious adverse events associated with the use of certain Chinese herbal medicines (56–59). A survey of the National Poison Information Service for the years 1991–1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs given for all indications, not just viral hepatitis, but hepatotoxicity was the most frequent side effect noted (60). In addition, it has been noted that the hepatotoxicity of CAM is underreported due to the lack of safety reporting system as is available for prescription medicines in developed countries (11). Other risks in addition to the hepatotoxicity caused by the direct effect of the herbal medication include misidentification of the plant, selection of a wrong part of the plant, inadequate storage, contamination of the plant by various chemicals, heavy metals, microorganisms, alteration during conditioning, and mislabeling of the final product (60). The use of CAM is underreported to the extent that 70% of patients will neglect to mention their use to their physicians (53). Some patients believe that physicians may have an underlying bias against or not be knowledgeable on this subject (61), while other patients may not be taking the herbal/CAM preparations for a medical reason and may perceive the relationship as unrelated (62). Physicians need to remain vigilant in taking accurate histories regarding medication use and approach their patients about this topic in an unbiased manner. Given the fact that 12–16% of those on prescription drugs utilize CAM, physicians should familiarize themselves on the use of herbal medications as well as on their side effects and interactions to safely and effectively counsel and treat the vast number of patients who seek therapy for chronic viral hepatitis (62).
REFERENCES 1. Eisenberg D, Davis R, Ettner S, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998;280:1569–75. 2. Russo M, Esposito S, Brown RJ, et al. Complementary alternative medicine (CAM) use amongst patients with chronic hepatitis C infection (HCV) (abstr). Gastroenterology 2001;120(Suppl 1):A409. 3. Flora K, Rosen H, Benner K. The use of naturopathic remedies for chronic liver disease (letter). Am J Gastroenterol 1996;91:2654–5.
302
Gagovic and Kwo
4. Berk B, Chaya C, Benner K, et al. Comparison of herbal remedies for liver disease: 1996 versus 1999 (abstr). Hepatology 1999;A478. 5. Peyton B, Spears T, Lindsey A, et al. A survey of the use of herbal medicine in patients with hepatitis C (abstr). Hepatology 1999;30(A123). 6. Strader D, Bacon B, Lindsay K, et al. Use of complementary and alternative medicine in patients with liver disease. Am J Gastroenterol 2002;97:2391–7. 7. Lavanchy D. Hepatitis B virus Epidemiology, disease burden, treatment and current emerging prevention and control measures. J Viral Hepatology 2004;11: 97–107. 8. Lauer G, Walker B. Hepatitis C virus infection. New England J Medicine 2001;345(1):41–52. 9. Hoofnagle J. Hepatitis C: The clinical spectrum of disease. Hepatology 1997;26(3 suppl 1):15S–20S. 10. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C liver diseases–a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials. Am J Gastroenterol 2005;100(11):2583–91. 11. Seeff LB LK, Bacon BR, et al. Complementary and alternative medicine in chronic liver disease. Hepatology 2001;34:595–603. 12. Mayer K, Myers R, Lee S. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepatitis 2005;12(6):559–67. 13. Flora K, Hahn M, Rosen H, et al. Milk thistle for the therapy of liver disease. Am J Gastroenterol 1998;93:139–43. 14. Pietrangelo A, Borella F, Casalgrandi G, et al. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology 1995;109:1941–9. 15. Jia J, Bauer M, Cho J, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol 2001;23:749–54. 16. Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996;23: 749–53. 17. Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. American J Gastroenterol 2003;98(3):538–44. 18. Verma S, Thuluvath P. Complementary and alternative medicine in hepatology: review of the evidence of efficacy. Clin Gastroenterol Hepatol 2007;5:408–16. 19. Bode J, Schmidt U, Durr H. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial. Med Klin 1977;72:513–8. 20. Levy C, Seeff L, Lindor K. Use of herbal supplements for chronic liver disease. Clin Gastroenterol Hepato 2004;2:947–56. 21. Magliulo E, Gagliardi B, Fiori GP. Results of a double-blind study on the effect of silymarin in the treatment of acute viral hepatitis carried out at two medical centres. Med Klin 1978;73:1060–5. 22. Takahara T, Watanabe A, Shiraki K. Effects of glycyrrhizin on hepatitis B surface antigen: a biochemical and orphological study. J Hepatol 1994;21:601–9. 23. Suzuki H, Ohta T, Takino T, et al. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis. Double blind trial. Asian Med J 1983;26: 423–38.
Herbal and Non-Traditional Therapies for Viral Hepatitis
303
24. Zhang L, Wang B. Randomized clinical trial with two doses (100 and 40 ml) of Stronger Neo-Minophagen C in Chinese patients with chronic hepatitis B. Hepatol Res 2002;24:220. 25. Liu JP, Lin H, McIntosh H. Genus Phyllanthus for chronic hepatitis B virus infection: a systematic review. J Viral Hepatitis 2001;8(5):358–66. 26. Thyagarajan S, Subramanian S, Thirunalasundari T, Venkateswaran P, Blumberg B. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2:764–6. 27. Shimizu I, Ma Y, Mizobuchi Y, et al. Effects of sho-saiho-to, a Japanese herbal medicine, on hepatic fibrosis in rats. Hepatology 1999;29:149–60. 28. Kakumu S, Yoshioka K, Wakita T, Ishikawa T. Effects of TJ-9 Shosaiko-to (Kampo medicine) on interferon gamma and antibody production specific for hepatitis B virus antigen in patients with type B chronic hepatitis. Int Immunopharmacol 1991;13:141–6. 29. Hirayama C, Okumura M, Tanikawa K. A multicentre randomized controlled clinical trial of Shosaiko-to in chronic active hepatitis. Gastroenterol Jpn 1989;24: 715–9. 30. Homma M, Ishihara M, Qian W, Kohda Y. [Effects of long term administration of Shakuyaku-kanzo-To and Shosaiko-To on serum potassium levels]. [Japanese] [English Abstract. Journal Article] Yakugaku Zasshi J Pharmaceutical Soc Jpn 2006;126(10):973–8. 31. Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997;92:703–4. 32. Itoh S, Marutani K, Nishijima T, et al. Liver injuries induced by herbal medicine, sho-saiko-to (xiao-chai-hu-tang). Dig Dis Sci 1995;40:1845–8. 33. Linde K, Mulrow C, Berner M, Egger M. St John’s wort for depression. [update of Cochrane Database Syst Rev]. Cochrane Database of Systematic Reviews 2005. 34. Jacobson J, Feinman L, Liebes L, et al. Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John’s wort plant, in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2001;45:517–24 35. Kaminsky L, Zhang Z. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67–74. 36. Ingram K, Dragosavac G, Benner K, Flora K. Risks of drug interactions with St. John’s Wort. Am J Gastroenterol 2000;95(11):3323–4. 37. Wang L, Wang J, Wang B, Xiao P, Qiao Y, Tan X. Effects of herbal compound 861 on human hepatic stellate cell proliferation and activation. World J Gastroenterol 2004;10(19):2831–5. 38. Batey R, Bensoussan A, Fan Y, et al. Preliminary report of a randomized, doubleblind placebo-controlled trial of a Chinese herbal medicine preparation CH-100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol 1998;13:244–7. 39. Huseini H, Alavian S, Heshmat R, Heydari M, K. A. The efficacy of Liv-52 on liver cirrhotic patients: a randomized, double-blind, placebo-controlled first approach. [Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov’t]. Phytomedicine 2005;12(9):619–24. 40. Dikici I, Mehmetoglu I, Dikici N, Bitirgen M, Kurban S. Investigation of oxidative stress and some antioxidants in patients with acute and chronic viral hepatitis B and the effect of interferon-alpha treatment. Source Clin Biochem 2005;38(12):1141–4.
304
Gagovic and Kwo
41. von Herbay A, Stahl W, Niederau C, Sies H. Title Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study. Source Free Radical Res 1997;27(6): 599–605. 42. Andreone P, Fiorino S, Cursaro C, et al. Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial. [Clinical Trial. Journal Article. Randomized Controlled Trial] Antiviral Res 2001;49(2):75–81. 43. Weiss L, Hildt E, Hofschneider P. Anti hepatitis B virus activity of Nacetylcysteine, new aspect a well established drug. Antiviral Res 1996;32:43–53. 44. Gunduz H, Karabay O, Tamer A, Ozaras R, Mert A, Tabak O. N-acetyl cysteine therapy in acute viral hepatitis. Source World J Gastroenterol 2003;9(12): 2698–700. 45. McClain C, Hill D, Song Z, et al. S-Adenosylmethionine, cytokines, and alcoholic liver disease. Alcohol 2002;27(3):185–92. 46. Yang Z, Yang S, Yang S, Chen D. A hospital-based study on the use of alternative medicine in patients with chronic liver and gastrointestinal diseases. Am J Chinese Med 2002;30(4):637–43. 47. Ang-Lee M, Moss J, Yuan C. Herbal medicines and perioperative care. JAMA 2001;286:208–16. 48. Calixto J. Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents). Brazilian J Med Biol Res 2000;33:179–89. 49. Vickers A, Goyal N, Harland R, Rees R. Do certain countries produce only positive results? A systematic review of controlled trials. [Comparative Study. Journal Article] Controlled Clinical Trials 1998;19(2):159–66. 50. Schulz K, Chalmers I, Hayes R, et al. Empirical evidence of bias. JAMA 1995;273:408–12. 51. Moher D, Pham B, Jones A, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609–13. 52. Kjaergard L, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001;135:982–9. 53. Kaye A, Clarke R, Sabar R, et al. Herbal medications: current trends in anesthesiology practice-a hospital survey. J Clin Anesth 2000;12:468–71. 54. De Smet P. Health risks of herbal remedies. Drug Saf 1995;13:81–93. 55. Liu J, Liu C, Leng T. Evaluation of clinical trials for viral hepatitis in the past nine years in Chinese medical literatures. West China Med J 1999;14:264–5. 56. Ishizaki T, Sasaki F, Ameshima S, et al. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J 1996;9:2691–6. 57. Melchart D, Linde K, Weidenhammer W, Hager S, Shaw D, Bayer R. Liver enzyme elevations in patients treated with traditional Chinese medicine. JAMA 1999;282:28–9. 58. Kaplowitz N. Hepatotoxicity of herbal remedies: insight into the intricacies of plant–animal warfare and cell death. Gastroenterology 1997;113:1408–12. 59. Larrey D, Pageaux G. Hepatotoxicity of herbal remedies and mushrooms. Sem Liver Dis 1995;15:183–18.
Herbal and Non-Traditional Therapies for Viral Hepatitis
305
60. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. A 5-year toxicological study (1991–1995). Drug Saf 1997;17:342–56. 61. Blendon R, DesRoches C, Benson J, Brodie M, Altman D. American’s views on the use and regulation of dietary supplements. Arch Intern Med 2001;161:805–10. 62. Eisenberg D. Advising patient who seek alternative medical therapy. Ann Intern Med 1997;127:61–9.
Hepatitis B Reactivation in the Setting of Chemotherapy and Immunosuppression Halim Charbel, MD and James H. Lewis, MD, FACP, FACG CONTENTS I NTRODUCTION H ISTORY OF H EPATITIS B R EACTIVATION I NCIDENCE /P REVALENCE OF H EPATITIS B R EACTIVATION R ISK FACTORS FOR R EACTIVATION PATHOPHYSIOLOGY OF R EACTIVATION C LINICAL M ANIFESTATIONS OF H EPATITIS B R EACTIVATION S CREENING OF PATIENTS P RIOR TO C HEMOTHERAPY OR I MMUNOSUPPRESSION I MMUNIZATION AGAINST H EPATITIS B M ANAGEMENT OF E STABLISHED HBV R EACTIVATION P REEMPTIVE A NTIVIRAL T HERAPY AGAINST HBV R EACTIVATION C OST-E FFECTIVENESS OF P REEMPTIVE T HERAPY AWARENESS OF HBV R EACTIVATION A MONG O NCOLOGISTS
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 12, C Humana Press, a part of Springer Science+Business Media, LLC 2009
307
308
Charbel and Lewis
A DDENDUM R EFERENCES
Key Principles
• Reactivation of hepatitis B is recognized as the reappearance of active necroinflammatory disease of the liver in a person known to have the inactive hepatitis B surface antigen (HBsAg) carrier state or resolved hepatitis B. • More recently, hepatitis B reactivation has been defined as a one log or greater increase in the HBV DNA level compared with the prereactivation level, or the reappearance of a previously negative HBsAg on two consecutive tests. • Reactivation may result in acute flares of HBV, with consequent clinical decompensation. • Patients at risk for hepatitis B reactivation are those with hematological or oncological malignancies who require chemotherapy, patients with non-malignant diseases who require immunosuppression, and patients with rheumatologic diseases or inflammatory bowel diseases treated with biologic response modifiers. • With the administration of cytotoxic or immunosuppressive agents, the immune response is suppressed, viral replication is enhanced, and widespread infection of hepatocytes ensues. With the discontinuation of the cytotoxic or immunosuppressive therapy, the immune function is restored. This immune reconstitution results in a rapid destruction of hepatocytes infected with hepatitis B. • Patients who are negative for HBsAg but have evidence of either circulating or intrahepatic hepatitis B viral (HBV) DNA are denoted as having occult HBV. It is well established that chemotherapy can cause HBV reactivation even in HBsAgnegative patients with occult HBV infection. • All patients should undergo screening for occult or overt HBV prior to the initiation of chemotherapy or immunomodulatory therapy. Seronegative patients should be vaccinated against HBV. • HBsAg-positive patients should be considered at high risk of reactivation and should be started on preemptive anti-HBV therapy. • If reactivation of HBV occurs, prompt antiviral therapy should be combined with aggressive supportive therapy in addition to the cessation of chemotherapy.
Hepatitis B Reactivation in the Setting of Chemotherapy
309
1. INTRODUCTION It is estimated that out of the 2 billion people who have been infected with the hepatitis B virus (HBV) worldwide, more than 350 million have chronic infection (1). The prevalence of chronic hepatitis B(CHB) infection varies widely throughout the world, ranging from as high as 25% in endemic countries to less than 0.5% in populations of the western world (2–4). A large reservoir of infected individuals harbor the virus without clinical evidence of liver disease (non-replicative or lowreplicative stage). In such individuals, immunosuppressive agents can precipitate an increase in HBV replication followed by a flare of hepatitis B that can be severe and even fatal. Reactivation of hepatitis B: This is defined as the reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved HBV (5,6). Reactivation results in acute flares of HBV, with consequent clinical decompensation. Spontaneous reactivation occurs more commonly in the setting of HIV infection, concurrent bacterial infection, surgery, or physical and emotional stress. Many patients with acute flares of HBV are asymptomatic, but some patients experience symptoms including nausea, vomiting, fatigue, and anorexia (7). Hepatic failure can be seen rarely, particularly in patients with underlying cirrhosis (8–10). Flares have been described in both the replicative phase and the nonreplicative phase. Frequently these flares of hepatitis precede clearance of the virus and HBeAg to anti-HBe seroconversion (5, 11). In anti-HBe-positive patients who have no detectable HBV DNA, an elevation of the serum aminotransferases occurs in response to the sudden reemergence of viral replication (5, 12–14). In patients who are in the active replicative stage of the infection, serum HBV DNA levels increase, and biochemical deterioration occurs without subsequent loss of HBeAg (15). These episodes can be viewed as an abortive attempt at seroconversion (12).
2. HISTORY OF HEPATITIS B REACTIVATION The first reported cases of HBV reactivation in patients receiving chemotherapy were published in 1975. Wands et al. described a decrease in anti-hepatitis B surface antigen (anti-HBs) titers in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders (16). In some patients this decrease was followed by reappearance of hepatitis B surface antigen (HBsAg). Patients who
310
Charbel and Lewis
were positive for HBsAg prior to the initiation of chemotherapy experienced a rise in HBsAg titers associated with an increase in serum aminotransferase levels. Galbraith et al. reported three cases of fulminant hepatic failure in patients with leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy (17). In 1977, reports of HBV reactivation in patient undergoing renal transplant were published (18). Many instances of HBV reactivation associated with chemotherapy have been published since. Most of them involved patients with lymphoma and other hematological malignancies from Asia where the incidence of HBV is highest (16, 19). HBV reactivation has also been well recognized with chemotherapy for solid tumors including lung cancer, ovarian cancer, cervical cancer, breast cancer, gastrointestinal cancers, hepatocellular carcinoma, embryonal carcinoma of the testes, and neuroendocrine tumors (19–28). In addition to chemotherapy, hepatitis B reactivation can also be seen with corticosteroid therapy (29) and with antitumor necrosis factor (anti-TNF) therapy for inflammatory bowel diseases or rheumatologic disorders (30–32).
3. INCIDENCE/PREVALENCE OF HEPATITIS B REACTIVATION The frequency of HBV reactivation in patients receiving chemotherapy varies widely among different reports, ranging from 14% to 67% in HBsAg carriers (20, 21, 24, 33–37), depending on the criteria used to define reactivation. Early reports defined HBV reactivation and flare using clinical features and increasing aminotransferase levels in the absence of other causes, or the reappearance or increase in the level of serum HBsAg in patients with previously undetectable or low levels. More recent publications have defined HBV reactivation as a one log or greater increase in the HBV DNA level compared with the prereactivation level, or the reappearance of a previously negative HBsAg on two consecutive tests (38–40). The wide range of incidence rates is also due to the differences in the types of malignancy being treated, chemotherapy regimens used, patient demographics, and the phase of chronic hepatitis B infection (i.e., active or inactive replication). Regardless of the exact risk of hepatitis B reactivation, it is clear that the administration of chemotherapy to cancer patients with chronic hepatitis B infection leads to an increased risk of liver-related morbidity and mortality (41). It is well established that anyone with a history of exposure to HBV is at risk of reactivation during immunosuppression, even after clearance of HBsAg. The presence of ostensibly protective anti-HBsAb does not
Hepatitis B Reactivation in the Setting of Chemotherapy
311
eliminate the risk of hepatitis B reactivation with chemotherapy (12, 16, 36). In a recent study using updated diagnostic criteria, 100 Chinese patients who underwent chemotherapy for lymphoma were studied. A high proportion (67% or 18 of 27) of those who were HBsAg-positive had a hepatitis flare. Of these 18, 13 (72%) were confirmed to have positive HBV DNA. Of the patients who were HBsAg-negative, and HBsAb-negative, 7 of 33 patients (21%) had a hepatitis flare, although only one had confirmed hepatitis B reactivation by HBV DNA testing (36). In a series from Greece, out of 50 HBsAg-positive patients receiving chemotherapy, 7 (14%) developed clinical and/or biochemical hepatitis (21). In hematopoietic stem cell transplants, hepatitis B reactivation has been reported in more than 50% of the patients (10, 41, 42). This is probably due to the intense immunosuppression produced by the chemotherapy regimens and due to the coexistence of graft vs host disease (41).
4. RISK FACTORS FOR REACTIVATION Patients at risk for HBV reactivation are those with hematological or oncological malignancies who require chemotherapy, patients with non-malignant diseases who require immunosuppression, and patients with rheumatologic diseases or inflammatory bowel diseases treated with biologic response modifiers. The various types of malignancies associated with hepatitis B reactivation are given in Table 1. Other risk factors are given in Table 2. Studies examining the significance of HBV genotypes suggest that they may correlate with clinical outcomes (43). Most of these studies have been performed in Asia, where genotypes B and C predominate. Genotype C is associated with more severe liver disease and a higher rate of progression to cirrhosis compared to genotype B (43–47). Data on the clinical course of patients infected with genotypes other than B and C are scarce. A study of 22 patients who underwent liver transplantation for hepatitis B suggested that patients with genotype A have the lowest risk for HBV recurrence despite having the highest rate of pretransplantation HBV viral replication. Patients with genotype D appeared to have the highest risk for HBV recurrence and mortality (48). This has not been as well studied in the setting of chemotherapy. It has been suggested that HBV reactivation seems to correlate with HBV genotypes B and C, but there are insufficient data to consider these genotypes as separate risk factors for HBV reactivation.
312
Charbel and Lewis Table 1 Malignancies Reported in Association with Hepatitis B Reactivation Acute myeloid leukemia Acute lymphoblastic leukemia Chronic myeloid leukemia Chronic lymphocytic leukemia Non-Hodgkin’s lymphoma Hodgkin’s disease Multiple myeloma Waldenstrom macroglobulinemia Plasmacytoma Aplastic anemia Myelodysplastic syndromes Hematopoietic stem cell transplantation Breast cancer Bladder cancer Hepatocellular carcinoma Small cell lung cancer Neuroendocrine tumor Nasopharyngeal carcinoma Cervical cancer Embryonal carcinoma of the testes Yolk sac tumor of mediastinum Pancreatic cancer Glioblastoma Ovarian carcinosarcoma
4.1. A. Host Risk Factors for HBV Reactivation Multiple host risk factors for hepatitis B reactivation have been suggested, several of which have been confirmed in clinical trials. In a study of 138 chronic HBV carriers treated with cancer chemotherapy, a multivariate analysis identified factors associated with a higher risk of developing HBV reactivation. These factors were detectable HBV DNA levels pre-chemotherapy, the use of steroids, a diagnosis of lymphoma and breast cancer. Another suggested risk factor was the use of anthracycline agents (daunorubicin, doxorubicin, epirubicin,
Hepatitis B Reactivation in the Setting of Chemotherapy
313
Table 2 Host Risk Factors for Hepatitis B Reactivation Proven Male sex Younger age HBsAg positivity HBeAg positivity Detectable HBV DNA Use of steroids Use of anthracyclines Diagnosis of lymphoma Diagnosis of breast cancer Intensity of immunosuppression Suggested but not proven Duration of chemotherapy Pretreatment ALT level Genotypes B and C
idarubicin). However, pretreatment ALT, bilirubin, and albumin levels were not associated with the development of HBV reactivation (49). In contrast, in a study of patients with hepatocellular carcinoma, pretreatment ALT elevation was shown to be a risk factor for HBV reactivation (22). Male sex, younger age, HBeAg positivity, and the presence of lymphoma were significant risk factors associated with HBV reactivation in other studies of HBsAg-positive cancer patients undergoing chemotherapy (20, 36, 50, 51). Although HBsAb positivity decreases the risk of HBV reactivation (36, 39), it does not confer absolute protection against HBV reactivation. In fact, several reports described a “reversion” with HBsAb going from positive to negative and HBsAg becoming positive. This phenomenon has been recognized since the earliest reports describing HBV reactivation (16). Following allogenic hematopoietic stem cell transplantation, HBV reactivation has been reported in HBsAg-positive as well as HBsAgnegative patients. The rate of reactivation varies between 14% and 50% (52, 53). The risk appears to be greatest in those treated for graftvs-host disease and is possibly reduced in recipients from HBsAbpositive donors. HBV reactivation has also been described in patients
314
Charbel and Lewis
with autologous hematopoietic stem cell transplant, although it may be less likely than in allogenic stem cell transplantation (39). A study of 137 autologous hematopoietic cell transplantation (HCT) patients found that pre-transplant HBV DNA level >105 copies/ml was the principal risk factor for HBV reactivation on multivariate regression analysis (39). High HBV DNA levels have been consistently found to be a risk factor for HBV reactivation in breast cancer and hematological malignancies as well (52, 53).
4.2. Role of Chemotherapeutic Agents/Steroids/Immunosuppressants Numerous chemotherapeutic agents have been reported to be associated with HBV reactivation (Table 3), two classes deserve special attention: corticosteroids and anthracyclines. The use of anthracyclines (daunorubicin, doxorubicin, epirubicin, and idarubicin) has been shown in vitro to stimulate HBV DNA secretion (54). The relationship between corticosteroids and HBV replication was observed as early as 1980. Long-term treatment with corticosteroids was noted to cause an increased expression of HBcAg in the serum (55). It was subsequently discovered that HBV DNA polymerase activity increased in association with a decrease in serum AST during a short course of corticosteroid therapy (56), and the opposite effect, a significant increase in AST in association with a decrease in HBV DNA polymerase, was observed after withdrawal of corticosteroid therapy (57). The hepatitis B virus was found to contain a glucocorticoid-responsive element that stimulates viral replication and transcriptional activity (58, 59). One potential means of minimizing the risk of HBV reactivation is the avoidance of corticosteroid therapy as part of chemotherapeutic/antiemetic regimens in HBsAg carriers (60–62). However, a steroid-free chemotherapy strategy may lead to suboptimal therapeutic response and may even jeopardize the patient’s chance of cure. For example, in a prospective study of 50 patients with non-Hodgkin’s lymphoma who were randomized to receive either the standard steroid-containing regimen or a steroid-free regimen, patients receiving a steroid-free regimen had a significantly lower rate of HBV reactivation (73% vs 38%; P = 0.03). However, patients in the steroid-free arm had a significantly lower rate of complete remission and shorter overall survival (68% vs 36%; P = 0.18), presumably due to suboptimal therapy (63). The degree of immunosuppression could also contribute to the development of reactivation. The intensity of the immune suppression induced by chemotherapy has been suggested to be a risk factor
Hepatitis B Reactivation in the Setting of Chemotherapy
315
for reactivation. One study found that the incidence of HBV reactivation was increased in patients receiving second- or third-line chemotherapy (65). On the other hand, patients with gastrointestinal malignancies who undergo cytotoxic chemotherapy, mainly consisting of lessimmunosuppressive agents such as 5-fluorouracil for colon cancer, have a lower risk of developing viral reactivation (66). The duration of the chemotherapy has not been proven to be an independent risk factor for HBV reactivation. Hematopoietic stem cell transplantation has been particularly associated with viral reactivation (67–72). The use of therapeutic monoclonal antibodies against B and T lymphocytes such as rituximab (a chimeric mouse human monoclonal antibody against anti-CD20+ lymphoid cells) and alemtuzumab (a humanized monoclonal antibody against anti-CD52+ lymphoid cells), used alone or in combination with cytotoxic therapy, has been associated with HBV reactivation (73–82). In October 2004, the U.S. Food and Drug Administration reported a possible relationship between fulminant hepatitis and rituximab use (83). There have been several reports of severe HBV reactivation, including fatalities, in patients who have received infliximab for Crohn’s disease and rheumatic disorders (30–32, 84). No cases of HBV reactivation associated with the use of adalimumab have been reported to date, although the adalimumab package insert carries a warning about the use of the medication in patients with history of hepatitis B infection, implying that patients should be screened for hepatitis B (85). Anti-TNF agents cause profound and long-lasting immunosuppression, which may account for the risk of HBV reactivation following their use.
4.3. Occult HBV Patients who are negative for the hepatitis B surface antigen but have evidence of either circulating or intrahepatic HBV DNA are denoted as having occult HBV. It is well established that chemotherapy can cause HBV reactivation even in HBsAg-negative patients with occult HBV infection (36, 64). HBV reactivation in patients who have cleared HBsAg is thought to be due to the persistence of hepatitis B as an occult infection in the hepatocytes as cccDNA (covalently closed circular DNA) (86). HBV DNA has also been found in peripheral blood mononuclear cells recovered from immune-suppressed transplanted patients with a serologic profile anti-HBc-positive/HBsAg-negative/anti-HBs-negative in the absence of HBV DNA in the serum (87).
316
Charbel and Lewis
5. PATHOPHYSIOLOGY OF REACTIVATION Most episodes of chemotherapy-induced hepatitis B reactivation are seen after chemotherapy is withdrawn and are caused by a change in the balance between the immunologic response to the hepatitis B virus and the extent of viral proliferation. The persistent necroinflammatory changes in the liver tissue that characterize chronic hepatitis B are caused by a suboptimal or an inadequate cellular immune response to nucleocapsid antigens (88). The greater the deficiency in the cellular immune response to the encoded viral antigens, the more likely the host will be immunotolerant to the virus. The more robust the immunologic response to these antigens is, the greater is the likelihood of substantial inflammatory changes and damage to hepatocytes (12). With the administration of cytotoxic or immunosuppressive agents, the immune response is suppressed and as a result, viral replication is enhanced and widespread infection of hepatocytes ensues (27, 36). With the discontinuation of the cytotoxic or immunosuppressive therapy, the immune function is restored and this immune reconstitution results in a rapid destruction of hepatocytes infected with hepatitis B (89–91). It is believed that the more potent the immunosuppression, the greater the level of viral replication and the greater the liver damage on withdrawal of the immunosuppressive agent (12). Hepatitis B reactivation that occurs during ongoing chemotherapy or immunosuppression suggests a direct cytopathic effect of the drugs on the hepatitis B virus (92). It has been shown that the glucocorticoid receptor recognizes a specific nucleotide sequence on the hepatitis B virus DNA and induces replication and transcription of the virus (93). Hepatitis B reactivation can also occur in patients with a history of a resolved hepatitis B infection (with positive HBsAb). Persistence of cccDNA (covalently closed circular DNA) is thought to act as a template for transcription of viral RNAs or mRNAs serving either as viral pregenome RNAs or as mRNAs coding for the multifunctional polymerase, core, X, and envelope (S) proteins (94, 95). It has been shown that cccDNA is the major reason for hepatitis B reactivation after stopping anti-HBV therapy (94, 96, 97).
6. CLINICAL MANIFESTATIONS OF HEPATITIS B REACTIVATION Hepatitis B reactivation can be associated with a wide range of clinical manifestations that vary from mild subclinical elevation of liver enzymes or serological evidence of reactivation to fulminant hepatic
Hepatitis B Reactivation in the Setting of Chemotherapy
317
failure and death. When symptomatic, HBV reactivation manifests by the classic symptoms of hepatitis including fatigue, jaundice, ascites, hepatic encephalopathy, and coagulopathy. As mentioned, hepatitis B virus reactivation typically occurs after cessation of chemotherapy, but it may occur during chemotherapy. When it occurs during treatment, it may be seen as early as 4 weeks to as late as 36 weeks after the initiation of chemotherapy (41, 98). Lethal hepatitis B reactivation has been reported 1 year after the completion of rituximab therapy for a low-grade cutaneous B-cell lymphoma (99). Seroreversion (from anti-HBs to HBsAg) was described 39 months after allogenic hematopoietic stem cell transplantation (100). The first sign of hepatitis B reactivation is the detection of a rising HBV DNA level. The rise in viremia is followed by an elevation in the ALT level, which usually lags behind the increasing viral load by several weeks (0–11 weeks) (98). In fact HBV DNA levels may be declining or even become undetectable by the time the ALT elevation is detected (19, 101). This pattern is explained by the pathophysiology of hepatitis B reactivation. As hepatitis B virus replication is enhanced by immunosuppression, there is an immunologically mediated attack on the hepatocytes infected with HBV, with rapid destruction of hepatocytes resulting in a decrease in the HBV viral load and an elevation in the ALT levels. This serologic and biochemical pattern may complicate the diagnosis of hepatitis B reactivation. If a patient becomes symptomatic or the ALT elevation is noticed after the HBV DNA becomes undetectable, the clinician might be left with a suspicion of HBV reactivation, with no way to confirm the diagnosis (19). Anti-HBc IgM can be detected during a hepatitis B flare, which may lead to a misdiagnosis of acute hepatitis B in patients with undiagnosed chronic hepatitis B or previous exposure to hepatitis B. A liver biopsy is not necessary for the diagnosis of hepatitis B flare; however, in the absence of a documented increase in HBV DNA levels, it may be very helpful in excluding other etiologies of liver injury. As in any patient with chronic hepatitis B, an acute flare may be induced either by HBV mutations such as the precore or DNA polymerase mutation or by a superinfection with another hepatotropic virus such as hepatitis A, hepatitis C, hepatitis D, hepatitis E, EBV, HSV, or CMV. Interaction with HIV or hepatotoxicity of anti-HIV medications may also play a role (102). HBV reactivation can be associated with an increase in ␣-fetoprotein which raises the concern about the development of hepatocellular carcinoma, but is often secondary to inflammation (36, 103, 104). Patients with underlying cirrhosis may rapidly decompensate and develop liver failure. Their mortality on chemotherapy ranges between 4% and 41% (36, 41, 65, 105, 106). These patients are at particularly
318
Charbel and Lewis
increased risk of sepsis in the setting of cirrhosis and immunosuppression. Patients undergoing chemotherapy for hepatocellular carcinoma were found to have a poor outcome with frequent cases of severe hepatitis and a mortality of 30% in the setting of reactivation (10, 22–24, 33–35, 41, 42 107–113). This high mortality may be explained by the presence of coexisting cirrhosis (19). It is very important that cirrhosis be recognized before starting chemotherapy as these patients require closer monitoring. In a series of 100 lymphoma patients from Hong Kong undergoing chemotherapy (36), among the patients who developed hepatitis, it was transient (lasting1 week to 3 months) in 50% of HBsAg-positive patients and 80% of HBsAg-negative patients. Hepatitis was recurrent (2–4 episodes) in 38% of HBsAg-positive patients during an observation period of 4–12 months. Recurrent hepatitis was not observed in the HBsAg-negative patients. In one patient in each group persistent hepatitis developed (lasting more than 6 months). Fifty percent of the hepatitis episodes were anicteric. Icteric hepatitis was more often seen in HBsAg-positive patients. Hepatic failure with ascites and coagulopathy developed in 7% of HBsAg-positive and 4% of HBsAg-negative patients. Mortality from hepatic failure was 4% for HBsAg-positive and 1% for HBsAg-negative patients (36). When a hepatitis B flare occurs during chemotherapy, the chemotherapy often has to be interrupted due to the hepatitis. This may jeopardize the patient’s prognosis. In a study of breast cancer patients, over 70% of patients who developed hepatitis B reactivation required either premature termination of chemotherapy or disruption in the treatment schedules, compared to 30% in those without hepatitis B reactivation (23).
7. SCREENING OF PATIENTS PRIOR TO CHEMOTHERAPY OR IMMUNOSUPPRESSION It seems obvious that all patients should be screened for hepatitis B infection prior to starting chemotherapy or immunosuppression, but the reality is sobering. Fewer than 40% of oncologists were screening their patients in a survey conducted in the Washington, DC area in early 2007 (114). The initial serological profile should include HBsAg, HBsAb, and HBcAb. Seronegative patients should be vaccinated against HBV. HBsAg-positive patients should be considered at high risk of reactivation and should be started on preemptive anti-HBV therapy. These patients should also be tested for HBeAg, HBeAb, and HBV DNA to distinguish between those who are chronically infected and those who are chronic carriers. Those who have chronic infection will need longterm active treatment and follow-up, whereas “carriers” may have their
Hepatitis B Reactivation in the Setting of Chemotherapy
319
prophylactic treatment stopped 6–12 months after chemotherapy is discontinued. Following the HBV DNA levels should allow for the diagnosis of a potential HBV reactivation prior to the development of hepatitis. HBsAg-negative patients who are HBcAb positive are also at risk of HBV reactivation, whether they are HBsAb positive or negative. Although reactivation is much less frequent than in HBsAg-positive patients, fatal cases of hepatic failure have been reported in these patients (115). While there is not enough information to recommend routine prophylaxis for these patients (116) and while adopting a routine prophylaxis strategy might not be cost-effective, the decision to start prophylactic antiviral therapy should be left to the discretion of the clinician and should be made on a case-by-case basis.
8. IMMUNIZATION AGAINST HEPATITIS B It is recommended that all patients be screened for HBV before starting chemotherapy or immunosuppression. HBV vaccine should be administered when appropriate. Frequently, in cancer patients, the urgent administration of chemotherapy does not allow the completion of the usual three-dose regimen over 6 months. In these cases, an effort should be made to administer three doses of the vaccine within a 3–4week interval. An additional dose can be delayed and given a few months after the completion of the chemotherapy. Rapid seroconversion has been demonstrated using this accelerated vaccination schedule (0–7–21–360 days) (117–120). Decreased response to the HBV vaccine is frequent in cancer patients, whether due to disease-induced or treatment-induced immunosuppression. Modified dosing regimens, including doubling the standard antigen dose or administering additional doses, might increase response rates (121–123).
9. MANAGEMENT OF ESTABLISHED HBV REACTIVATION Until recently, aggressive supportive therapy and discontinuation of cytotoxic chemotherapy had been the mainstay of treatment for hepatitis B reactivation while on chemotherapy. Interferon has been shown to control hepatitis B during chemotherapy (65). However, its use may be limited by side effects such as thrombocytopenia and leucopenia and by the possibility of fatal hepatitis flare via augmentation of the host’s immune response to HBV, resulting in increased destruction of hepatocytes. Interferon is also contraindicated in cirrhosis and decompensated liver disease. Lamivudine, the first in the class of oral nucleoside
320
Charbel and Lewis Table 3 Chemotherapeutic Agents Associated with Hepatitis B Reactivation
Class
Agent
Alkylating agents
Cyclophosphamide; temozolomide; ifosfamide; chlorambucil; carboplatin; cisplatin Cytarabine; fluouracil; gemcitabine; mercaptopurine; methotrexate; thioguanine Daunorubicin; doxorubicin; epirubicin, idarubicin; Bleomycin; mitomycin C, actinomycin D Vincristine; vinblastine Prednisolone; dexamethasone; methylprednisolone Asparaginase; procarbazine; docetaxel; etoposide; fludarabine; imatinib mesylate
Antimetabolites Antitumor antibiotics AnthracyclinesOthers Plant alkaloids Corticosteroids Others
analogues with anti-HBV activity, was initially utilized in 1998 in two studies that documented resolution of reactivation in one case of fulminant hepatitis following chemotherapy for lymphoma and in a case of acute icteric hepatitis in an allogenic bone marrow transplant patient receiving immunosuppression for graft-vs-host disease (124, 125). The effectiveness of lamivudine in the treatment of chemotherapy-induced HBV reactivation has been shown in several additional reports (25, 124–126); and lamivudine became the main agent for the treatment of HBV reactivation. It was suggested, however, that some of the reported cases of response to lamivudine in the setting of HBV reactivation might have been a coincidence, as the spontaneous resolution of viral reactivation was a common outcome, even before the widespread availability of lamivudine (19). And despite lamivudine therapy, the mortality associated with HBV reactivation has been reported in up to 20% of HBsAg-positive patients which was not different from untreated patients (127). Mortality rates as high as 40% have been reported when therapy was initiated after severe hepatic injury had already occurred (19, 20, 105, 128). Such studies emphasize the importance of starting lamivudine therapy as soon as a flare is diagnosed, preferably when a rise in the HBV DNA is detected and before irreversible hepatic damage occurs. The detection of HBV reactivation at a very early stage requires an intense monitoring regimen with frequent testing of HBV viral loads and liver enzymes. Such a program may be difficult to implement and may not be cost-effective. Along with prompt antiviral therapy,
Hepatitis B Reactivation in the Setting of Chemotherapy
321
aggressive supportive therapy should be instituted in addition to the cessation of chemotherapy and the withdrawal of any potentially hepatotoxic agents. Once the reactivation is under control with normal aminotransferases, chemotherapy can be restarted, if it had been held.
10. PREEMPTIVE ANTIVIRAL THERAPY AGAINST HBV REACTIVATION Since viral replication manifested by a rise in HBV viral load precedes ALT elevation and clinical hepatitis, it has been shown that early treatment with antiviral therapy prior to hepatic injury is superior to deferred intervention (127). The use of lamivudine or other oral antiHBV agents prophylactically prior to the administration of chemotherapy has been recommended (129). Indeed, with the low side effect profile, tolerability, and once-a-day dosing of lamivudine and other nucleoside analogues, therapy for chronic HBsAg carriers receiving immunosuppression or chemotherapy has shifted from treatment after the diagnosis of reactivation toward prophylaxis with the initiation of chemotherapy. The first case series of primary prophylaxis utilized lamivudine and was published in 2001 (130). It included 20 patients with hematological malignancies treated with different chemotherapy regimens, the majority of which included steroids. With a rate of HBV reactivation of 5%, the role of lamivudine for prophylaxis among HBsAg carriers appeared to be indicated. Since then the efficacy of preemptive lamivudine therapy has been demonstrated in several additional retrospective series (37, 90, 91, 131–135). More recent studies have been conducted prospectively (Table 4) (91, 130, 136–139). A systematic review of nine prospective trials and one randomized-controlled trial showed a four- to sevenfold decrease in the rate of hepatitis and hepatitis B virus reactivation in patients who received lamivudine prophylaxis (140). Of patients receiving prophylaxis, 0–24% developed hepatitis B virus reactivation, compared with 29–56% of controls. Three reactivation-related mortalities were reported (one receiving prophylaxis, two controls). A meta-analysis of 11 studies included 220 patients who received lamivudine prophylaxis and 400 patients who did not receive prophylaxis (141). Patients given lamivudine prophylaxis had an 87% decrease in HBV reactivation compared to patients not given prophylaxis. The number needed to treat to prevent one reactivation was 3. The lamivudine prophylaxis group was also associated with a 70% reduction in reactivation-related mortality compared with controls. There was a
Diagnosis
20 6 10 10
Hematological malignancies Breast cancer Hematological malignancies Hematological malignancies
Hematological malignancies
Prospective trials Rossi et al. (2001) Dai et al. (2004b) El-Sayed et al. (2004) Vassiliadis et al. (2005)
Hui et al. (2005)
NA
NA NA NA NA
9 10 193 61 21 116
37
15
No. of Controls (No Prophylactic Lamivudine)
11
1 1 0 0
0 vs 5 0 vs 5 5 vs 23 2 vs 19 0 vs 6 7 vs 60
1 vs 15
0 vs 8
Number of HBV Reactivation Cases (Lamivudine vs Control)
1
0 0 0 0
0 vs 1 0 vs 0 0 vs 5 0 vs 0 0 vs 1 0 vs 6
0 vs 1
0 vs 0
Number of HBV-Related Deaths (Lamivudine vs Control)
CT, chemotherapy; HCC, hepatocellular carcinoma; mo, months; wk, weeks; WBC, white blood cell count. Trials with newer nucleotide/nucleoside agents are currently lacking.
46
11 8 65 31 16 40 Until 4 wk after CT Until 4 wk after CT Until last day of CT Continued throughout follow-up Until 3 mo after CT and when WBC>4.0 × 109 /L
Until 4 wk after CT Until 12 mo after CT Until 8 wk after CT Until 8 wk after CT Until 8 wk after CT Until 8–64 wk after CT
36
Jang et al. (2006) HCC Prospective trials with historical controls Dai et al. (2004) Breast cancer Idilman et al. (2004) Hematological malignancies Yeo et al. (2004) Various malignancies Yeo et al. (2004) Breast cancer Yeo et al. (2005) Nasopharyngeal cancer Li et al. (2006) Lymphoma
15
No. of Duration of Patients in Lamivudine Therapy Lamivudine Group
Until 6 wk after CT and when WBC>4.0 × 109 /L Until 12 mo after CT
Randomized-controlled trials Lau et al. (2003) Lymphoma
Author
Table 4 Trials of Prophylactic Lamivudine Therapy for Prevention of Hepatitis B Reactivation
Hepatitis B Reactivation in the Setting of Chemotherapy
323
reduction in treatment delays and premature termination of chemotherapy in the lamivudine prophylaxis arm. All prospective adult trials have used equivalent daily doses of lamivudine, i.e., 100 mg daily (33, 53, 98, 130, 136, 142). Three studies using higher doses of lamivudine have shown similar and not superior efficacy in preventing HBV reactivation (132, 143, 144). Few data exist to recommend dosing lamivudine on a regimen other than 100 mg/day. The use of the newer nucleoside/nucleotide analogues in this setting has not been well studied to date; although with more potent agents such as entecavir and tenofovir, the rate of reactivation may be lower. The optimal timing for beginning preemptive anti-viral therapy has not been established. In many instances, lamivudine was started 1 week prior to chemotherapy. Idilman et al. and Jang et al. started their patients on lamivudine at the start of chemotherapy. We recommend starting preemptive therapy at least 1 week prior to chemotherapy and definitely not later than the first day of chemotherapy. The duration of nucleoside analogue therapy after completion of chemotherapy has varied widely among studies with HBV reactivation rates increasing in incidence following withdrawal of chemotherapy and prophylaxis. The HBV reactivation rates tended to be higher in the prospective trials with longer follow-up, and the only HBV reactivation-related mortality among the prospective trials occurred following discontinuation of lamivudine (53). Idilman et al. continued lamivudine for 1 year following chemotherapy and reported no HBV reactivation or reactivation-related mortality (91). Vassiliadis et al. continued lamivudine prophylaxis indefinitely and observed no events of HBV reactivation or reactivation-related mortality (142). Given that HBV reactivation has been reported up to 1 year after completion of chemotherapy (99), and lamivudine therapy is well tolerated, an argument can be made to continue lamivudine or one of the newer nucleotide or nucleoside agents indefinitely. This strategy might be reasonable and cost-effective in high-risk patients, such as those diagnosed with high HBV viral loads or liver transplant patients undergoing liver transplant for HBV. Continuing therapy 6–12 months after completion of chemotherapy might be more appropriate in lower risk individuals. A major clinical concern regarding prophylactic therapy with lamivudine is the development of lamivudine-resistant mutant strains of HBV (145–147). In the case of chronic HBV infection, prolonged therapy with lamivudine has been associated with an increased likelihood of treatment-resistant HBV variants with YMDD mutations (148, 149), from 24% at 1 year to nearly 70% at 4 years (150, 151). The incidence of lamivudine-resistant YMDD mutations among chronic HBsAg
324 HBsAg (+) HBeAg (+) DNA (+) (wild type)
Charbel and Lewis HBsAg (+) HBeAg (–) DNA (+) (mutant precore)
HBsAg (+) HBeAg (–) DNA (–) (carrier)
HBsAg (–) HBsAb (–) HBcAb (+)
Low risk consider prophylaxis
Start antiviral therapy
Chronic treatment until e Ag seroconversion
Chronic indefinite treatment
Stop 6–12 months after chemo completion
HBsAg (–) HBsAb (+) HBcAb (+)
Stop 6–12 months after chemo completion
HBsAg (–) HBsAb (–) HBcAb (–)
Vaccinate for HBV using accelerated schedule
Stop 6–12 months after chemo completion
Fig. 1. Algorithm for the prevention of hepatitis B reactivation associated with chemotherapy.
carriers receiving lamivudine as prophylaxis rather than treatment has not been well studied. Low rates of YMDD mutations have been reported (152), but this is likely due to the short duration of therapy. Among case series of HBsAg carriers following liver transplantation or receiving stem cell transplantation, emergence of YMDD mutants was significantly increased by lamivudine prophylaxis, observed in 21% of patients at 1 year and 34% at 2 years (153, 154). In case of treatment emergent YMDD mutation, the addition of newer antivirals such as adefovir, entecavir, or tenofovir can be used, all of which are associated with lower rates of resistance (155). Figure 1presents a possible algorithm to patients who are at risk for HBV reactivation.
11. COST-EFFECTIVENESS OF PREEMPTIVE THERAPY It is clear that a preemptive strategy is effective in preventing HBV reactivation related to chemotherapy and immunosuppression. However, recommending the widespread implementation of such a strategy carries with it a certain economic burden that must be balanced against the risks and costs of reactivation. Saab et al. used a decision analysis model to simulate the clinical outcomes, effectiveness, and costs associated with lamivudine prophylaxis for hepatitis B reactivation in patients receiving chemotherapy (156). They applied the model to a cohort of 1000 patients, with 500 patients in each treatment strategy (prophylaxis vs no prophylaxis). Lamivudine prophylaxis increased the cost
Hepatitis B Reactivation in the Setting of Chemotherapy
325
approximately $1,500 from $17,177 to $18,707 per patient. However, prophylaxis was effective in reducing the number of HBV reactivations (48 vs 219), liver-associated deaths (0 vs 20), and cancer-associated deaths (39 vs 47). Prophylaxis was also associated with prolonging life years from 0.876 in the no-prophylaxis group to 0.922 in the prophylaxis group. The incremental cost-effectiveness ratio (ICER) was $33,514 per life year, which was below the generally accepted price ceiling of $50,000 per life year saved. This study provided strong pharmacoeconomic support to the use of lamivudine prophylaxis in patients undergoing chemotherapy. Newer nucleoside analogues are somewhat more expensive but have fewer treatment failure rates and lower resistance, which would likely offset their higher costs.
12. AWARENESS OF HBV REACTIVATION AMONG ONCOLOGISTS The risk of HBV reactivation with chemotherapy is being increasingly recognized. However, many oncologists have not seen this complication or are not aware of the current recommendations for HBV prophylaxis. Farhadi et al. administered a questionnaire to 131 Hematology–Oncology physicians in the Washington, DC area, asking them about HBV reactivation (114). While most oncologists (78%) were aware of the potential risk of HBV reactivation, only 30% have ever seen a reactivation and most (62%) were not screening patients for HBV prior to chemotherapy. Fewer than half of the responders were aware that prophylactic antiviral agents are available, and even fewer were aware that prophylaxis has been shown to reduce HBV flares, and most were not sure what agent to select. A majority would, however, seek the recommendations of a gastroenterologist or a hepatologist. A similar survey from Los Angeles found nearly identical results (157). These surveys demonstrate that there is still a need to improve awareness of HBV reactivation and antiviral prophylaxis in the Hematology– Oncology community.
13. ADDENDUM In September 2008, the U.S. Centers for Disease Control and Prevention (CDC) released new guidelines for health-care providers to increase routine testing for chronic hepatitis B. The CDC now recommends serologic testing for all markers of HBV infection (HBsAg, anti-HBc, and anti-HBs) in persons needing cytotoxic or immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic
326
Charbel and Lewis
or gastroenterologic disorders. Chronically infected (HBsAg positive) patients are at elevated risk of fulminant hepatitis once suppressive therapy is initiated and should be referred for medical management and anti-viral treatment. Those with resolved infection (anti-HBc positive, HBsAg-negative) are at risk for reactivation and should be monitored closely with blood tests for liver enzymes (158).
REFERENCES 1. Hepatitis B, WHO fact sheet 204, accessed April 2008. 2. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004 Mar;11(2):97–107. Review. 3. Lok AS, Lai CL, Wu PC, Leung EK, Lam TS. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 1987 Jun;92(6):1839–43. 4. Yu MC, Yuan JM, Govindarajan S, Ross RK. Epidemiology of hepatocellular carcinoma. Can J Gastroenterol 2000;14(8):703–9. 5. Perrillo RP, Campbell CR, Sanders GE, Regenstein FG, Bodicky CJ. Spontaneous clearance and reactivation of chronic hepatitis B virus infection among male homosexuals with chronic type B hepatitis. Ann Intern Med 1984;100: 43–46. 6. Davis GL, Hoofnagle JH. Reactivation of chronic hepatitis B virus infection. Gastroenterology 1987;92:2028–2031. 7. Levy P, Marcellin P, Martinot-Peignoux M, Degott C, Nataf J, Benhamou JP. Clinical course of spontaneous reactivation of hepatitis B virus infection in patients with chronic hepatitis B. Hepatology 1990;12:570–574. 8. Gupta S, Govindarajan S, Fong TL, Redeker AG. Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 1990; 12:562–568. 9. Webster A, Brenner MK, Prentice HG, Griffiths PD. Fatal hepatitis B reactivation after autologous bone marrow transplantation. Bone Marrow Transplant. 1989 Mar;4(2):207–8. 10. Caselitz M, Link H, Hein R, Maschek H, B¨oker K, Poliwoda H, Manns MP. Hepatitis B associated liver failure following bone marrow transplantation. J Hepatol. 1997 Sep;27(3):572–7. 11. Hoofnagle JH, Seeff LB. Natural history of chronic type B hepatitis. Prog Liver Dis 1982;7:469–479. 12. Perrillo RP. Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120: 1009–22. 13. Mels GC, Bellati G, Leandro G, Brunetto MR, Vicari O, Borzio M, Piantino P, Fornaciari G, Scudeller G, Angeli G, Bonino F, Ideo G. Fluctuations in viremia, aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations. Liver 1994;14:175–81. 14. Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 1984;86:230–5.
Hepatitis B Reactivation in the Setting of Chemotherapy
327
15. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis. A clinicopathological study. J Hepatol 1985;1:227–233. 16. Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitisassociated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 1975; 68:105–12. 17. Galbraith RM, Eddleston ALWF, Williams R, et al. Fulminant hepatic failure in leukaemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 1975; 2: 528–30. 18. Nagington J. Reactivation of hepatitis b after transplantation operations. Lancet 1977; 1(8011): 558–60. 19. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006 Feb;43(2):209–20. 20. Yeo W, Chan PKS, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000;62:299–307. 21. Alexopoulos CG, Vaslamatzis M, Hatzidimitriou G. Prevalence of hepatitis B virus marker positivity and evolution of hepatitis B virus profile, during chemotherapy, in patients with solid tumours. B J Cancer 1999;81:69–74. 22. Yeo W, Lam KC, Zee B, Chan PSK, Mo FKF, Ho WM, et al. Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy. Ann Oncol 2004;15:1661–1666. 23. Yeo W, Chan PKS, Hui P, HoWM, Lam KC, Kwan WH, et al. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70:553–561. 24. Cheng JC, Liu MC, Tsai SY, Fang WT, Jer-Min Jian J, Sung JL. Unexpectedly frequent hepatitis B reactivation by chemoradiation in postgastrectomy patients. Cancer 2004;101:2126–2133. 25. Vento S, Cainelli F, Longhi MS. Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy: an unresolved issue. Lancet Oncol. 2002 Jun;3(6):333–40. 26. Lightdale CJ, Ikram H, Pinsky C. Primary hepatocellular carcinoma with hepatitis B antigenemia: effects of chemotherapy: Cancer 1980; 46: 1117–22. 27. Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982; 96: 447–49. 28. Pinto PC, Hu E, Bernstein-Singer M, et al. Acute hepatic injury after the withdrawal of immunosuppressive chemotherapy in patients with hepatitis B. Cancer 1990; 65: 878–84. 29. Yang CH, Wu TS, Chiu CT. Chronic hepatitis B reactivation: a word of caution regarding the use of systemic glucocorticosteroid therapy. Br J Dermatol. 2007 Sep;157(3):587–90. Epub 2007 Jun 26. 30. Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Forn´e M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut. 2004;53:1363–1365. 31. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003;62:686–687.
328
Charbel and Lewis
32. Wendling D, Auge B, Bettinger D, et al. Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy. Ann Rheum Dis. 2005;64:788–789. 33. Dai MS, Wu PF, Lu JJ, Shyu RY, Chao TY. Preemptive use of lamivudine in breast cancer patients carrying hepatitis B virus undergoing cytotoxic chemotherapy: a longitudinal study. Support Care Cancer. 2004 Mar;12(3):191–6. 34. Ho J, Wu PC, Kung TM. An autopsy study of hepatocellular carcinoma in Hong Kong. Pathology 1981;13:409–416. 35. Nagamatsu H, Kumashiro R, Itano S, Matsugaki S, Sata M. Investigation of associating factors in exacerbation of liver damage after chemotherapy in patients with HBV-related HCC. Hepatol Res 2003;26:293–301. 36. Lok ASF, Liang RS, Chiu EKW, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100:182–188 37. Ozguroglu M, Bilici A, Turna H, Serdengecti S. Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin’s lymphoma. Med Oncol. 2004;21(1):67–72. 38. Mindikoglu AL, Regev A, Schiff ER. Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention. Clin Gastroenterol Hepatol. 2006 Sep;4(9):1076–81. Epub 2006 Jul 24. 39. Lau GKK, Leung YH, Fong DYT, et al. High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation. Blood 2002;99: 2324–2330. 40. Yeo W, Chan PKS, Chan HLY, et al. Hepatitis B virus reactivation during cytotoxic chemotherapy-enhanced viral replication precedes overt hepatitis. J Med Virol 2001;65:473–477. 41. Liang R, Lau GKK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncol 1999;17: 394–398. 42. Lau GKK, Lee CK, Liang R. Hepatitis B virus infection and allogenic bone marrow transplantation. Crit Rev Oncol Hematol 1999;31:71–76. 43. Kao JH, Chen PJ, Lai MY. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554–559. 44. Lindh, M, Hannoun, C, Dhillon, AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis 1999;179:775. 45. Chu, CM, Liaw, YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: A longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol 2005;43:411. 46. Sumi, H, Yokosuka, O, Seki, N, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19. 47. Orito, E, Mizokami, M, Sakugawa, H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology 2001;33:218. 48. Devarbhavi HC, Cohen AJ, Patel R, et al. Preliminary results: Outcome of liver transplantation for hepatitis B virus varies by hepatitis B virus genotype. Liver Transpl 2002; 8:550.
Hepatitis B Reactivation in the Setting of Chemotherapy
329
49. Yeo W, Zee B, Zhong S, Chan PKS, Wong WL, Ho WM, Lam KC, Johnson PJ. Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004; 90:1306–11. 50. Liaw YF, Tai DI, Chu CM, Pao CC, Chen TJ. Acute exacerbation in chronic type of B hepatitis: comparison between HBeAg and antibody positive patients. Hepatology 1987;7:20–3 51. Liang RHS, Lok ASF, Lai CL, Chan TK, Todd O, Chiu EKW. Hepatitis B infection in patients with lymphomas. Hematol Oncol 1990;8:261–70 52. Zhong S, Yeo W, Schroder C, Chan PK, Wong WL, Ho WM, Mo F, Zee B, Johnson PJ. High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy. J Viral Hepatol 2004;11:55–9. 53. Hui CK, Cheung WW, Au WY, Lie AK, Zhang HY, Yueng YH, Wong BC, Leung N, Kwong YL, Liang R, Lau GK. Hepatitis B reactivation after withdrawal of preemptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut 2005;54:1597–603 54. Hsu CH, Hsu HC, Chen HL, Gao M, Yeh PY, Chen PJ, Cheng AL. Doxorubicin activates hepatitis B virus (HBV) replication in HBV-harboring hepatoblastoma cells. A possible novel mechanism of HBV reactivation in HBV carriers receiving systemic chemotherapy. Anticancer Res 2004;24:3035–3040. 55. Sagnelli E, Manzio G, Maio G, Pasquale G, Felaco FM, Filippini P, Izzo CM, Piccinino F. Serum levels of hepatitis B surface and core antigens during immunosuppressive treatment of HBsAg-positive chronic active hepatitis. Lancet 1980;2:395–7. 56. Nair PV, Tong MJ, Stevenson D, Roskamp D, Boone C. Effects of short-term, high-dose prednisone treatment of patients with HBsAg-positive chronic active hepatitis. Liver 1985;5:8–12. 57. Scullard GH, Smith CI, Merigan TC, Robinson WS, Gregory PB. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 1981;81:987–91. 58. Chou CK, Wang LH, Lin HM, Chi CW. Glucocorticoid stimulates hepatitis B viral gene expression in cultured human hepatoma cells. Hepatology 1992;16: 13–18. 59. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proceedings of the National Academy of Science, USA, 1986;83:1627–31. 60. Nakamura Y, Motokura T, Fujita A, Yamashita T, Ogata E. Severe hepatitis related to chemotherapy in hepatitis B virus carriers with hematologic malignancies. Survey in Japan, 1987–1991. Cancer 1996;78:2210–15. 61. Cheng AL. Steroid-free chemotherapy decreases the risk of hepatitis flareup in hepatitis B virus carriers with non-Hodgkin’s lymphoma [letter]. Blood 1996;87:1202. 62. Lok ASF, Wu PC, Lai CL, Lau JY, Leung EK, Wong LS, et al. A controlled trial of interferon with or without prednisolone priming for hepatitis B. Gastroenterology 1992;102:2091–2097. 63. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, Kao WY, Uen WC, Hsu CH, Tien HF, Chao TY, Chen LT, Whang-Peng J. Lymphoma Committee of Taiwan Cooperative Oncology Group. Steroid-free chemotherapy decreases
330
64.
65.
66. 67.
68.
69.
70.
71.
72.
73.
74.
75.
Charbel and Lewis risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 2003 Jun;37(6):1320–8. Hui CK, Cheung WWW, Zhang HY, Au WY, Yueng YH, Leung AYH, Leung N, Luk JM, Lie AKW, Kwong YL, Liang R, Lau GKK. Kinetics and risk of de novo hepatitis B infection in HBsAg negative patients undergoing chemotherapy. Gastroenterology 2006;131:59–68. Kumagai K, Takagi T, Nakamura S, Sawada U, Kura U, Kodama F, Shimano S, Kudoh I, Nakamura H, Sawada K, Ohnoshi T. Hepatitis B virus carriers in the treatment of malignant lymphomas: an epidemiological study in Japan. Ann Oncol 1997;8(Suppl. 1):107–9. Liaw YF. Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol 1998;13:14–20. Chen PM, Fan S, Liu CJ, Hsieh RK, Liu JH, Chuang MW, Liu RS, Tzeng CH. Changing of hepatitis B virus markers in patients with bone marrow transplantation. Transplantation 1990;49:708–713. Dhedin N, Douvin C, Kuentz M, Saint Marc MF, Reman O, Rieux C, Bernandi F, Novol F, Cordonnier C, Bobin D, Metreau JM, Vernaut JP. Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pre-transplant anti-HBs and anti-HBc. Transplantation 1998; 66:616–9. Kn¨oll A, Boehm S, Hahn J, Holler E, Jilg W. Reactivation of resolved hepatitis B virus infection after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 2004;33:925–9. Seth P, Alrajhi AA, Kagevi I, Chaudhary MA, Colcol E, Sahovic E, Aljurf M, Gyger M. Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease. Bone Marrow Transplant 2002;30:189–94. Onozawa M, Hashino S, Izumiyama K, Kahata K, Chuma M, Mori A, Kondo T, Toyoshima N, Ota S, Kobayashi S, Hige S, Toubai T, Tanaka J, Imamura M, Asaka M. Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection. Transplantation 2005;79:616–9. Goyama S, Kanda Y, Nannya Y, Kawazu M, Takeshita M, Niino M, Komeno Y, Nakamoto T, Kurokawa M, Tsujino S, Ogawa S, Aoki K, Chiba S, Motokura T, Shiratory Y, Hirai H. Reverse seroconversion of hepatitis B virus after hematopoietic stem cell transplantation. Leukemia and Lymphoma 2002;43:2159–2163. Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordon L, LoBuglio AF, et al. Treatment of patients with low grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268–76. Skrabs C, Muller C, Agis H, Mannhalter C, Jager U. Treatment of HBV-carrying lymphoma patients with rituximab and CHOP: a diagnostic and therapeutic challenge. Leukemia 2002;16:1884–6. Jager G, Neumeister P, Brezinschek R, Hofler G, Quehenberger F, Linkesch W, et al. Rituximab (anti-CD20 monoclonal antibody) as consolidation of first-line CHOP chemotherapy in patients with follicular lymphoma: a phase II study. Eur J Haematol 2002;69:21–6.
Hepatitis B Reactivation in the Setting of Chemotherapy
331
76. Lundin J, Kimby E, Bjorkholm M, Broliden PA, Celsing F, Hjalmar V, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;100:768–73. 77. Tsutsumi Y, Tanaka J, Kawamura T, Miura T, Kanamori H, Asaka M, et al. Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin’s lymphoma. Ann Hematol 2003;83:58–60. 78. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Eng J Med 2001;344: 68–69. 79. Westhoff TH, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer JH, Zidek W, et al. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003;102:1930. 80. Iannitto E, Minardi V, Calvaruso G, Mule A, Ammatuna E, Trapani RD, et al. Hepatitis B virus reactivation and alemtuzumab therapy. Eur J Haematol 2005;74:254–8. 81. Sarrecchia C, Cappelli A, Aiello P. HBV reactivation with fatal fulminating hepatitis during rituximab treatment in a subject negative for HBsAg and positive for HBsAb and HBcAb. J Infect Chemother 2005;11:189–191. 82. Law JK, Ho JK, Hoskins PJ, Erb SR, Steinbrecher UP, Yoshida FM. Fatal hepatitis B virus reactivation post-chemotherapy in a hepatitis B core antibodypositive patient: potential implications for future prophylaxis recommendation. Leuk Lymphoma 2005;46:1085–9. 83. Rituxan [package insert]. Biogen Idec Inc. and Genentech, Inc. 84. Sakellariou GT, Chatzigiannis I. Long-term anti-TNF␣ therapy for ankylosing spondylitis in two patients with chronic HBV infection. Clin Rheumatol 2007;26:950–2. 85. Humira [package insert]. Abbott Park, Ill: Abbott. 86. Locarnini S. Molecular virology of hepatitis B virus. Semin Liver Dis 2004;24(Suppl. 1): 3–10. 87. Mason AL, Xu L, Guo L, Kuhns M, Perrillo RP. Molecular basis for persistent hepatitis B infection in the liver after clearance of serum hepatitis B surface antigen. Hepatology 1998;27:1736–42. 88. Dusheiko G. Hepatitis B: an overview. In: Rizzetto M, Purcell RH, Gerin JL, Verme G, eds. Viral hepatitis and liver disease: proceedings of IX Triennial International Symposium on Viral Hepatitis and Liver Disease. Turin: Edizioni Minerva Medica 1997;57–72. 89. Thung SN, Gerber MA, Klion F, Gilbert H. Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier. Arch Intern Med 1985;145:1313–4. 90. Lau GKK, He ML, Fong DYT, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogenic hematopoietic cell transplantation. Hepatology 2002;36:702–9. 91. Idilman R, Arat M, Soydan E, et al. Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. J Viral Hepat 2004;11:141–7.
332
Charbel and Lewis
92. Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neo-plasias treated with chemotherapy. Leuk Lymphoma 2003;44:759–66. 93. Tur-Kaspa R, Shaul Y, Moore DD et al. The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology 1988;167:630–3. 94. Seeger C, Mason WS. Hepatitis B Virus Biology. Microb Molec Biol Rev 2000;64:51–58 95. Summers J, Mason WS. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 1982;29:403–15 96. 21 Lewin SR, Ribeiro RM, Walters T, Lau GK, Bowden S, Locarnini S, Perelson AS. Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed. Hepatology 2001;34:1012–20 97. Yokosuka O, Omata M, Imazeki F, Okuda K, Summers J. Changes of hepatitis B virus DNA in liver and serum caused by recombinant leukocyte interferon treatment: analysis of intrahepatic replicative hepatitis B virus DNA. Hepatology 1985;5:728–34 98. Lau GKK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, Cheung M, Zhang HY, Lie A, Ngan R, Liang R. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125:1742–9. 99. Perceau G, Diris N, Estines O, Derancourt C, L´evy S, Bernard P. Late lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma. Br J Dermatol 2006 Nov;155(5):1053–6. 100. Kn¨oll A, Boehm S, Hahn J, Holler E, Jilg W. Long-term surveillance of haematopoietic stem cell recipients with resolved hepatitis B: high risk of viral reactivation even in a recipient with a vaccinated donor. J Viral Hepat 2007 Jul;14(7):478–83. 101. Xunrong L, Yan AW, Liang R, Lau GKK. Hepatitis B reactivation after cytotoxic or immunosuppressive therapy-pathogenesis and management. Rev Med Virol 2001;11:287–99 102. Puoti M, Torti C, Bruno R, Filice G, Carosi G. Natural history of chronic hepatitis B in co-infected patients. J Hepatol 2006;44(Suppl. 1):S65–S70; epub 28 November 2005. 103. Lok AS, Lai CL. Alpha-fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma. Hepatology 1989; 9: 110–5. 104. Eleftheriou N, Heathcote J, Thomas HC, Sherlock S. Serum alpha-fetoprotein levels in patients with acute and chronic liver disease. Relation to hepatocellular regeneration and development of primary liver cell carcinoma. J Clin Pathol. 1977 Aug;30(8):704–8. 105. Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepato-Gastroenterology 1999;46:2925–30. 106. Tillman HL, Wedemeyer H, Manns MP. Treatment of hepatitis B in special patient groups: hemodialysis, heart and renal transplant, fulminant hepatitis, hepatitis B virus reactivation. J Hepatol 2003;39(Suppl. 1):206–11.
Hepatitis B Reactivation in the Setting of Chemotherapy
333
107. Jilg W, Hottentr¨ager B, Weinberger K, Schlottmann K, Frick E, Holstege A, et al. Prevalence of markers of hepatitis B in the adult German population. J Med Virol 2001;63:96–102. 108. Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology 2002;122:1554–1568. 109. De Vita VT Jr, Hubbard SM, Longo DL. The chemotherapy of lymphoma— looking back, moving forward: the Richard and Hinda Rosenthal Foundation award Lecture. Cancer Res 1987;47:5810–24. 110. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 1990;8:963–77. 111. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, and fluorouracil in node-positive breast cancer. The results of 20 years follow-up. N Engl J Med 1995;332:901–6. 112. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21: 1431–39. 113. Yeo W, Mok TS, Zee B, Leung WT, Lau PBS, Lau WY, et al. Phase III study of adriamycin versus cisplatin/interferon -2b/adriamycin/fluorouracil combination chemotherapy for inoperable hepatocellular carcinoma. J Natl Cancer Inst 2005;97(20):1532–38. 114. Farhadi A, Lewis JH, Khokhar O, McGrail LH. Oncologists and hepatitis B: Results of a questionnaire survey to determine their current level of awareness and clinical practice of antiviral prophylaxis to prevent reactivation. AASLD abstract. Hepatology 2007; 46(4), Suppl. 1: 657A. 115. Gwak GY, Koh KC, Kim HY. Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surface antigen-negative patient with rheumatoid arthritis receiving low dose methotrexate. Clin Exp Rheumatol 2007;25(6):888–9. 116. Lok AS, McMahon BJ: chronic hepatitis B. Hepatology 2007;45:507–539. 117. Van Herck K, Leuridan E, Van Damme P. Schedules for hepatitis B vaccination of risk groups: balancing immunogenicity and compliance. Sex Transm Infect 2007 Oct;83(6):426–32. 118. Zuckerman J. The place of accelerated schedules for hepatitis A and B vaccinations. Drugs 2003;63(17):1779–84. 119. Ahmed SM, Volpellier M, Forster G. The use of the super accelerated hepatitis B vaccination regimen in a north London sexual assault referral centre (SARC). J Forensic Leg Med 2007 Feb;14(2):72–4. 120. Jones O, Sankar KN. Audit of outcome of super-accelerated hepatitis B vaccination schedule in a genitourinary medicine clinic. Int J STD AIDS. 2005 Sep;16(9):636–7. 121. Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. Vaccine 2000;18:1161–5. 122. Choudhury SA, Peters VB. Responses to hepatitis B vaccine boosters in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1995;14:65–7.
334
Charbel and Lewis
123. Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902–8. 124. Clark FL, Drummond MW, Chambers S, Chapman BA, Patton WN. Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin’s lymphoma. Ann Oncol 1998;9:385–7. 125. Picardi M, Selleri C, De Rosa G, et al. Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation. Bone Marrow Transplant 1998;21:1267–9. 126. Ahmed A, Keeffe EB. Lamivudine therapy in chemotherapy-induced reactivation of hepatitis B virus infection. Am J Gastroenterol 1999;94:249–51. 127. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, Lin TH, Hsiao HH, Young JH, Chang MC, Liao YM, Li CC, Wu HB, Tien HF, Chao TY, Liu TW, Cheng AL, Chen PJ. A revisit of prophylactic lamivudine for chemotherapyassociated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology 2008 Mar;47(3):844–53. 128. Iwai K, Tashima M, Itoh M, Okazaki T, Yamamoto K, Ohno H, Marusawa H, Ueda K, Nakamura T, Chiba T, Uchiyama T. Fulminant hepatitis B following bone marrow transplantation in an HBsAg-negative, HBsAb-positive recipient; reactivation of dormant virus during the immunosuppressive period. Bone Marrow Transplant 2000;25:105–8. 129. Lalazar G, Rund D, Shouval D. Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies. Br J Haematol. 2007 Mar;136(5):699–712. 130. Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 2001;115:58–62. 131. Lee GW, Ryu MH, Lee JL, Oh S, Kim E, Lee JH, et al. The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with non-Hodgkin’s lymphoma who receive cytotoxic chemotherapy. J Korean Med Sci 2003;18:849–54. 132. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002;100:391–396. 133. Persico M, De Marino F, Russo GD, Morante A, Rotoli B, Torella R, et al. Efficacy of lamivudine to prevent hepatitis reactivation in hepatitis B virus-infected patients treated for non-Hodgkin lymphoma. Blood 2002; 99:724–725. 134. Lim LL, Wai CT, Lee YM, Kong HL, Lim R, Koay E, et al. Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Aliment Pharmacol Ther 2002;16:1939–1944. 135. Nagamatsu H, Itano S, Nagaoka S, Akiyoshi J, Matsugaki S, Kurogi J, et al. Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive patients with hepatocellular carcinoma undergoing transhepatic arterial infusion chemotherapy. Am J Gastroenterol 2004;99: 2369–2375. 136. Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int 2004;24:540–6.
Hepatitis B Reactivation in the Setting of Chemotherapy
335
137. Yeo W, Hui EP, Chan AT, et al. Prevention of hepatitis B virus reactivation in patients with nasopharyngeal carcinoma with lamivudine. Am J Clin Oncol 2005;28:379–84. 138. Li YH, He YF, Jiang WQ, Wang FH, Lin XB, Zhang L, Xia ZJ, Sun XF, Huang HQ, Lin TY, He YJ, Guan ZZ. Lamivudine prophylaxis reduces the incidence and severity of hepatitis in hepatitis B virus carriers who receive chemotherapy for lymphoma. Cancer 2006;106:1320–5. 139. Jang JW, Choi JY, Bae SH, et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 2006;43:233–40. 140. Kohrt HE, Ouyang DL, Keeffe EB. Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol Ther 2006 Oct ;24(7):1003–16. 141. Martyak LA, Taqavi E, Saab S. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients: a meta-analysis. Liver Int 2008 Jan;28(1):28–38. 142. Vassiliadis T, Garipidou V, Tziomalos K, et al. Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy – a prospective case series. Am J Hematol 2005; 80: 197–203 143. Hamaki T, Kami M, Kusumi E, et al. Prophylaxis of hepatitis B reactivation using lamivudine in a patient receiving rituximab. Am J Hematol 2001; 68: 292–4. 144. Grellier L, Dusheiko GM. Hepatitis B virus and liver transplantation: concepts in antiviral prophylaxis. J Viral Hepat 1997;4 (Suppl. 1):111–6. 145. Gutfreund KS, Williams M, George R, et al. Genotypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance. J Hepatol 2000;33:469–75. 146. Fischer KP, Gutfreund KS, Tyrrell DL. Lamivudine resistance in hepatitis B: mechanisms and clinical implications. Drug Resist Updat 2001; 4:118–28. 147. Zoulim F. Detection of hepatitis B virus resistance to antivirals. J Clin Virol 2001;21:243–53. 148. Gauthier J, Bourne EJ, Lutz MW, Crowther LM, Dienstag JL, Brown NA, et al. Quantitation of hepatitis B viraemia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine. J Infect Dis 1999;180: 1757–1762. 149. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Lamivudine Clinical Investigation Group. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology 1998;27:1670–7. 150. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125:1714–1722. 151. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521–31. 152. Pelizzari AM, Motta M, Cariani E, et al. Frequency of hepatitis B virus mutant in asymptomatic hepatitis B virus carriers receiving prophylactic lamivudine during chemotherapy for hematologic malignancies. Hematol J 2004;5:325–8.
336
Charbel and Lewis
153. Chan HL, Chui AK, Lau WY, et al. Outcome of lamivudine resistant hepatitis B virus mutant post-liver transplantation on lamivudine monoprophylaxis. Clin Transplant 2004;18:295–300. 154. Chen PM, Yao NS, Wu CM, et al. Detection of reactivation and genetic mutations of the hepatitis B virus in patients with chronic hepatitis B infections receiving hematopoietic stem cell transplantation. Transplantation 2002;74:182–8. 155. Keeffe EB, Dieterich DT, Pawlotsky JM, Benhamou Y. Chronic hepatitis B: preventing, detecting, and managing viral resistance. Clin Gastroenterol Hepatol 2008 Mar;6(3):268–74. 156. Saab S, Dong M H, Joseph T A, Tong M J. Hepatitis B prophylaxis in patient undergone chemotherapy for lymphoma: A decision analysis model. Hepatology 2007;46(4):1049–56. 157. Tran T, Oh M, Poordad F, Martin P. Screening for hepatitis B in chemotherapy patients: survey of current oncology practices. AASLD abstract Hepatology 2007;46(4), suppl. 1, 678A. 158. MMWR 2008; 57(No.RR 8).
Support of Patients During Antiviral Therapy for Hepatitis B and C Alyson N. Fox and Thomas W. Faust CONTENTS I NTRODUCTION C HRONIC H EPATITIS C H EPATITIS B C ONCLUSION R EFERENCES
Key Principles
• The mainstay of treatment for the viral hepatitides are immunomodulators (interferons) and antiviral agents. • While many of these therapies are effective at suppressing and eliminating the virus, their use can be inhibited by the side effects that they cause. Treatment for chronic hepatitis B and C can therefore be complex and requires a strong therapeutic alliance between the patient and the health-care provider. • The standard of care for the treatment of hepatitis C is centered around combination therapy with pegylated interferon-␣ and ribavirin. Prior to initiating treatment, it is crucial for the provider to screen the patient for contraindications to therapy and to outline potential medication-related side effects for the patient. • Hematologic side effects are common with interferon-based therapy and may require the use of growth factors. Other side effects
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 13, C Humana Press, a part of Springer Science+Business Media, LLC 2009
337
338
Fox and Faust
experienced with hepatitis C therapy include psychiatric, ophthalmologic, endocrine, and dermatologic events. • There are now several approved oral agents used to treat chronic hepatitis B (CHB). Unlike the treatment for hepatitis C, the treatment for hepatitis B can be indefinite, so recognition of a management strategy for side effects is paramount. Fortunately, most of these therapies appear safe and well tolerated. • The therapies for chronic hepatitis B and C have dramatically evolved over the last decade. Principal in treating patients for chronic hepatitis is choosing a regimen that is suitable for an individual patient, disclosing the expected and potential side effects, and early identification and management of adverse effects.
1. INTRODUCTION Worldwide, over 300 million people are affected by chronic viral hepatitis. On a yearly basis, millions of those affected die from progression of end-stage liver disease and hepatocellular carcinoma. In the last decade, our understanding of and treatments for chronic hepatitis B and C have dramatically improved. While the goals of hepatitis care have remained unchanged – to halt the progression of disease and prevent long-term complications – our ability to accomplish those goals has improved. The mainstay of treatment for the viral hepatitides are immunomodulators (interferons) and antiviral agents. While many of these therapies are effective at suppressing and eliminating the virus, their use can be inhibited by the side effects that they cause. Treatment for chronic hepatitis B and C can therefore be complex and requires a strong therapeutic alliance between the patient and the health-care provider. The goal of this chapter is to discuss the current standard of care therapies for hepatitis B and C, treatment considerations, side effects, and their management.
2. CHRONIC HEPATITIS C The standard of care for the treatment of hepatitis C is centered around combination therapy with pegylated interferon-␣ and ribavirin. In multiple clinical trials, it has been established that the highest levels of efficacy at achieving a sustained viral response have been with pegylated interferon and ribavirin combination therapy (1, 2). Combination therapy with pegylated interferon and ribavirin can produce a variety of side effects that can often be treatment limiting and may require dose reduction or cessation of the medications. Due to the fact that viral
Support of Patients During Antiviral Therapy for Hepatitis B and C
339
suppression is compromised when the medications are dose reduced or withdrawn, it is of primary importance to have a working management strategy for side effects in order to prevent unnecessary treatment cessation. Prior to initiating treatment, it is crucial for the provider to screen the patient for contraindications to therapy and to outline potential medication-related side effects for the patient. Absolute contraindications to pegylated interferon/ribavirin treatment are known drug allergy, the presence of any major comorbid medical or neuropsychiatric condition, decompensated liver disease, history of a solid organ transplant other than the liver, uncontrolled autoimmune disease, pregnancy and active substance abuse. Ribavirin is renally cleared and thus contraindicated in those with renal disease; it is not cleared during dialysis, so is likewise contraindicated in those on hemodialysis. Side effects of hepatitis C therapy can potentially be avoided by adequate pretreatment screening to identify those most at risk for the development of certain adverse effects. The goal of this section is to acquaint the prescriber with the most common side effects experienced by patients on pegylated interferon and ribavirin combination therapy for HCV in a systems-based approach.
2.1. Hematologic Side Effects 2.1.1. A NEMIA The anemia experienced with pegylated interferon and ribavirin combination therapy is primarily caused by a ribavirin-mediated hemolysis and secondarily by an interferon-induced bone marrow toxicity. The mechanism of ribavirin toxicity is ribavirin phosphate accumulation within erythrocytes and the red cells’ inability to breakdown these phosphates, thus causing red cell oxidative injury and cell lysis (3). Typically, the development of anemia occurs within the first months of therapy. In a trial comparing peginterferon alfa-2a plus ribavirin, standard interferon alfa-2b and ribavirin, and peginterferon alfa-2a alone, Fried et al. found that maximal hemoglobin decreases were 3.7 g/dL, 3.6 g/dL, and 2.2 g/dL, respectively, and returned to close to baseline after the completion of treatment (1). A similar decrease in hemoglobin was seen in a comparison of peginterferon alfa-2b and ribavirin with standard interferon alfa-2b and ribavirin, where mean hemoglobin decreases were reportedly 2.5 g/dL (2). Since the anemia seen with ribavirin treatment is dose dependent, the standard approach to managing the anemia is dose reduction of ribavirin from the standard 1,000–1,200 mg/day dose to 600 mg/day for
340
Fox and Faust
hemoglobin values less than 10 g/dL and discontinuation if hemoglobin falls under 8.5 g/dL (4). The use of epoetin alfa in the management of ribavirin-induced anemia was evaluated in a trial of 185 chronic hepatitis C-infected patients with hemoglobin values ≤12 g/dL while on combination therapy (5). The authors found that in those patients randomized to receive weekly subcutaneous erythropoietin injections, the average hemoglobin increased by 2.2 g/dL and ribavirin doses were maintained in 88% of patients versus only 60% in the placebo group. As a secondary endpoint, the authors also looked at quality of life. Those in the erythropoietin group had a significantly better quality of life assessment, which may have implications for the sustenance of therapy and ultimately the achievement of a sustained viral response. Similar findings have been reported with the use of darbepoetin, which is given on a biweekly basis instead of weekly. Recommendations: • Recombinant erythropoietin is not currently FDA approved to treat ribavirin-medicated anemia; however, trials suggest that it can be used to raise hemoglobin, maintain ribavirin dose, and improve quality of life in those being treated for hepatitis C. • If it is used, the goal of erythropoietin therapy should be to maintain hemoglobin in the 11–12 g/dL range.
2.1.2. T HROMBOCYTOPENIA Thrombocytopenia is a typical complication of chronic hepatitis C and is largely due to viral-mediated bone marrow inhibition, splenic sequestration of platelets, and decreased thrombopoietin production by the impaired liver. Thrombocytopenia can be exacerbated by the interferon-mediated bone marrow suppression and can limit treatment for patients. Typically, the thrombocytopenia can be managed by interferon reduction or discontinuation depending on the severity of the thrombocytopenia. The manufacturers of pegylated interferon alfa-2a and alfa-2b have recommended dose reduction and/or discontinuation for given platelet values listed in their respective dosing guides (available at www.pegasys.com and www.pegintron.com). A recent phase II study was conducted by McHutchinson et al. to evaluate the efficacy of eltrombopag, an oral thrombopoietin receptor agonist in patients with hepatitis C-related cirrhosis and platelet counts between 20,000 and 70,000/mm3 (6). Seventy-four patients were randomized to receive placebo or three graduated doses of eltrombopag. At 4 weeks of treatment, 95% of those getting the highest dose of eltrombopag (75 mg) had platelet counts of 100,000/mm3 or
Support of Patients During Antiviral Therapy for Hepatitis B and C
341
greater, while none of the patients in the placebo arm had greater than 100,000/mm3 platelets. Antiviral combination therapy was commenced for 12 weeks in those with platelet counts greater than 70,000/mm3 . Although platelet counts were found to decrease during antiviral therapy, those receiving concurrent eltrombopag maintained higher platelet counts than those in the placebo group. Recommendations: • Thrombocytopenia that is exacerbated by interferon therapy is managed by dose reduction or discontinuation of interferon. • Thrombopoietin receptor agonists may provide an alternative to medication reduction or cessation but are currently under investigational use only. 2.1.3. N EUTROPENIA The neutropenia that accompanies peginterferon/ribavirin treatment is related to an interferon-mediated bone marrow toxicity. When compared on the basis of the development of neutropenia, up to 48% of patients receiving pegylated interferon developed absolute neutrophil counts lower than 1,000 cells/mL as compared to 9% of patients receiving standard interferon (7). The danger of neutropenia is the subsequent development of infection. In a recent study to evaluate the relationship between neutropenia and risk of infection while being treated with pegylated interferon and ribavirin, the authors found that the incidence of infection was 41 per 100 person years and the development of infection had a greater association with age than with the presence of or the severity of neutropenia (8). These findings are consistent with previous data suggesting that interferon-mediated neutropenia did not confer increased risk of sepsis; however, despite several trials the manufacturers of both peginterferon alfa-2a and alfa-2b recommend dose reductions in peginterferons when the absolute neutrophil counts fall below 750 cells/mm3 and discontinuation when ANC falls below 500 cells/mm3 . The use of granulocyte colony-stimulating factor (G-CSF) to boost neutrophil counts in an effort to maintain peginterferon therapy has had only limited evaluation. Koirala et al. examined a group of 163 patients being treated for hepatitis C with pegylated interferon and ribavirin (9). Thirty of the 163 developed neutropenia and were started on weekly G-CSF, the remainder did not develop neutropenia. Of those who got G-CSF, 70% had an undetectable end of treatment viral response as compared to 90% in the non-G-CSF group. The findings of this study suggest that adjuvant G-CSF may allow treatment continuation in patients who develop neutropenia; however, further investigation is necessary to demonstrate the efficacy of G-CSF for routine use.
342
Fox and Faust
Recommendations: • Given the lack of evidence for increased rates of infection or sepsis development with interferon-mediated neutropenia and the lack of evidence regarding the routine use of G-CSF, there are no firm recommendations for the use of G-CSF. • We would, however, advocate its use in order to maintain counts so that patients can continue antiviral therapy.
2.2. Psychiatric Side Effects Twenty-one to fifty-eight percent of patients treated with interferon alfa will experience significant depressive symptoms ranging from mood alteration to neurovegetative disturbance. Those at highest risk for the development of these symptoms are those with preexisting mood conditions. The options for management of interferon-induced depression are to pretreat with antidepressants or to initiate antidepressant therapy should depressive symptoms occur. For those patients already being treated with an antidepressant, therapy should be continued. Pretreatment should be highly considered for those patients at greatest risk for developing depression (10). Initiation of antidepressants for those who develop depression is indicated and has been proven effective at providing symptom relief and allowing for continuation of antiviral therapy (11). Most studies on treating interferon-based depression have used selective serotonin reuptake inhibitors as the antidepressant agent. Rarely, patients have experienced suicidal ideations while being treated with interferon and ribavirin. Clearly, if depressive symptoms are extreme, consideration should be given to the discontinuation of treatment. Although depression is the most common neuropsychiatric side effect of interferon therapy, mania can also emerge during treatment. Since mania is considered a psychiatric emergency, it is recommended that antiviral therapy be discontinued and urgent psychiatric evaluation be obtained. Recommendations: • Recognize depression as a common side effect of interferon therapy. • Prescreen patients for psychiatric disorders prior to initiating interferon therapy. • Consider pretreatment in those at highest risk for the development of depression. • Consider initiation of antidepressants in those who develop symptoms. • Recognize the potential for the development of mania and stop antiviral treatment and seek psychiatric consult.
Support of Patients During Antiviral Therapy for Hepatitis B and C
343
2.3. Ophthalmologic Side Effects The most common ophthalmologic side effect of interferon-␣ and ribavirin treatment is an interferon-induced retinopathy that occurs as a constellation of cotton wool spots, microaneurysms, and retinal hemorrhages. The risk of developing this retinopathy is likely increased in those patients with preexisting diabetes or hypertension. Reported ophthalmologic events include neurovisual impairment, exophthalmia, subconjunctival hemorrhage, papilledema, retinal artery occlusion, and retinal vein thrombosis (12). In 2006, a prospective trial was published by d’Alteroche et al. to identify ophthalmologic complications and their frequency in those being treated for viral hepatitis. Of the 156 patients followed, serial exams revealed the development of retinopathy in 24%. The authors also reported that more than twice the cases of retinopathy occurred in those receiving pegylated interferon in contrast to standard interferon. Of note, all lesions regressed with either withdrawal or completion of therapy. Management of ophthalmologic side effects must be tailored to symptoms; if asymptomatic, one can continue interferon at the same dose with close ophthalmologic monitoring; however, if lesions become symptomatic, consideration should be given to the withdrawal of interferon. Recommendations: • Regular ophthalmologic exams in those predisposed to retinal disease. • Ophthalmologic evaluation and dose reduction or withdrawal in anyone who develops symptoms.
2.4. Pulmonary Side Effects The pulmonary complications of hepatitis C therapy are very rare and most are found only as case reports. Pulmonary complications are primarily due to an interferon-mediated lung toxicity; however, ribavirin can cause dry cough and anemia-related dyspnea. The reported interferon-attributable lung complications include asthma exacerbations, pleural effusions, bronchiolitis obliterans with organizing pneumonia, or most commonly an interstitial pneumonitis. Typically, these complications have occurred months into interferon therapy. Kumar et al. reviewed the literature on the topic and found that by 2004, there were 32 reported cases of parenchymal lung disease in patients receiving interferon for hepatitis C (13). Almost half of the cases they reviewed were of interstitial pneumonitis, which is marked by the presence of dry cough, dyspnea, inspiratory crackles, and patchy infiltrates and/or consolidation on radiography. After interstitial pneumonitis, the
344
Fox and Faust
most commonly reported pulmonary complication of interferon treatment was a sarcoid-like reaction. Given the infrequent nature of pulmonary complications of HCV therapy, there are no formal recommendations on management in this setting. In the practice of pulmonary medicine, the typical treatment of interstitial pneumonitis is to remove the inciting agent; therefore, consideration must be given to the withdrawal of therapy. Many of the reported interstitial pneumonitis cases were treated with steroids; however, almost all of these patients recovered with or without corticosteroid treatment (14). Recommendations: • Pulmonary complications of combination therapy are rare; however, when they occur can cause significant parenchymal lung disease. • Pulmonary adverse effects usually occur months into interferon and ribavirin therapy. • Concerning pulmonary symptoms should lead to an evaluation which includes physical exam and chest radiography.
2.5. Endocrine Side Effects The two major endocrine side effects of interferon/ribavirin treatment are the development of diabetes and thyroid dysfunction. Both increased insulin resistance and insulin dependence have been reported. Those with a family history of type I or II diabetes may be at higher risk for developing diabetes. Schreuder et al. followed 189 nondiabetic patients being treated with pegylated interferon alfa and ribavirin and found that 2.6% developed type I diabetes mellitus, while 1.6% developed type II diabetes mellitus (18). Based on these findings, the authors suggested routine monitoring of blood glucose levels for patients undergoing antiviral therapy for chronic hepatitis C. An interferon-induced thyroiditis has been well described in the literature and is thought to consist of an autoimmune subtype and nonautoimmune subtype of disease (19). Typically, disease develops 6–12 months into therapy and patients can present with classic hyperthyroid or hypothyroid symptoms. The emergence of thyroid disease while on interferon/ribavirin therapy can usually be managed with symptomatic therapy or thyroid hormone replacement but can necessitate consultation with an endocrinologist for definitive treatment. Recommendations: • Both type I and type II diabetes can develop during combination therapy for chronic hepatitis C. • Routine monitoring of blood glucose should occur during follow-up visits.
Support of Patients During Antiviral Therapy for Hepatitis B and C
345
• Patients undergoing therapy for chronic hepatitis C should be screened for thyroid disease by obtaining a serum TSH at 3–6-month intervals. • Symptoms of thyroid disease should be assessed and if they develop should be investigated in consultation with an endocrinologist.
2.6. Dermatologic Side Effects In the landmark trial comparing peginterferon alfa-2b and ribavirin to standard interferon and ribavirin, over 18% of patients experienced a dermatologic side effect (2). The reported dermatologic complications of interferon/ribavirin treatment include injection site erythema/induration, an eczematous reaction, xerosis with pruritus, hyperpigmentation, photosensitivity, and alopecia (15). These reactions most commonly occur with interferon/ribavirin combination therapy; however, ribavirin is thought to be responsible for the most common rash, a generalized xerosis associated with pruritus, while interferon is responsible for injection side reactions. In the aforementioned peginterferon alfa-2b trial (2), 29% of patients experienced some degree of alopecia. The alopecia seen with interferon and ribavirin treatment is reversible with completion or withdrawal of therapy. Kartal et al. reported a case of alopecia universalis during treatment with peginterferon alfa-2b and ribavirin with hair regrowth beginning within 3 months after therapy completion (16). Management of these dermatologic complications has primarily been handled conservatively. Depending on the lesion or symptoms, patients have been treated with topical emollients, steroids, oral antihistamines, or even oral corticosteroids for more generalized reactions. Recommendations: • Over 18% of patients experience a dermatologic side effect while being treated with interferon and ribavirin. • Many of these side effects can be managed conservatively with topical steroids/emollients and oral antihistamines. • The alopecia experienced during combination treatment is reversible.
2.7. General Side Effects While generalized symptoms such as fatigue, nausea, vomiting, anorexia, and flu-like symptoms are rarely the cause for medication discontinuation in patients being treated for hepatitis C, they can impose a significant quality of life burden on patients. Up to 80% of patients on interferon therapy will experience the flu-like symptoms of low-grade fevers, fatigue, and myalgias. These symptoms are most common during the first month of therapy and occur predictably within 48 hours
346
Fox and Faust
of interferon injection. These symptoms should be managed conservatively with acetaminophen and NSAIDS. Anorexia, nausea, and vomiting are most likely attributed to interferon. These effects can be dose dependent but unless they are extremely severe, antiviral therapy should not be interrupted for those symptoms. Most commonly, antiemetic medications and dietary supplements can be prescribed to combat these symptoms. Results from a small retrospective cohort study recently suggested that oral cannabinoid-containing medications can be used to manage anorexia and nausea in patients being treated for chronic hepatitis C (20). The authors found that 64% of patients who were given the oral cannabinoid-containing medication had subjective improvement in symptoms. Likewise, the treatment group had a higher proportion of patients completing a full course of antiviral therapy and a higher percentage achieving a sustained viral response. Recommendations: • Flu-like symptoms are experienced by most patients during interferon therapy and can be managed conservatively. • Anorexia, nausea, and vomiting should likewise be managed conservatively with the aid of antiemetic medications and dietary supplements. There is investigation into the use of appetite stimulants; however, none are routinely utilized to combat anorexia in patients being treated for hepatitis C.
3. HEPATITIS B There are seven approved agents used to treat chronic hepatitis B (CHB). Selection of a singular agent or a combination of agents must be individualized and based on a variety of patient factors, disease factors, and the severity of liver disease. Unlike the treatment for hepatitis C, the treatment for hepatitis B can be indefinite, so recognition of a management strategy for side effects is paramount. The goal of this section is to outline the common side effects and management of the approved CHB therapies in a medication-based approach.
3.1. Standard Interferon Alfa-2b or Pegylated Interferon Alfa-2a Both standard and pegylated forms of interferon-␣ have been evaluated in clinical trials and are efficacious in decreasing hepatitis B DNA levels, causing loss of hepatitis B e antigen(HBeAg) and hepatitis B surface antigen(HBsAg), and conversion to hepatitis Be antibody (HBeAb) (21, 22). Interferon treatment for CHB carries with it all of
Support of Patients During Antiviral Therapy for Hepatitis B and C
347
the interferon-mediated side effects discussed in the hepatitis C section with the additional potential for a significant hepatitis flare. Approximately 25–40% of patients treated for CHB with interferon will experience a hepatitis flare, which can be life threatening (23). The interferon-mediated hepatitis flare typically occurs during the first few months of therapy and can indicate seroconversion from HBeAg to HBeAb. Mechanisms of a flare are thought to be related to interferon stimulation of cytotoxic T cells or an immune-mediated hepatocyte lysis. Depending on the severity of the flare, interferon therapy may need to be curtailed or stopped.
3.2. Lamivudine Lamivudine is a nucleoside analogue that incorporates into the viral DNA via HBV reverse transcriptase and results in chain termination. It is effective as a solo agent for the treatment of replicative hepatitis B and has also been used in combination with interferon and other antiviral agents; however, the long-term efficacy of those combinations remains under investigation. In general, lamivudine is a safe and effective medication; however, it has been associated with the development of a severe lactic acidosis, severe hepatomegaly with steatosis, emergence of viral resistance, posttreatment hepatitis flares, and pancreatitis. Given the frequent development of resistant viral mutants, the efficacy of lamivudine may be limited as a long-term therapy. Depending on the severity of these reactions, discontinuation of therapy may be necessitated.
3.3. Adefovir Dipivoxil Adefovir is a nucleotide reverse transcriptase inhibitor which acts by interfering with HBV DNA polymerase and inhibits viral replication. Adefovir has been proven effective in the treatment of both hepatitis B e antigen-positive and antigen-negative patients (24, 25). Like lamivudine, adefovir can cause a severe lactic acidosis, severe hepatomegaly with steatosis, viral resistance, and posttreatment hepatitis, which usually occur within 12 weeks of drug discontinuation and can occur in up to 25% of patients. The limiting toxicity of adefovir is that it can cause renal impairment at high doses and when used for a prolonged period. In the trial evaluating the efficacy of adefovir in HBeAg-positive patients, those receiving 30 mg had a higher rate of renal abnormalities than those receiving 10 mg (24). When HBeAg-negative patients were followed on adefovir for 5 years, 3% developed a ≥ 0.5 mg/dL increase in creatinine over baseline values (27).
348
Fox and Faust
3.4. Entecavir Entecavir is another nucleoside reverse transcriptase inhibitor that was approved by the Food and Drug Administration (FDA) in 2005 for the treatment of CHB. Entecavir has been proven efficacious in treating lamivudine-resistant CHB and also as a primary agent to improve virologic, biochemical, and histologic disease (27, 28). The quality of entecavir that makes it most desirable is its very low evidence of viral resistance. Similar to the other reverse transcriptase inhibitors, its most dangerous side effects are the occurrence of lactic acidosis, hepatomegaly with steatosis, and posttreatment hepatitis flare. There has been a warning issued with regard to the development of HIV resistance in those HIV-positive patients not on highly active antiretroviral therapy who are being treated with entecavir as HBV monotherapy (29).
3.5. Telbivudine Telbivudine is a nucleoside reverse transcriptase inhibitor approved to treat hepatitis B. In clinical trials, it has shown improved HBV clearance when compared with lamivudine and adefovir (30, 31). The major side effects are the same as seen with the other RTIs as well as a myopathy in association with elevated creatine kinase levels. There are emerging reports of increased rates of peripheral neuropathy when used in conjunction with pegylated interferon alfa-2a.
3.6. Tenofovir Tenofovir is the newest nucleotide analogue to be approved by the FDA. Its side effect profile is similar to that of adefovir. It has a propensity to cause renal dysfunction and needs to be dose reduced in patients with impaired creatinine clearance. Like the other agents described, it may cause hepatomegaly and lactic acidosis. Gastrointestinal side effects occur in about 10% of users and are usually mild. Recommendations: • Standard interferon-␣, pegylated interferon alfa, lamivudine, adefovir dipivoxil, entecavir, and telbivudine are the approved treatments for chronic hepatitis B. • All of the nucleotide/nucleoside reverse transcriptase inhibitors carry a risk of lactic acidosis, hepatomegaly with steatosis, and posttreatment hepatitis flare. • Lamivudine is associated with a high degree of viral resistance. • Adefovir can cause renal impairment when given at higher doses or for a prolonged period of time. • Entecavir has a very low rate of viral resistance but may be associated with HIV resistance in HIV-positive patients not on HAART.
Support of Patients During Antiviral Therapy for Hepatitis B and C
349
• Telbivudine has initially demonstrated increased antiviral activity when compared to adefovir and lamivudine; however, it may be associated with the development of a myopathy and when used in conjunction with peginterferon may cause a peripheral neuropathy. • Tenofovir is a potent antiviral with an excellent resistance profile. It may cause azotemia when used for prolonged periods of time.
4. CONCLUSION The therapies for chronic hepatitis B and C have dramatically evolved over the last decade. With the addition of new antiviral agents, we are seeing rates of viral suppression and elimination that have previously been unachievable. Principal in treating patients for chronic hepatitis is choosing a regimen that is suitable for an individual patient, disclosing the expected and potential side effects, and early identification and management of adverse effects. Despite the myriad side effects of these medications, we move closer to the goal of eradicating virus and preventing long-term sequelae of hepatitis infection.
REFERENCES 1. Fried MW, Shiffman ML, Reddy KR, Smith C, Mannos G, Goncales FL Jr., Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. NEJM 2002;347(13):975–82 2. Manns MP, McHitchinson JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus Ribavirin compared with interferon alfa-2b plus Ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358(9286):958–65 3. DeFranceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, Noventa F, Stanzial AM, Solero P, Corrocher R. Hemolytic anemia induced by Ribavirin therapy in patients with chronic hepatitis C virus infection: the role of membrane oxidative damage. Hepatology 2000;31(4):997–1004 4. McHutchinson JG, Manns MP, Longo DL. Definition and management of anemia in patients infected with Hepatitis C virus. Liver International 2006;26(4): 389–98 5. Afdhal NH, Dieterich, DT, Pockros PJ, Schiff ER, Schiffman ML, Sulkowski MS, Wright T, Younossi Z, Goon BL, Tang KL, Bowers PJ, Proactive Study Group. Epoetin alfa maintains Ribavirin dose in HCV-infected Patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004;126(5): 1302–11 6. McHutchinson JG, Dusheiko G, Shiffman M, Rodriguez-Torres M, Siagl S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH; TPL102357 Study Group. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. NEJM 2007;357:2227–36
350
Fox and Faust
7. Puoti M, Babudieri S, Rezza G, Viale P, Antonini MG, Maida I, Rossi S, Zanini B, Putzolu V, Fenu L, Baiguera C, Sassu S, Carosi G, Mura MS. Use of pegylated interferons is associated with an increased incidence of infections during combination treatment of chronic hepatitis C: a side effect of pegylation? Antivir Ther 2004;9(4):627–30 8. Antonini S, Babudieri I, Maida C, Baiguera B, Zanini B, Fenu L, Dettori G, Manno D, Mura MS, Carosi G, Puoti M. Incidence of neutropenia and infections during combination treatment of chronic hepatitis C with pegylated interferon alfa2a or alfa-2b Plus Ribavirin. Infection 2008;36:250–55 9. Koirala J, Gandotra SD, Rao S, Sangwan G, Mushtag A, Htwe TH, Adamski A, Blessman D, Khardori NM. Granulocyte Colony- Stimulating factor dosing in pegylated interferon alfa induced neutropenia and its impact on outcome of HCV therapy. J Viral Hepat. 2007;14(11):782–7 10. Schafer M, Schwaiger M, Garkisch AS,Pich M, Hinzpeter A, Uebelhack R, Heinz A, vanBoemmel F, Berg T. Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 2005;42(6): 793–8 11. Kraus MR, Schafer A, Schottker K, Keicher C, Weissbrich B, Hofbauer I, Scheurlen M. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut 2008;57(4):531–6 12. d’Alteroche L, Majzoub S, Lecuyer AI, Delplace MP, Bacq Y. Ophthalmologic side effects during alpha-interferon therapy for viral hepatitis. J Hepatol 2005;44:56–61 13. Midturi J, Sierra-Hoffman M, Hurley D, Winn R, Beissner R, Carpenter J. Spectrum of pulmonary toxicity associated with the use of interferon therapy for Hepatitis C: case report and review of the Literature. Clin Infect Dis 2004;39:1724–9 14. Kumar KS, Russo MW, Borczuk AC, Brown M, Esposito SP, Lobritto SJ, Jacobson IM, Brown RS. Significant pulmonary toxicity associated with interferon and Ribavirin therapy for Hepatitis C. Am J Gastroenterol 2002;97:2432–2440 15. Hashimoto Y, Kanto H, Itoh M. Adverse Skin Reactions due to pegylated interferon alpha-2b and Ribavirin combination therapy in a patient with chronic hepatitis C Virus. J Dermatol 2007;34:577–82 16. Kartal ED, Alpat SN, Ozgures I, Usluer G. Reversible alopecia universalis secondary to PEG-interferon alpha-2b and Ribavirin combination therapy in a patient with chronic hepatitis C Virus infection. Eur J Gastroenterol Hepatol 2007;19(9): 817–20 17. Chamberlain AJ, Poon E. Letter to the editor general correspondence: cutaneous reactions to interferon and Ribavirin. Internal Med J 2004;34:519 18. Schreuder TC, Gelderblom HC, Weegink CJ, Hamann D, Reesink HW, Derries JH, Hoekstra JB, Jansen PL. High incidence of Type I diabetes mellitus during or shortly after treatment with pegylated interferon alpha for chronic hepatitis C Virus infection. Liver Int 2008;28(1):39–46 19. Mandac J, Chaudhry S, Sherman KE, Tomer Y. The clinical and physiological spectrum of interferon-alpha inducted thyroiditis: toward a new classification. Hepatology 2006;43(4):661–72 20. Costiniuk C, Mills E, Cooper CL. Evaluation of oral cannabinoid-containing medications for the management of interferon and ribavirin-induced anorexia, nausea and weight loss in patients treated for chronic hepatitis C virus. Can J Gastroenterology 2008;22(4):376–80
Support of Patients During Antiviral Therapy for Hepatitis B and C
351
21. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcoate EJ. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Int Med 1993;119:312–23 22. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N. Peginterferon alfa-@a HBeAg-positive chronic hepatitis B study group. Peginterferon alfa-2a, lamivudine and the combination for HBeAg- Positive chronic hepatitis B. NEJM 2005;352(26):2682–95 23. Flink HJ, Sprengers D, Hansen BE, van Zonneveld M, de Man RA, Schalm SW, Janssen HLA; for the HBV 99-01 study group. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon a-2b therapy. Gut 2005;54:1604–9 24. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Bosgart CL; Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of Hepatitis B E antigen positive chronic hepatitis B. NEJM 2003;348(9):808–16 25. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzettoni, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL; Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of Hepatitis B E Antigen negative chronic hepatitis B. NEJM 2003;348(9):800–7 26. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzettoni, Marcellin P, Lim SG, Goodman Z, Ma J, Brosgart CL, Borroto-Esoda K, Arterburn S, Chuck S; Adefovir Dipivoxil 438 Study Group. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 Years. Gastro 2006;131(6):1743–51 27. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, BoronKaczmarska A, Martin P, Goodman Z, Colanno R, Cross A, Denisky G, Kreter B, Hindes R; AI463026 BEHoLD Study Group. Enetcavir for lamivudine-refractory HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130(7):2039–49 28. Chang TT, Gish RG, deMan R, Gadano A, Sallano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Collano R, Apelian D; BEHoLD AI 463022 Study Group. A comparison of entecavir and lamivudine fir HBeAg-Positive chronic hepatitis B. NEJM 2006;354(10):1001–10 29. Sasadeusz J, Audsley J, Mijch A, Baden R, Caro J, Hunter H, Matthews G, McMahon MA, Olender SA, Siliciano RF, Lewin SR, Thio CL. The anti-HIV activity of entecavir: a multicentre evaluation of lamivudine-experienced and lamivudine-Na¨ıve patients. AIDS 2008;22(8):947–55 30. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, DiBisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA; Globe Study Group. Telbivudine versus lamivudine in patients with chronic hepatitis B. NEJM 2007;357(25):2576–88 31. Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, Chao YC, Myers KP, Minuk GY, Jeffers L, Sievert W, Bzowej N, Harb G, Kaiser R, Qiao XJ, Brown NA; 018 Study Group. Treatment of Hepatitis B E antigen positive chronic hepatitis with Telbivudine or Adefovir: a randomized trial. Ann Int Med 2007;147(11):745–54
Viral Hepatitis, A Through E, In Pregnancy Eashen Liu, MD and Jacqueline Laurin, MD CONTENTS I NTRODUCTION E FFECT OF P REGNANCY ON L IVER F UNCTION V IRAL H EPATITIS IN P REGNANCY C ONCLUSIONS R EFERENCES
Key Principles
• Pregnancy causes physiological changes in liver function and biochemical testing, which should be recognized before embarking on an extensive workup of liver disease in pregnancy. • Viral hepatitis A through D does not affect the pregnant woman any differently. However, hepatitis E develops into fulminant hepatic failure in 25–70% of pregnant women. • The treatment for acute infection during pregnancy is similar to the treatment of adults who are not pregnant and consists mainly of supportive care. • It is recommended that all pregnant women undergo testing for HBsAg during an early prenatal visit even if they have been previously tested or vaccinated.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 14, C Humana Press, a part of Springer Science+Business Media, LLC 2009
353
354
Liu and Laurin
• Perinatal transmission represents one of the most common routes of transmission of chronic hepatitis B worldwide and probably accounts for more than half of the world’s chronic carriers. • A number of strategies have been employed to prevent mother-toinfant transmission. The most effective strategy is the combination of hepatitis B immune globulin (HBIG) and hepatitis B virus (HBV) vaccination within 12 h of birth followed by the completion of the vaccine series at 1 and 6 months of age. • Nucleos(t)ide analogue therapy with an FDA-approved anti-HBV agent is appropriate for managing CHB infection in mothers whose serum tests positive for HBsAg and who have high serum HBV DNA concentrations. • Vertical transmission of hepatitis D virus (HDV) has been reported but it is uncommon. The therapeutic strategies to prevent perinatal transmission of HBV are also effective in preventing the transmission of HDV • Vertical transmission of hepatitis C virus (HCV) is less common than in HBV infection but has been well documented. The treatment for acute and hepatitis C infection in pregnant women is supportive. • Breastfeeding is not contraindicated in women with hepatitis A virus (HAV) infection or chronic viral hepatitis B, C, or D. It is unclear at this time whether HEV transmission occurs while breastfeeding and therefore no formal recommendations can be made.
1. INTRODUCTION Jaundice during pregnancy may be the result of liver disease unique to pregnancy or a disease unrelated to pregnancy. Liver diseases unique to pregnancy include the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), acute fatty liver of pregnancy, and cholestasis of pregnancy. In the United States, viral hepatitis is the most common cause of jaundice in pregnancy. Viruses which uniquely cause hepatitis are hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D or delta hepatitis (HDV), and hepatitis E (HEV). Other viruses which may be associated with hepatitis include cytomegalovirus, Epstein–Barr virus, herpes simplex virus, varicellazoster virus, human parvovirus B19, and adenoviruses. The clinical course of hepatitis E is distinctive in pregnant woman. Otherwise, viral hepatitis does not differ between pregnant and nonpregnant populations (1).
Viral Hepatitis, A Through E, In Pregnancy
355
2. EFFECT OF PREGNANCY ON LIVER FUNCTION In evaluating the pregnant woman, one must be aware of how the gestational state affects liver function and other biochemical tests. There is a progressive increase in alkaline phosphatase to 1.5–2 times the nonpregnant values because of the release of placental and bone alkaline phosphatase. Also, leucine aminopeptidase levels progressively increase because of release by placental enzymes. There may be a slight increase in serum bilirubin because of mild impairment of bilirubin transport with decreased hepatic clearance caused by estrogen’s effect on organic anion-transporting pumps. Also, with impaired hepatic transport and biliary secretion caused by estrogen’s effect on bile-salt transport pumps, serum bile acids increase to 200–300% of nonpregnant values. Serum aminotransaminases do not change, nor does the prothrombin time (2, 3). Gamma-glutamyl transpeptidase levels are normal to low because of impaired release. Serum albumin levels decrease 10–60% because of hemodilution by expanded plasma volume and decrease in synthesis. Changes in physical examination occur during pregnancy as well. The liver, which is normally palpable 1–2 cm below the right costal margin, may become more difficult to palpate because of the expanding uterus within the abdominal cavity. Large amounts of estrogen and progesterone are produced by the placenta. As the liver cannot metabolize these hormones quickly, telangiectasia and palmar erythema, suggestive of liver disease in nonpregnant woman, may develop in up to 60% of normal pregnancies.
3. VIRAL HEPATITIS IN PREGNANCY Acute hepatitis, presumably viral, accounted for 40% of 654 cases of jaundice during pregnancy reviewed in the 1950s and 1960s (2, 4–6). A review of hepatitis in pregnancy from Parkland Hospital in Dallas noted an incidence of 1 in 700 deliveries (7). Viral hepatitis A through D does not manifest differently in pregnant women compared to men or nonpregnant women. Also, the laboratory manifestations are similar in pregnant and nonpregnant populations (1). In developed countries, maternal mortality from fulminant hepatic failure is low, about 1.2% (2, 8). However, reports from India (9), the Middle East (10), and Africa (11) describe disease of greater severity, often leading to fulminant hepatitis, particularly in the third trimester, with maternal mortality rates of about 30%. Studies in Israel have shown a reduction in mortality among pregnant women with viral hepatitis during pregnancy as socioeconomic class in the country has risen (12). The higher mortality in underdeveloped countries may be due to poor
356
Liu and Laurin
nutritional status and inadequate prenatal care. Hepatitis E develops into fulminant hepatic failure in 25–70% of pregnant women. Many series report mother and infant mortality rates of almost 100% in hepatitis Einduced fulminant hepatitis. Acute viral hepatitis is associated with premature birth in about 25% of cases (range 8–54%) and a fetal/neonatal death rate of 8% in developed countries such as the United States, Australia, and Israel and about 50% in India and the Middle East (2).
3.1. Hepatitis A Hepatitis A (HAV) virus was identified in 1973. It is a single-stranded RNA virus belonging to the family Picornaviridae (13). The incidence of hepatitis A varies globally. According to the CDC, high areas of prevalence include Greenland, Mexico, Central America, South America, Africa, the Middle East, and all of Asia. Intermediately prevalent areas include Eastern Europe, territories formally known as the Soviet Union and the Siberian peninsula. Low prevalence areas include the United States, Canada, Western Europe, Scandinavia, Australia, and New Zealand. The incidence in the United States in 2005 was 1.5 per 100,000, which is the lowest reported rate in United States history (14). The main mode of transmission is fecal-oral and most patients that acquire the illness have had direct contact with an infected person. Rare cases of parenteral transmission have been reported. In the United States, a higher incidence of hepatitis A occurs in areas where sanitation and/or hygiene are poor. Outbreaks have occurred with contaminated water, food, such as imported green onions from Mexico, contaminated frozen strawberries or shellfish, and within neonatal units or daycare centers (15–17). Vertical transmission of hepatitis A is extremely rare. The incubation period is usually 30 days, with a range of 15–40 days. Among children and adolescents, 80% are asymptomatic and without jaundice. However, more than 80% of infected adults develop jaundice. The presentation does not differ with pregnancy; it begins with acute constitutional symptoms of fevers, chills, fatigue, nausea, vomiting, anorexia, right upper quadrant pain, and occasionally diarrhea, progressing to dark urine, acholic stool, jaundice, and pruritus. The disease is self-limited with no long-term sequela. Relapsing disease has been reported and no unique risk factors have been identified for individuals who relapse after full recovery. Rarely, intrahepatic cholestasis with prolonged jaundice and pruritus may occur. Hepatitis A rarely causes fulminant hepatitis and the fatality rate is <0.1% (18, 19). There is an increased incidence of fulminant hepatitis occurring during the third trimester of pregnancy; however, fulminant hepatitis has been reported only in populations where prenatal care is not as available or nutrition
Viral Hepatitis, A Through E, In Pregnancy
357
not as plentiful, such as India, the Middle East, and Africa (9–11). Atypical presentations of hepatitis A occurring in pregnancy have included acalculous cholecystitis in a rare case report (20). Cases that have been identified during pregnancy are usually a result of the pregnant mother having direct contact with an infected person. There are no reported cases of transmission through breast milk. Perinatal transmission of hepatitis A from an infected mother to the fetus has been described in two case reports. The mothers are described as being infected within the first trimester and the fetuses subsequently develop meconium peritonitis from perforation of the terminal ileum. The fetuses recovered fully after postdelivery bowel resection. The authors suggest serial ultrasonographic examinations after maternal hepatitis A for detection of fetal ascites and meconium peritonitis (21, 22). HAV can be isolated from the stool and other body fluids, which typically can be identified before the identification of antibodies in the serum. The gold standard for diagnosis is serum anti-HAV IgM with clinical symptoms of acute infection. The anti-HAV IgM can persist for months and a positive result does not necessarily mean active infection. Anti-HAV IgG can be detected as early as the convalescent phase and persist for decades (23–25). If a pregnant woman reports exposure, two options are available to prevent the acute infection: hepatitis A vaccination and immune serum globulin. The immune serum globulin is most useful if given within 2 weeks of known exposure. The administration of immune serum globulin gives months of immunoprotection, while the vaccination will produce immunity that lasts for a lifetime. The vaccine is more than 85% effective in preventing acute infection. Vaccination is not routine in the United States, unless the woman falls into a high-risk population, has known exposure, has underlying liver disease, or has a travel history to an endemic area. The vaccine is considered safe in pregnancy, since it contains an inactivated form of the virus. The administration of immune serum globulin does have side effects and carries risk of infection with other viruses since it is derived from a pool of donors. Therefore, it should be reserved for patients that have allergies to the vaccine (26–29). The treatment for acute infection during pregnancy is similar to the treatment of adults who are not pregnant, which is supportive care. Antiemetics with potential teratogenic properties should be avoided or minimized. Hospitalization becomes necessary if the woman develops severe hepatitis manifested by markedly elevated aminotransaminases, usually greater than 1000 IU/L, elevated prothrombin time, hypoglycemia, jaundice, or acute mental status changes. In this case,
358
Liu and Laurin
the woman should be admitted to a hospital where liver transplantation is available. Other possible reasons to hospitalize pregnant women with acute illness include inability to self-hydrate. Vertical transmission of hepatitis A is rare. Infants born to mothers with acute hepatitis A may be given immune serum globulin and the first dose of the hepatitis A vaccine immediately after delivery and this may be repeated at 5–6 months of age (30, 31). There have not been any reported cases of transmission of hepatitis A with breastfeeding, which is safe.
3.2. Hepatitis E Hepatitis E virus (HEV) is an enterically transmitted hepatitis virus that causes large-scale epidemics and sporadic cases of acute viral hepatitis in developing countries. As with hepatitis A, hepatitis E causes acute hepatitis; chronic infection never develops. Prior to the identification of hepatitis E, this virus was called “waterborne or enterically transmitted non-A and non-B hepatitis.” It is a single-stranded RNA virus that has characteristics similar to the Caliciviridae family (32, 33). The highest incidences of acute hepatitis E occurs in Asia, Africa, the Middle East, and Central America. Sporadic cases have been documented in Western countries. The main source of transmission of HEV is drinking water contaminated with sewage causing large waterborne outbreaks. Infection among household contacts indicates that person-toperson spread may also occur and transmission with blood transfusions has been reported. The mean incubation time is about 45 days, with a range from 15 to 60 days (34, 35). In men and nonpregnant women, the disease is usually self-limited with a mild disease presentation. Most common symptoms include nausea, vomiting, abdominal pain, fever, and jaundice. Other signs and symptoms include diarrhea, arthralgias, pruritus, and urticarial rash. Fulminant hepatitis can occur, although it is rare. The overall fatality rate associated with men and nonpregnant women with HEV infection is <0.1%. However, in pregnant women, HEV infection is more severe, often leading to fulminant hepatic failure and death in up to 15–20% of cases. Acute infection has not been associated with the development of chronic hepatitis. Laboratory abnormalities include elevated serum bilirubin, alanine aminotransaminase (ALT), and aspartate aminotransaminase (AST). Resolution of these laboratory abnormalities can take 1–6 weeks (36–40). The diagnosis of acute hepatitis E is made with a positive anti-HEV IgM and anti-HEV IgG is detectable in the convalescent phase or after the acute infection has resolved.
Viral Hepatitis, A Through E, In Pregnancy
359
A 2007 report from a tertiary hospital in India followed 220 consecutive pregnant women presenting with jaundice caused by acute viral hepatitis. Infection with HEV caused acute viral hepatitis in 60% of included women (41). Fulminant hepatic failure (FHF) was more common [relative risk, 2.7 (95% DI, 1.7–4.2); P = 0.001] and maternal mortality was greater [relative risk, 6.0 (CI 2.7–13.3); P <0.001] in HEVinfected women than in non-HEV-infected women. The overall maternal mortality rate was 41% (54/132) in HEV-infected women and 7% (6/88) in non-HEV-infected women and occurred exclusively in women with FHF. FHF was more common among HEV-infected women than non-HEV-infected women [73 of 132 (55%) vs. 18 of 88 (0%)]. FHF particularly affected HEV-infected women in their third trimester [46 of 88 (52%) vs. 11 of 71 (15%) non-HEV-infected women]. The frequency of FHF did not differ between HEV-infected women and non-HEVinfected women in their second trimester. More HEV-infected women died, had obstetric complications, or had worse fetal outcomes than did women who had jaundice and acute viral hepatitis caused by other hepatitis viruses. The mechanism of vertical transmission is unclear at this time. Previous studies have demonstrated vertical transmission in five newborns whose mothers had developed HEV in the third trimester and delivered vaginally. Vertical transmission was also documented in 26 cases of HEV RNA-positive women by testing for HEV RNA in cord blood or newborn blood. However, the possibility of contamination of cord blood with the maternal blood could not be excluded. It is unclear at this time whether transmission occurs while breastfeeding and therefore no formal recommendations can be made. The reasons for the high frequency of FHF, in pregnant women with HEV infection, are unclear. A shift in the Th1–Th2 balance toward a Th2 response in pregnant but not in nonpregnant women with HEV infection may point toward a primary immunologic cause of severe disease in pregnancy. Also, hormones of pregnancy, i.e., estrogen and progesterone, may impair cellular immunity by triggering an adapter protein (ORF3 of HEV), which could facilitate viral replication and lead to release of cytokines and liver cell apoptosis (42–44). Treatment for HEV infection is supportive care. There are current clinical trials evaluating vaccines for prevention and treatment, which have been shown to prevent transmission in 96% of their participants. Intravenous immune serum globulin has also been used for prophylaxis and initial treatment after exposure. However, it has not been shown to decrease mortality or duration of symptoms (45, 46). Because of the high mortality rate and lack of effective treatment of acute infection, prevention of HEV infection in pregnant women is of
360
Liu and Laurin
utmost importance. Pregnant women should be advised to avoid travel to endemic areas, to avoid drinking water of unknown purity, uncooked shellfish, and uncooked fruits and vegetables from endemic areas.
3.3. Hepatitis B Hepatitis B virus (HBV) is a double-stranded DNA virus in the family Hepadnaviridae (47). Hepatitis B is a major global health problem. Of the 2 billion who have been infected, more than 350 million are chronic carriers (48–50). 3.3.1. P ERINATAL T RANSMISSION This is the major mode of disease acquisition in endemic areas, accounting for 90% of the affected population. The risk of perinatal transmission is associated with maternal hepatitis B e antigen status and viral load. The HBV transmission rate of HBeAg-positive mothers to their infants is higher, 70–90%, compared with HBeAg-negative, antiHBe-positive mothers, 5–20%. Similarly, a high maternal viral load, greater than 5 pg/ml, was associated with a higher rate of perinatal transmission (51, 52). The mode of perinatal transmission is presumed to be via exposure to maternal blood during passage through the birth canal or immediately postdelivery, or from exposure in utero. Studies examining rates of HBsAg, HBeAg, or HBV DNA detection in cord blood or infant sera within 24 h of delivery suggested that in utero infection was not a significant mode of transmission, accounting for less than 5% of cases of perinatal transmission (53,54). Rates of in utero transmission may be increased during acute HBV infection in the third trimester of pregnancy or if a history of threatened preterm labor was present (54). Bhat and Anderson (55) have shown that HBV has the ability to translocate across the trophoblastic layer of the early placenta during the first trimester, which is a possible mechanism of intrauterine infection. 3.3.2. P ROPHYLAXIS TO P REVENT P ERINATAL T RANSMISSION According to the Centers for Disease Control and Prevention (CDC) in the United States, in an infant born to a mother who is positive for both HBsAg and HBeAg, the risk of chronic HBV infection is 70–90% by the age of 6 months without the use of postexposure immunoprophylaxis. In mothers who are HBsAg-positive and HBeAg-negative, the risk for chronic infection is <10% in the absence of postexposure immunoprophylaxis (56, 57). Cases of fulminant hepatitis B as a result of perinatal transmission have been reported, although much less so than the development of chronic disease. A report by Friedt et al.
Viral Hepatitis, A Through E, In Pregnancy
361
proposed that selection for an HBeAg-negative strain is responsible for the rare development of fulminant hepatitis in the fetus (62). A number of strategies have been employed to prevent mother-toinfant transmission: the use of HBIG alone, HBV vaccine alone, or the combination of HBIG plus HBV vaccine. All strategies have varying success in preventing acquisition of HBV in the newborn, but the most effective strategy is the combination of HBIG (.06 ml/kg IM) plus HBV vaccination within 12 h of birth followed by the completion of the vaccine series at 1 and 6 months of age. This strategy was 89–98% effective at preventing acute and chronic hepatitis B in infants born to HBsAg/HBeAg-positive women (58,59). 3.3.3. S CREENING OF P REGNANT W OMEN A long-term study of the prevalence of hepatitis B seropositivity among pregnant women in the United States was reported by Euler et al. in 2003. They found that of 10,523 women in four urban centers, 0.97% of blacks, 0.6% of whites, 0.14% of Hispanics, and 5.79% of AsianAmericans were seropositive for the HBV with a positive hepatitis B surface antigen (51). In the United States, the Advisory Committee on Immunization Practices (ACIP) recommended testing of all pregnant women for HBsAg during an early prenatal visit, even though previously tested or vaccinated (60). Women who were not screened prenatally, or who engaged in high-risk behavior, had an HBsAg-positive sex partner, or those treated for sexually transmitted disorders should be tested at the time of admission to the hospital for delivery. If HBsAg testing is not available, it is recommended to vaccinate the neonate within 12 h of birth and to complete the vaccine schedule according to that recommended for infants born to HBsAg-positive mothers. 3.3.4. P OSTEXPOSURE P ROPHYLAXIS D URING P REGNANCY Postexposure prophylaxis using hepatitis B immune globulin (HBIG) and active vaccination during pregnancy appears to be safe for both mother and fetus (61–67). The Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis reported that there was no apparent risk for adverse effects toward developing fetuses when hepatitis B vaccine was administered to pregnant women (56). Therefore, postexposure prophylaxis should be offered to all pregnant women. Breastfeeding and HBV: Before the availability of HBV vaccine and HBIG, several case series have shown transmission of HBV through breast milk. Although the mechanism of transmission by breast milk was unclear, many physicians did not recommend breastfeeding to
362
Liu and Laurin
mothers with HBV. Now, breastfeeding is considered safe whether the mother has acute HBV, chronic HBV infection, or a carrier HBV state as long as the infant receives a full course of the hepatitis B vaccine series with the first dose being given within 12 h of birth in combination with hepatitis B immunoglobulin. These recommendations are based on prospective longitudinal studies done by Hill, Sheffield et al. (63). Neither the World Health Organization (WHO) nor the CDC discourages breastfeeding between a mother with HBV and her infant as long as the HBV vaccine series was given at birth or HBIG and the vaccine was given within 12 hours of birth. 3.3.5. M ATERNAL O UTCOME IN P REGNANCY A recent investigation of women infected with hepatitis B who had 38 pregnancies between 1998 and 2006 revealed that there was an increase in liver disease activity in 45% of the women in the months following delivery (64). Predicting who was going to have an exacerbation during pregnancy was not possible using HBV DNA level, ALT, or HBeAg status. Even in those women treated with lamivudine during the last trimester of pregnancy, this exacerbation occurred 62% of the time. The researchers concluded that a significant increase in liver inflammation can often occur after pregnancy, perhaps due to reactivation of the immune system after delivery. Women should be monitored closely after delivery and treated if necessary. 3.3.6. T REATMENT OF HBV IN P REGNANCY A strategy to reduce vertical transmission of HBV infection is administering lamivudine during pregnancy (65). The first report of lamivudine therapy during pregnancy was by van Zonneveld M et al. in The Netherlands (68). They treated eight mothers with HBV infection and high viral loads, >1.2 × 109 genome Eq/mL, with lamivudine 150 mg daily during the last month of pregnancy. HBV DNA level, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb) of the infants were measured at birth and at 3, 6, and 12 months, respectively. Twenty-four children born to untreated HBsAg-seropositive mothers with HBV-DNA levels greater than or equal to 1.2 × 109 genome Eq/L served as historical controls. All the children received passive–active immunization with HBIG 30 IU at birth and hepatitis B vaccine at 2, 3, 4, and 11 months of age. Seven of the eight mothers who received lamivudine had a reduction in serum HBV DNA concentration; serum HBV concentrations were less than 1.2 × 108 genome Eq/mL in five of these mothers. Maternal ALT levels were normal or near normal at the time of delivery (range, 20–49 U/L). At follow-up 1–7 months post delivery, ALT levels had increased
Viral Hepatitis, A Through E, In Pregnancy
363
in seven women but remained below five times the upper limit of normal in all eight participants. In the lamivudine-treated group, one of the eight (12.5%) infants who tested positive for HBsAg had a detectable serum HBV DNA concentration at the age of 12 months. Among the 24 untreated historical control subjects, perinatal transmission occurred in 7 (28%) infants. There were no obvious adverse effects from lamivudine in the mothers or in the infants born to mothers in the treatment group. A multicenter, randomized, double-blind, placebo-controlled study from Xu et al. (69) strongly suggests that the use of lamivudine in the third trimester of pregnancy is more effective than passive and active immunization alone in reducing vertical transmission in mothers with high serum HBV DNA concentrations. One hundred and fourteen HBVinfected mothers with HBV DNA greater than 1000 Meg/mL were randomized to receive either lamivudine 100 mg daily (n = 68) beginning at the 32nd week of gestation and continuing until 4 weeks postpartum or matched placebo (n = 52). All of the infants received standard prophylaxis with HBIG within 24 h of birth and vaccination with recombinant HBV vaccine; three injections over the first 6 months of life. The proportion of mothers with serum HBV DNA levels less than or equal to 1000 Meq/mL at the time of delivery was higher in the lamivudine than the placebo group [55/56 (98%) vs. 18/59 (31%), respectively]. Infants born to mothers with a lower serum viral load had a lower likelihood of HBsAg positivity at 1 year of age (84 and 61%; p = 0.008). The incidence of adverse effects in the mothers and infants was not significantly different in the two groups (17, 9). The authors suggested that lamivudine should be considered for use in the third trimester in HBV-infected mothers with high serum HBV DNA concentrations. Thus, nucleos(t)ide analogue therapy with an FDA-approved antiHBV agent is appropriate for managing HBV infection in mothers whose serum tests positive for HBsAg and who have high serum HBV DNA concentrations. The five oral nucleos(t)ide analogues are listed as either a category B or a category C agent by the FDA. Category B drugs are those that, according to the results of animal studies, carry no teratogenic or embryonic risk and for which there have been no controlled human studies to refute these findings. Category C drugs are those that exert teratogenic or embryocidal effects on animals and for which there are no controlled studies in humans. Lamivudine, adefovir, and entecavir are designated category C drugs; telbivudine and tenofovir are category B drugs (65). In her review of the Antiretroviral Pregnancy Registry 2006, Terrault (65, 70) reports that more than 4000 women have been treated with lamivudine, making it the anti-HBV therapy most extensively used in
364
Liu and Laurin
pregnancy. This report notes that between 1989 and 2006, the rate of birth defects among 1662 women who were exposed to lamivudine during the first trimester of pregnancy was 2.7% [95% confidence interval (CI), 2.0–3.6%]. Among 3000 women who were exposed during the second or third trimester, the rate of birth defects was 2.4% (95% CI, 1.9–3.1%). These birth defect rates are similar to the rate of major birth defects in live births in the general populations (3%, according to the Center for Disease Control and Prevention). There has been only limited use of the other nucleos(t)ide analogues, adefovir, entecavir, telbivudine, or tenofovir during pregnancy. Thus lamivudine is considered the treatment of choice for pregnancy women with HBV infection, although the use of any agents remains controversial (65). Terrault notes there are no consensus guidelines for the treatment of hepatitis B in women who become pregnant during the course of antiviral therapy. For patients who become aware of their pregnancy during the first several weeks of gestation, one option is to stop therapy, monitor HBV DNA levels and ALT throughout the pregnancy, and restart therapy during the postpartum period. Other options are to continue therapy or to switch to lamivudine or to a category B agent. For pregnant women with treatment-na¨ıve HBV infection, prophylactic therapy may be considered during the third trimester of pregnancy. However, Keeffe et al. (71) caution that therapy should be postponed until after pregnancy in women with mild liver disease. All women of childbearing age and infected with HBV should be counseled about the various treatment options for HBV and the associated risks of each. For mothers with serum HBV DNA concentrations of 108 or higher, antiviral therapy during the third trimester may be considered as a means of reducing the risk of perinatal HBV transmission (65).
3.4. Hepatitis D (Delta) Delta hepatitis is caused by an RNA virus that can only replicate in the presence of HBV, which acts as a helper virus. Infection occurs only in persons with hepatitis B, with hepatitis D being acquired as a coinfection, i.e., simultaneous infection with HBV and HDV, or as a superinfection in a person who is already HBsAg-positive. HDV infection in chronic HBV carriers is associated with more active and progressive disease and cases of fulminant hepatic failure have been reported. The modes of transmission are the same as with HBV (72, 73). Vertical transmission of HDV has been reported but it is uncommon. The therapeutic strategies to prevent perinatal transmission of HBV are also effective in preventing the transmission of HDV. Since HDV cannot
Viral Hepatitis, A Through E, In Pregnancy
365
be transmitted in the absence of HBV, routine vaccination of all newborn infants with the HBV vaccine will protect against HDV (74).
3.5. Hepatitis C Hepatitis C virus (HCV) is one of the leading known causes of liver disease in the United States (75, 76). The prevalence among pregnant women varies from 1 to 5%, with more cases seen in the urban population. There is ethnic variation, with HCV being more prevalent among African-Americans (6.1%) than nonHispanic Caucasians (3.1%) and Hispanics (2.8%) (77, 78). HCV is not spread by breastfeeding, even in mothers whose milk contains HCV RNA, casual contact, sharing eating utensils or drinking glasses, food, or water (79). The World Health Organization and Center for Disease Control recommend breastfeeding. Infected mothers should put breastfeeding on hold if their nipples are cracked or bleeding. 3.5.1. S CREENING OF P REGNANT W OMEN In the United States, routine screening of pregnant women for HCV is not recommended. Pregnancy screening for HCV is recommended only in women who have a history of IV drug use or a partner with drug use, have a history of receiving blood, blood products, or organ transplant before 1992, have received hemodialysis, have HIV or hepatitis B infection, have elevated liver enzymes, or have a history of tattooing (80, 81). Initial screening is performed by identification of the hepatic C antibody by enzyme immunoassay. This test is 97% sensitive and 99% specific. Confirmation of a positive antibody test may be performed with the recombinant immunoblot assay (RIBA) against specific antigens. The antibody may not develop in some infected individuals until 2–8 weeks after evidence of liver injury and may not be present in patients with initial signs and symptoms of disease. Active infection is diagnosed with a reverse transcriptase polymerase chain reaction (RT-PCR) assay to determine viral load (82). 3.5.2. V ERTICAL T RANSMISSION OF HCV Mother-to-infant, vertical, transmission of HCV is less common than in HBV infection, but transmission has been well documented. The risk of vertical transmission is approximately 2% for infants of hepatitis C antibody-positive mothers. When a pregnant women is HCV RNA-positive at delivery, the risk increases to 4–7%. Regardless of HIV status, a viral load of greater than 1 × 10 5 copies/mL has been shown to increase the rate of transmission (83, 84). The highest rate of vertical transmission occurs in mothers who have HCV with HIV coinfection. Transmission rates increase to 20% in this coinfected group.
366
Liu and Laurin
This increased risk is likely due to high viremia (85). The pathogenesis of transmission is unclear. It seems to occur in utero and perinatally; there have been no documented cases of postnatal transmission between mother and infant. Among 54 HCV-infected children, 17 (31%) were positive in the first 3 days of life and were assumed to have acquired the infection in utero. These children with evidence of intrauterine infection were significantly more likely to be of lower birth weight and infected with genotype 1 (58% vs. 12%, p = 0.01). HIV coinfection did not significantly increase the risk of in utero transmission of HCV. Twentyseven of the children (50%) were first HCV RNA PCR-positive at 3 months, nine (5%)were first HCV RNA PCR-positive after 3 months, and one had no further tests (86). The mode of delivery has not been shown to affect the vertical transmission rate (3.5). Some observational studies show a decreased rate of transmission between vaginal and caesarean section; however, most studies do not (87). In the European Pediatric Hepatitis C Virus Network study, the women with HCV infection showed no difference in transmission rate with caesarean vs. vaginal delivery (odds ratio = 1.46; p = 0.16). In women coinfected with HCV and HIV, caesarean delivery is protective against HCV transmission (odds ratio = 0.36; p = 0.01), but in those who received antiretroviral treatment, this protective effect is not evident. A cost-effective analysis by Plunkett et al. noted that an elective caesarean section is cost-effective only if it reduces the risk of perinatal transmission by greater than 77%. Studies have not shown this reduction in the risk of HCV perinatal transmission with caesarean section (88). Steininger et al. reported an increased risk of transmission of HCV with intrapartum exposure to virus-contaminated maternal blood during vaginal delivery (89). Other possible risk factors are ruptured membrane >6 h prior to delivery, internal fetal monitoring or fetal blood sampling, and the presence of HCV in maternal mononuclear cells (78). Avoiding fetal scalp monitoring and prolonged labor after rupture membranes may reduce the risk of transmission to the infant. Finally, a Cochrane collaboration review by McIntyre et al. does not recommend one mode of delivery over the next, based on the fact that no randomized clinical trails have been done and that in published studies on this subject, HIV- and HCV-coinfected mothers were combined with HIV-negative mothers (90). Vertically acquired HCV infection predominantly is asymptomatic in infancy, although elevated alanine aminotransaminase levels in the first 6–12 months of life have been observed. Infants born to HCV-positive mothers should be tested for HCV infection by serum HCV RNA tests on two occasions between the ages of 2 and 6 months and/or have HCV antibody tests after 15 months of age. Positive HCV antibody in infants
Viral Hepatitis, A Through E, In Pregnancy
367
prior to 15 months of age may be due to transplacental transfer of maternal HCV antibody (82). The long-term outcome of vertically infected infants is unknown. Limited data indicate that less than 10% of the infected children develop chronic hepatitis and less than 5% develop cirrhosis (78). The treatment for acute and hepatitis C infection in pregnant women is supportive. The Federal Drug Administration approved treatment for chronic HCV is ribavirin and pegylated interferon. Ribavirin has been shown to be teratogenic in rodents and is considered a category X for use in pregnancy. Interferon has been shown to increase the incidence of fetal loss and low birthweight in some studies (91). On the other hand, there are several case reports of pregnant women being treated with interferon during the early part of pregnancy, without any problems being reported in the fetus; however, the cases are few (92–95). There are no data to determine whether antiviral therapy reduces perinatal transmission of HCV and treatment is not recommended. There is currently no active or passive immunization available for HCV. The virus genome mutates rapidly making vaccine development difficult. In addition, in chimpanzees, primary infection does not protect against subsequent infection to the same viral strain or a heterologous strain. To date, there are no trials to conclude that intravenous immunoglobulin can decrease transmission of infection.
4. CONCLUSIONS The clinical presentation of acute viral hepatitis in a pregnant women is not different than that in a man or a nonpregnant woman. Acute viral hepatitis increases the risk of premature delivery and fetal/neonatal death rate, especially in developing countries. Infants whose mothers have acute hepatitis A at delivery can be protected against infection with HAV vaccination or immune serum globulin. HEV infection in pregnancy is associated with a high maternal and infant mortality rate and there is no effective treatment. HEV vaccine development shows promising results but is not available for widespread use. Infants can be protected from acquiring HBV and HDV from mothers with acute or chronic HBV infection or HBV plus HDV coinfection with hepatitis B vaccine and hepatitis B immune serum globulin. This active plus passive immunization may fail when the mother has high serum HBV DNA levels. Infants may contract HCV infection from their mothers in the perinatal period. The risk is highest in women with high serum HCV RNA levels, which is more commonly seen in those mothers with HIV coinfection. There is no active or passive immunization available against hepatitis C.
368
Liu and Laurin
If treatment guidelines are used, i.e., passive or active immunization and treatment for HIV infection in those mothers with coinfection, caesarean section does not decrease the risk of transmission of viral hepatitis to the infant. Breastfeeding is not contraindicated in women with HAV infection or chronic viral hepatitis B, C, or D. It is unclear at this time whether HEV transmission occurs while breastfeeding and therefore no formal recommendations can be made.
REFERENCES 1. Mishra L, Seeff, L. Viral Hepatitis, A through E, complicating pregnancy. Gastroenterology Clinics of North America 1992;21:873–887. 2. Van Dyke RW. The liver in pregnancy. In: Boyer TD, Wright TL, Manns MP, eds, Zakim and Boyer’s Hepatology, A Textbook of Liver Diseases, 5th Edition, Saunders, Elsevier 2006, pp 1003–1029. 3. Seymour CA, Chadwick VS. Liver and gastrointestinal function in pregnancy. Postgrad Med J 1979;55:343–52. 4. Haemmerli P. Jaundice during pregnancy with special emphasis on recurrent jaundice during pregnancy and its differential diagnosis. Acta Med Scand 1966;179(suppl 444):1. 5. Thorling L. Jaundice in pregnancy; a clinical study. Acta Med Scand 1955;302: 1–123. 6. Friedlander P, Osler M. Icterus and pregnancy. Am J Obstet Gynecol 1967;97:894. 7. Hieber JP, Dalton D, Shorey J, Combes B. Hepatitis and pregnancy. J Pediatr 1977;91:545–9. 8. Hsia DY, Taylor RG, Gellis SS. A long-term follow-up of infectious hepatitis during pregnancy. J Pediatr 1952;41:13–7. 9. Tripathi BM, Misra NP. Viral hepatitis with pregnancy. J Assoc Physicians India 1981;29:463–9. 10. Delons S, Berbich A, Reynaud R, Lebon P. Severe jaundice in pregnant woman in Morocco. Rev Med Chir Mal Foie 1968;43:117–30. 11. Tsega E. Viral hepatitis during pregnancy in Ethiopa. East Afr Med J 1976;53: 270–7. 12. Shalev E, Bassan HM. Viral hepatitis during pregnancy in Israel. Int J Gynaecol Obset 1982;20:73–8. 13. Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science 1973;182:1026–8. 14. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of vaccination. JAMA 2005;294:194–201. 15. CDC. Hepatitis surveillance report no 56. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, CDC, 1995. 16. Dentinger CM, Bower WA, Nainan OV, et al. An outbreak of hepatitis A associated with green onions. J Infect Dis. 2001;183:1273–6. 17. Wheeler C, Vogt TM, Armstrong GL, et al. An outbreak of hepatitis A associated with green onions. N Engl J Med 2005;353:890–7.
Viral Hepatitis, A Through E, In Pregnancy
369
18. Lednar WM, Lemon SM, Kirkpatrick JW, et al. Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 1985;122:226–33. 19. Taylor RM, Davern T, Munoz S, et al. Fulminant hepatitis A virus infection in the United States: Incidence, prognosis, and outcomes. Hepatology 2006;44:1589–97. 20. Basar O, Kisacik B, Bozdogan E, et al. An unusual cause of acalculous cholecystitis during pregnancy: hepatitis A virus. Dig Dis Sci 2005;50:1532. 21. McDuffie RS Jr, Bader T. Fetal meconium peritonitis after maternal hepatitis A. Am J Obstet Gynecol. 1999;180:1031–2. 22. Leikin E, Lysikiewicz A, Garry D, Tejani N. Intrauterine transmission of hepatitis A virus. Obstet Gynecol 1996;88(4 Pt 2):690–1. 23. Wasley A, Miller JT, Sinelli, L. CDC. Surveillance for acute viral hepatitis— United States, 2005. MMWR Surveill Summ 2007;56:1–24. 24. CDC. Positive test results for acute hepatitis A virus infection among persons with no recent history of acute hepatitis—United States, 2002–2004. MMWR 2005;54:453–6. 25. Wesley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis—United States, 2006. MMWR 2008;57:1–24. 26. Duff B, Duff P. Hepatitis A vaccine: ready for prime time. Obstet Gynec 1998;91:468–71. 27. Stokers J, Neefe JR. The prevention and attenuation of infectious hepatitis by gamma globulin: Preliminary note. JAMA 1945;127:144. 28. Winokur PL, Stapleton JT. Immunoglobulin prophylaxis for hepatitis A. Clin Infect Dis 1992;14:580–6. 29. Conrad ME, Lemon SM. Prevention of endemic icteric viral hepatitis by administration of immune serum gamma globulin. J Infect Dis 1987;156:56–63. 30. Michielsen PP, Van Damme P. Viral hepatitis and pregnancy. Acta Gastroenterol Belg 1999;62:21–9. 31. Urganci N, Arapoglu M, Akyildiz B, Nuhoglu A. Neonatal cholestasis resulting from vertical transmission of hepatitis A infection. Pediatr Infect Dis J 2003;22:381–2. 32. Balayan MS, Andjaparidze AG, Savinskaya SS et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 1983;20: 23–31. 33. Krawczynski K, Bradley DW. Enterically transmitted non-A, non-B hepatitis: identification of virus-associated antigen in experimentally infected cynomolgus macaques. J Infect Dis 1989;159:1042–9. 34. Sarin SK, Kumar M. Hepatitis E. In: Boyer TD, Wright TL, Manns MP, eds. Zakim and Boyer’s Hepatology, A Textbook of Liver Diseases. 5th ed. Philadelphia: Saunders Elsevier, 2006:693–723. 35. Arankalle VA, Chadha MS, Mehendale SM, Tungatkar SP. Epidemic hepatitis E: serological evidence for lack of intrafamilial spread. Indian J Gastroenterol 2000;19:24–8. 36. Khuroo MS. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. Am J Med. 1980;68:818–24 37. Khuroo MS. Acute liver failure in India [Letter]. Hepatology 1997;26:244–6. 38. Krawczynski K, Aggarwal R, Kamili S. Hepatitis E. Infect Dis Clinic North Am. 2000;14:669–87.
370
Liu and Laurin
39. Khuroo MS, Teli MR, Skidmore S, et al. Incidence and severity of viral hepatitis in pregnancy, Am J Med. 1981;70:252–5. 40. Khuroo MS, Kamili S. Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy. J Viral Hepat. 2003;10:61–9. 41. Patra S, Kumar A, Trivedi SS, et al. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med 2007;147: 28–33. 42. Khuroo MS, Kamili S, Jameel S. Vertical transmission of hepatitis E virus. Lancet 1995;345:1025–6. 43. Kumar RM, Uduman S, Rana S, et al. Sero-prevalence and mother-to-infant transmission of hepatitis E virus among pregnant women in the United Arab Emirates. Eur J Obstet Gynecol Reprod Biol 2001:100:9–15. 44. Pal R, Aggarwal R, Naik SR, et al. Immunological alterations in pregnant women with acute hepatitis E. J Gastroenterol Hepatol 2005; 20:1094–101. 45. Tsarev SA, Tsareva TS, Emerson SU, et al. Successful passive and active immunization of cynomolgus monkeys against hepatitis E. Proc Natl Acad Sci U S A 1994;91:10198–202. 46. Khuroo MS, Dar MY. Hepatitis E: evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 1992;11:113–6. 47. Ganem D, Varmus HE. The molecular biology of the hepatitis B viruses. Annu Rev Biochem 1987;56:651–93. 48. Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000:61;362–6. 49. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–45. 50. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11: 97–107. 51. Euler F, Wooten KG, Baughman AL, et al. Hepatitis B surface antigen prevalence among pregnant women in urban areas: implications for testing, reporting and preventing perinatal transmission. Pediatrics 2003;111 (5 Pt 2):1192–7. 52. Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA. Lancet 1989;1(8635):406–10. 53. Lin HH, Lee TY, Chen DS, et al. Transplacental leakage of HBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. J Pediatr 1987;111(6 Pt 1):877–81. 54. Xu DZ, Yan YP, Choi BC, et al. Risk factors and mechanism of transplacental transmission of hepatitis B virus: a case-control study. J Med Virol 2002;67(1): 20–6. 55. Bhat P, Anderson DA. Hepatitis B translocates across a trophoblastic barrier. J Virol 2007;81:7200–7. 56. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1–33; quiz CE1-4. 57. Andre FE, Zuckerman AJ. Review: protective efficacy of hepatitis B vaccines in neonates. J Med Virol 1994;44:144–151.
Viral Hepatitis, A Through E, In Pregnancy
371
58. Stevens CE, Toy PT, Tong MJ, et al. Perinatal hepatitis B virus transmission in the United States. Prevention by passive-active immunization. Jama 1985;253(12):1740 59. Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;2(8359):1099–102. 60. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep 2001;50(RR-11):1–52. 61. Grosheide PM, Schalm SW, van Os HC, Fetter WP, Heijtink RA. Immune response to hepatitis B vaccine in pregnant women receiving post-exposure prophylaxis. Eur J Obstet Gynecol Reprod Biol 1993;50(1):53–8. 62. Levy M, Koren G. Hepatitis B vaccine in pregnancy: maternal and fetal safety. Am J Perinatol 1991;8(3):227–32. 63. Hill JB, Sheffield JS, Kim MJ, Alexander JM, Sercely B, Wendel GD. Risk of hepatitis B transmission in breast-fed infants of chronic hepatitis B carriers. Obstet Gynecol 2002;99:1049–52. 64. ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of hepatitis B infection after delivery. J Viral Hepat 2008;15:37–41. 65. Terrault NA, Jacobson IM. Treating chronic hepatitis B infection in patients who are pregnant or are undergoing immunosuppressive chemotherapy. Semin Liv Dis 2007;27(Suppl 1):18–24. 66. del Canho R, Grosheide PM, Mazel JA, et al. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982–1992: protective efficacy and long-term immunogenicity. Vaccine 1997;15:1624–30. 67. Ngui SL, Andrews NJ, Underhill GS, et al. Failed postnatal immunoprophylaxis for hepatitis B: characteristics of maternal hepatitis B virus as risk factors. Clin Infect Dis 1998;27:100–6. 68. van Zonneveld M, van Nunen AB, Niesters HG, et al. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat 2003;10:294–7. 69. Xu W-M, Cui Y-T, Wang L, et al. Efficacy and safety of lamivudine in late pregnancy for the prevention of mother-child transmission of hepatitis B; a multicentre, ramdomised, double-blind, placebo-controlled study. Hepatology 2004;40(suppl 4):272A. Abstract 246. 70. The Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2006. Wilmington, NC: Registry Coordinating Center; 2006. Available at: http://www.apregistry.com/forms/apr˙report˙106.pdf. Accessed 30 July 2008. 71. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol 2006;4:936–62. 72. Pasetti G, Calzetti C, Degli Antoni A, et al. Clinical features of hepatitis delta virus infection in a northern Italian area. Infection 1988;16:345–8. 73. Lok AS, Lindsay I, Scheuer PJ, Thomas HC. Clinical and histological features of delta infection in chronic hepatitis B virus carriers. J Clin Pathol 1985;38: 530–3. 74. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. N Engl J Med 1997;336:196204.
372
Liu and Laurin
75. Houghhton M, Hepatitis C viruses. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology, 3rd ed. Philadelphia. Lippincott – Raven, 1996:1035–1058. 76. Purcell RH. Hepatitis C virus. In: Webster RG, Granoff A, eds. Encyclopedia of Virology, London, Academic Press Ltd. 1994:569–574. 77. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999–2002. Ann Intern Med 2006;144:705–14. 78. Jain S, Goharkhay N, Saade G, et al. Hepatitis C in Pregnancy. Am J Perinatol 2007;24:251–6. 79. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med 1994;330:744–50. 80. Mast EE, Alter MJ, Margolis HS. Strategies to prevent and control hepatitis B and C virus infections: a global perspective. Vaccine 1999;17:17303. 81. Granovsky MO, Minkoff HL, Tess BH, et al. Hepatitis C virus infection in the mothers and infants cohort study. Pediatrics 1998;102(2 Pt 1):355–9. 82. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002 (June 10–12, 2002). Gastroenterology. 2002;123:2082–99. 83. Hunt CM, Carson KL, Sharara AI. Hepatitis C in pregnancy. Obstet Gynecol 1997;89(5 Pt 2):883–90. 84. Lin HH, Kao JH, Hsu HY, et al. Possible role of high-titer maternal viremia perinatal transmission of hepatitis C virus. J Infect Dis 1994;169:638–41. 85. EASL International Consensus Conference on Hepatitis C. Paris, 26–28, February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol. 1999;30:956–61. 86. Mok J, Pembrey L, Tovo PA, Newell ML. European Paediatric Hepatitis C Virus Network. When does mother to child transmission of hepatitis C virus occur? Arch Dis Child Fetal Neonatal Ed 2005;90:F156–60. 87. European Paediatric Hepatitis C Virus Network. A significant sex- but not elective cesarean section- effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005;192:1872–9. 88. Plunkett BA, Grobman WA. Elective cesarean delivery to prevent perinatal transmission of hepatitis C virus: a cost-effectiveness analysis. Am J Obstet Gynecol 2004;191:998–1003. 89. Steininger C, Kundi M, Jatzko G, et al. Increased risk of mother-to-infant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis 2003;187:345–51. 90. McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database Syst Rev 2006 Oct 18;(4):CD005546. 91. Boskovic R, Wide R, Wolpin J, et al. The reproductive effects of betainterferon therapy during pregnancy: a longitudinal cohort. Neurology 2005;65: 807–11. 92. Hiratsuka M, Minakami H, Koshizuka S, Sato I. Administration of interferonalpha during pregnancy: effects on the fetus. J Perinat Med 2000;28:372–6. 93. Mukarak AA, Kakil IR, Awidi A, et al. Normal outcome of pregnancy in chronic myeloid leukemia treated with interferon-alpha during the 1st trimester: report of 3 cases and review of the literature. Am J Hematol 2002;69:115–8.
Viral Hepatitis, A Through E, In Pregnancy
373
94. Mesquita MM, Pestana A, Mota A. Successful pregnancy occurring with interferon-alpha therapy in chronic myeloid leukemia. Acta Obstet Gynecol Scand 2005;84:300–1. 95. Sandberg-Wolheim M, Frank D, Goodwin TM, et al. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology 2005;65:802–6.
Chronic Viral Hepatitis and Liver Transplantation Kirti Shetty, MD, FACG CONTENTS I NTRODUCTION L IVER T RANSPLANTATION FOR V IRAL H EPATITIS B P OST-LT HBV R ECURRENCE A NTIVIRAL T HERAPY L IVER T RANSPLANTATION FOR V IRAL H EPATITIS C P OST-LT R ECURRENCE OF HCV A NTIVIRAL T HERAPY T HE U SE OF V IROLOGICALLY C OMPROMISED O RGANS IN L IVER T RANSPLANTATION L IVER T RANSPLANTATION IN HIV C OINFECTED I NDIVIDUALS C ONCLUSIONS R EFERENCES
Key Principles
• Chronic hepatitis B and C are the most common etiological factors worldwide for cirrhosis and hepatocellular carcinoma (HCC). • Liver transplantation (LT) is the only option for those with complicated cirrhosis and early HCC.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 15, C Humana Press, a part of Springer Science+Business Media, LLC 2009
375
376
Shetty
• Outcomes of LT for viral hepatitis are compromised by recurrent viral infection, resulting in allograft failure. • Combined passive immunoprophylaxis and the use of oral antiviral agents have dramatically improved outcomes in hepatitis B virus (HBV) related LT. • Persistent challenges related to LT for HBV include the costs of immunoprophylaxis and the emergence of drug-resistant mutants. • Hepatitis C virus (HCV) recurrence is encountered universally following LT. In an attempt to manage recurrence, interferonbased therapies are used pre-LT, preemptively post-LT, and for treatment of established disease. • Present therapeutic regimens for post-LT HCV are limited by poor tolerability and limited efficacy. However, emerging evidence suggests a long-term beneficial effect in those patients achieving a sustained virological response (SVR). • The role of hepatitis C immunoglobulin, and orally available small molecules such as polymerase and protease inhibitors, is not well studied in the post-LT population. • Future strategies in HCV-related LT will require to focus on combinations of drugs that will effectively eradicate the virus and prevent long-term graft failure.
1. INTRODUCTION Chronic viral hepatitis is an important contributor to liver disease worldwide. Globally, the two hepatotrophic viruses, hepatitis B and C, together constitute the most common etiological factor for cirrhosis and hepatocellular carcinoma (HCC) (1, 2). Liver transplantation (LT) is the only option for those with advanced cirrhosis or early HCC which satisfies Milan criteria (3). In the United States, listing for LT is currently under the auspices of the United Network for Organ Sharing (UNOS), and organ allocation is based on the model for end-stage liver disease (MELD) score (4). Hepatitis C (HCV) cirrhosis is the most common indication for LT in this country, comprising 27% of all liver transplants performed, while hepatitis B (HBV) accounts for 4–6% of transplants (5). Advances in immunosuppression and surgical technique have dramatically improved outcomes of LT over the past two decades. However, outcomes following LT for viral hepatitis have lagged behind those for conditions such as cholestatic and alcoholic liver disease. Compromised post-LT survivals are mainly attributable to a high rate of recurrence of the primary viral infection (5). This challenge has been
Chronic Viral Hepatitis and Liver Transplantation
377
admirably met in HBV with the development of highly efficacious preventative and therapeutic strategies. HCV, on the other hand, has continued to evade efforts to prevent post-LT recurrence and is the focus of intense ongoing study.
2. LIVER TRANSPLANTATION FOR VIRAL HEPATITIS B In patients who develop HBV cirrhosis, 5-year survival rates range from 84% in those with compensated liver disease to 14% in decompensated cirrhosis (6). Thus, all patients with complications of HBV cirrhosis should be considered for LT. However, the initial LT experience for HBV was disappointing. Reinfection, manifesting as detectable hepatitis B surface antigen (HBsAg), occurred in 80% of recipients (7, 8). Left untreated, cirrhosis developed within 1–2 years of reinfection, and 3-year patient survival rates were unacceptably low at under 50% (8, 9). Fortunately, rapid advances in antiviral therapy and immunoprophylaxis have dramatically decreased the rate of HBV reinfection to under 10%. Current 5-year patient survival rates following LT for HBV are in the range of 70–75% (10), transforming our attitudes toward a disease previously considered to be a relative contraindication for LT.
3. POST-LT HBV RECURRENCE 3.1. Mechanisms of Recurrent Hepatitis B Without prophylaxis, reinfection of graft tissue generally occurs within 16 months of transplantation, with a range of 2–37 months (11). Various mechanisms of reinfection have been identified. Immunosuppressant therapy, in particular steroids and azathioprine, has been demonstrated to have a stimulatory effect on viral replication in vitro. Steroid therapy enhances the glucocorticoid-responsive element in the HBV genome, resulting in enhanced HBV replication (12). Another contributory factor is the presence of extrahepatic reservoirs of HBV such as the spleen, peripheral mononuclear cells, and thyroid (13, 14). LT recipients may also develop HBV reinfection due to the emergence of resistant and immune escape mutants (15, 16). A point mutation in the S gene results in the disruption of the antigenicity of HBsAg, allowing escape from neutralization by Hepatitis B Immune Globulin (HBIG). These mutations have been described in patients who received HBIG alone or HBIG plus lamivudine monotherapy after LT (16, 17).
378
Shetty
3.2. Patterns of Recurrent Hepatitis B HBV reinfection typically first manifests by elevations in alanine aminotransferase (ALT) and detectable serum HBV DNA, which often sprecedes detection of HBsAg (18). Reinfection presents along a spectrum of hepatic injury, ranging from asymptomatic transaminase elevation to chronic hepatitis, subacute graft failure, and cirrhosis (19). A severe variant of HBV-associated liver injury occurs in 5–10% of LT recipients and is termed fibrosing cholestatic hepatitis (FCH) (20). This entity is characterized histologically by prominent cholestasis and fibrosis, minimal necroinflammation, and intense expression of HBsAg and HB core antigen. The mortality of FCH in the pretreatment era was 100%.
3.3. Factors Affecting HBV Recurrence Several studies have explored risk factors that may impact on the severity and timing of HBV recurrence (Table 1). The best-studied recipient variable is pretransplantation HBV DNA. Several studies have demonstrated that elevated viral load at the time of transplantation representing active viral replication portends a poor outcome (21, 22). In a review of 177 patients by Marzano et al. (21), a linear relationship was Table 1 Risk Factors Associated with HBV Recurrence After Transplantation High risk HBV DNA >100,000 copies/mL prior to transplant Evidence of antiviral resistance prior to transplant HBeAg positivity in recipient HBIG monotherapy Shorter interval to HBV DNA detection after transplant Anti-HBc positivity in donor organ High-dose immunosuppression after transplant Low risk Combined HBIG and antiviral prophylaxis Hepatitis D coinfection Fulminant hepatitis B HBeAg negativity in recipient
Chronic Viral Hepatitis and Liver Transplantation
379
noted between HBV DNA level and recurrence risk. Other recipient factors affecting outcomes adversely are pre-transplant antiviral resistance, HBeAg positivity, HBIG monoprophylaxis, shorter interval to HBV DNA positivity after transplantation, and the presence of HCC (11, 23, 24, 25). Factors predicting a lower risk of recurrence include hepatitis D coinfection, fulminant hepatitis B infection, and HBeAg negativity (26). There is little data to suggest age and race as independent risk factors for compromised outcomes; several case series have demonstrated that Asian race does not predict poor outcomes as originally believed (27, 28).
4. ANTIVIRAL THERAPY The primary goal of antiviral therapy in patients with chronic HBV awaiting LT is to maintain viral suppression. The secondary goals are to improve or stabilize cirrhosis complications and to decrease the rate of HBV recurrence post-LT. Following LT, the goal of therapy is to prevent reinfection of the graft. If reinfection occurs, the goal then becomes to treat the infection adequately so as to prevent graft failure and the need for retransplantation.
4.1. Treatment Prior to LT Antiviral therapy has been demonstrated to provide clinical benefit in patients with HBV cirrhosis. According to guidelines from the American Association for the Study of Liver Diseases (AASLD) (29), treatment should be reserved for cirrhotic patients who have HBV DNA levels >2000 IU/mL or an elevated ALT associated with HBV DNA levels between 200 and 2000 IU/ml. Patients with decompensated cirrhosis should be referred for LT evaluation. A separate treatment algorithm proposed by an US expert panel (30) liberalizes treatment to all patients with decompensated cirrhosis, irrespective of HBV DNA level (Fig. 1). Antiviral Agents in the Management of HBV Cirrhosis: Five nucleotide/nucleoside analogues (lamivudine, adefovir, entecavir, telbivudine, and most recently, tenofovir) and the interferons (peginterferon alpha-2a and standard interferon alpha-2b) are approved by the Food and Drug Administration (FDA) for the treatment of chronic hepatitis B (CHB). Interferon alpha-2b/Pegylated interferon: The interferons are contraindicated in patients with cirrhosis, as they may exacerbate underlying liver disease.
380
Shetty
Fig. 1. Approach to hepatitis B in the liver transplant setting modified from AASLD Practice Guidelines 2007 (29). ∗ According to Expert Consensus Guidelines (30), all patients with decompensated cirrhosis should be treated irrespective of HBV DNA level.
Lamivudine: This was the first orally administered antiviral agent approved for the treatment of CHB and the first agent demonstrated to have utility in those with decompensated HBV cirrhosis. A retrospective analysis of 154 North American patients with decompensated HBV cirrhosis who were treated with lamivudine demonstrated a biphasic survival pattern, with most mortalities (78%) occurring within the first 6 months of initiating lamivudine therapy (31). For those who lived beyond 6 months, the 3-year survival approximated 88%. It appears that those with advanced HBV cirrhosis may be stratified into two groups: those who will require expedited liver transplantation and those who will enjoy prolonged survival with antiviral therapy. The three major risk factors associated with 6-month mortality were baseline serum bilirubin, creatinine, and HBV DNA >7 × 105 copies/ml. Stabilization or improvement in liver biochemistry was demonstrated in a multicenter trial, which showed that the actuarial survival of treated patients was better than that of untreated historical controls (32) This was also confirmed in a single-center series (33). The main limitation of lamivudine is the emergence of drug-resistant mutants, which increases to 65% after 5 years of treatment (34). Those with advanced liver disease have cumulative rates of lamivudine resistance approximating 15%–20% annually (35, 36). With the advent of newer oral antiviral agents with demonstrably lower resistance rates, the utility of lamivudine monotherapy is limited. This drug can no longer be recommended as first-line therapy.
Chronic Viral Hepatitis and Liver Transplantation
381
Adefovir dipivoxil is a nucleotide analogue of adenosine monophosphate and can inhibit replication of wild-type (37) and lamivudineresistant HBV (38). A large multicenter trial (39) studied a total of 324 patients (128 pre-LT and 196 post-LT) with lamivudine-resistant HBV. In the pre-LT population, addition of adefovir was associated with undetectable serum HBV DNA levels in 81% of patients. No resistance was identified after 48 weeks of therapy. Follow-up data on 226 patients showed that viral suppression was maintained in 65% of patients after 96 weeks of treatment with accompanying improvement in liver function (and Child-Pugh scores) (40). Resistance to adefovir develops at a lower rate compared to lamivudine. Recent studies have demonstrated that adding adefovir to lamivudine rather than switching to adefovir is more efficacious and results in lower resistance rates (41). The major concern with adefovir use in cirrhosis is the potential for nephrotoxicity. At the approved dose of 10 mg daily, nephrotoxicity (which is defined as an increase in creatinine to 0.5 mg/dL above baseline) was observed in 2% of treated patients but did not prompt discontinuation of the medication (39). The extent to which renal dysfunction was solely attributable to adefovir is debatable, given the multiple other etiologies for renal disease in this population. However, dosing interval modification is recommended for those patients with creatinine clearance under 50 ml/min. Entecavir: This is an oral nucleoside analogue that inhibits hepatitis B viral polymerase, reducing viral DNA synthesis. This drug has more potent antiviral activity than lamivudine. It is effective in suppressing lamivudine-resistant HBV but has less antiviral activity in this subgroup as compared to wild-type HBV. Clinical trials in patients with compensated liver disease have shown an excellent safety profile (42). However, its use has not been well studied in those with decompensated cirrhosis. Resistance to entecavir has not been observed up to 2 years of treatment in nucleoside-na¨ıve patients but has been reported in 7% of patients with prior lamivudine resistance. The possibility of crossresistance makes entecavir an unattractive choice for monotherapy in lamivudine-resistant patients. Telbivudine: Telbivudine is a nucleoside analogue and a potent inhibitor of HBV DNA polymerase. The GLOBE trial, a randomized phase III study, established the superiority of telbivudine to lamivudine in HBeAg-positive and HBeAg-negative patients after 1 and 2 years of therapy (43). Resistance to telbivudine has been reported as 4.4% and 21.6% in HBeAg-positive patients and 2.7% and 8.6% in HBeAg-negative patients after 1 and 2 years of therapy, respectively (43). Cross-resistance of telbivudine-resistant mutations to lamivudine
382
Shetty
makes telbivudine unsuitable for use as monotherapy or in the treatment of lamivudine-refractory HBV. Its use in decompensated cirrhosis has not been studied. Tenofovir: Tenofovir is structurally related to adefovir and has been in clinical use for the treatment of human immunodeficiency virus (HIV). It was recently approved by the FDA in August 2008 for treatment of CHB. It was more potent than adefovir in achieving viral suppression defined as <400 copies/mL (76% versus 13%), histological improvement (67% versus 12%), and higher rates of HBsAg loss (3.2% versus 0%) at 48 weeks in patients with HBeAg-positive CHB (44). Both adefovir and tenofovir were well tolerated in these studies, with no evidence of significant renal toxicity. No resistance to tenofovir has been detected to date. Tenofovir has been shown to be effective against lamivudine- and adefovir-resistant HBV. Its use in decompensated cirrhosis has not been studied. Emtricitabine: Emtricitabine is a nucleoside analogue structurally similar to lamivudine that is currently approved for use with other antiretroviral drugs in the treatment of HIV infection, but not for HBV. It demonstrates activity against HBV and shares the same drug-resistant mutation as lamivudine (M204V/I ± L180M). A 48-week course of therapy with emtricitabine is associated with a 62% improvement in fibrosis and inflammation compared to 25% in the placebo group (45). Viral suppression to <400 copies/mL was achieved in 54% versus 2% in the emtricitabine and placebo groups, respectively. Resistance development occurred in 9% of patients after 1 year and 13% after 2 years of therapy. The rate of emergence of resistance and cross-resistance with lamivudine limits the use of emtricitabine as monotherapy in the management of CHB. However, it is a good candidate for use with other antiviral agents and is currently being tested in combination with tenofovir in the management of CHB.
4.2. Management of Hepatitis B in Liver Transplant Recipients 4.2.1. P REVENTION OF H EPATITIS B F OLLOWING L IVER T RANSPLANTATION Hepatitis B Immune Globulin Prophylaxis for HBV Reinfection In 1993, the European Concerted Action on Viral Hepatitis study demonstrated for the first time that perioperative and long-term administration of hepatitis B immunoglobulin (HBIG) following LT resulted in decreased reinfection rates and improved survival (46). This study demonstrated that HBIG administered over a longer term (>6 months) led to a 33% recurrence rate as opposed to the 75% recurrence rate in
Chronic Viral Hepatitis and Liver Transplantation
383
those receiving no immunoprophylaxis. Improved patient survival was also noted in the long-term treatment arm (46). Recurrent disease, however, was frequent when HBIg was discontinued. Subsequent protocols used high-dose antibody therapy for longer or indefinite periods, with even more efficacious results. In recent years, combination therapy of HBIG and nucleoside/nucleotide analogues has been proven to be most effective. HBIG Preparations HBIG is prepared from human plasma containing high titers of antibodies to hepatitis B surface antigen (anti-HBs). Donors documented to be HBsAg-negative are immunized with FDA-licensed plasma-derived recombinant hepatitis B vaccine. High responders are selected for repeated plasmapheresis. After additional processing and sterilization procedures, this product is aliquoted into 5-ml vials for storage. The principal manufacturer in the United States currently provides a virologically safe product (NABI-HB, NABI – Rockville, MD) that is licensed for intramuscular OMLT use. Despite the central role of HBIG in the management of post-LT HBV patients, its use was not officially sanctioned until recently. In March 2008, the FDA granted orphan drug exclusivity status to HepaGam BTM (Cangene Corporation, Winnipeg, Manitoba, Canada), a solvent and detergent-treated sterile solution of purified gamma globulin (5% or 50 mg/ml) containing >312 IU/mL of anti-HBs. Efficacy of HBIG The mechanisms whereby passive immunization prevents recurrent HBV infection are unknown. It is hypothesized that the exogenously administered antibody binds to virus in the serum, which limits viral entry into the new allograft (47, 48). Viral eradication does not seem to occur, as evidenced by the detection of HBV DNA in the liver, plasma, and peripheral blood mononuclear cells of HBsAg-negative patients (47). HBIG monotherapy had been utilized in the past, and cumulative experience showed that the median rate of recurrent HBV infection was about 20% in those receiving long-term HBIG (49). The standard of care in the post-LT care of HBV-infected patients is now the use of HBIG in combination with nucleoside/nucleotide analogues, which halves recurrence rates to approximately 10%. It has become increasingly clear that the determinant of efficacy is the titer of protective hepatitis B surface antibody (anti-HBs). Using “prevention of detectable HBsAg” as a treatment endpoint, pharmacokinetic studies showed that the anti-HBs titer needed to provide effective pro-
384
Shetty
phylaxis was >500 U/L during the first week, >250 IU/L during weeks 2–12, and >100 IU/L after 12 weeks (50). Patients who were HBeAgpositive required more HBIG to achieve these target anti-HBs titers, especially in the first week post-LT. Protocols for HBIG administration vary by transplant center. In general, most protocols utilize high-dose HBIG initially (10,000 IU) in the anhepatic phase, followed by 10,000 IU daily for the first postLT week (48–50). After the early post-transplant period, frequency of HBIG administration is based on two different approaches. The first method is based on a fixed dosage of HBIG that estimates anti-HBs levels to be well above target levels (50). This method requires less frequent monitoring but is more expensive. The second method is based on adjusting the dosage and frequency of HBIG based on protective titers (48). This method saves costs by preventing excess doses of HBIG but requires more frequent monitoring. Limitations of HBIG Therapy The primary limitation of HBIG prophylaxis is cost. The estimated total cost per patient varies by report, but most regimens can range anywhere from $80,000 to $120,000 in the first year, followed by $50,000 to $60,000 in subsequent years (47, 51). Other limitations include the need for parenteral administration (which adds significantly to cost), the frequency of side effects such as back or chest pain, headache, and flushing. The newer intravenous formulation of HBIG (NABI-HB) contains a lower protein content and is associated with a lower frequency of these side effects. Another major limitation is HBV reinfection, despite treatment with HBIG. Two patterns of treatment failure are noted. The first is allograft infection with wild-type HBV in the early post-operative period and is presumably caused by inadequate doses of HBIG or high levels of viral replication pre-LT. The second type is noted after at least 6 months of HBIG therapy and is presumed to be due to the emergence of mutant virus. These mutants have been noted to revert to wild-type HBV following cessation of HBIG therapy (52, 53). Combination Therapy with HBIG and Lamivudine The combination of lamivudine and HBIG may be synergistic. Since lamivudine is a potent inhibitor of viral replication, the viral binding capacity of HBIG is less likely to be overwhelmed. Overall, HBV recurrence rates with combination therapy are less than 10% at 2 years following LT, with HBV DNA levels by PCR being undetectable in 90% of patients (54, 55). A recent meta-analysis of six high-quality studies examining the use of a combination of HBIG and lamivudine confirmed
Chronic Viral Hepatitis and Liver Transplantation
385
the efficacy of such an approach. The cumulative rate of HBV recurrence in the HBIG and lamivudine combination therapy group versus HBIG alone was 4.1% versus 36.1%, respectively; the HBV-related death and all-cause mortality rates were 0.8% versus 15.1% and 5.1% versus 22.2%, respectively (56). Combination Therapy with HBIG and Adefovir For those patients who develop lamivudine-resistant mutants while receiving the drug in the pre-transplant setting or who become primarily infected with a lamivudine-resistant mutant, the use of lamivudine for post-LT prophylaxis is inappropriate. Adefovir has been demonstrated to improve post-LT outcomes in such patients. A study of 241 LT recipients with lamivudine-resistant HBV who were treated with adefovir, achieved HBV DNA loss of 65% at 96%. The cumulative rate of adefovir resistance was 2% at 96 and 144 weeks (40). Another study of 16 lamivudine-resistant patients examined response to lamivudine and adefovir, with or without HBIG. All patients cleared HBV DNA with no evidence of recurrence (57). This suggests that add-on adefovir is the preferred approach in patients with demonstrated lamivudine resistance. An area of future investigation is whether adefovir should be utilized in combination with lamivudine and HBIG. The theoretical benefits of a combined approach would be that breakthrough mutations to either drug are significantly diminished. Use of Intramuscular HBIG Several centers have used intramuscular instead of intravenous HBIG, after the first week post-LT. Intramuscular HBIG administration has several unique characteristics. The intramuscular route has a depot effect with maximal intravascular levels of antibodies reached between 3 and 5 days following the injection. Also, only 40–45% of the antibodies administered pass into the intravascular compartment. However, levels of anti-HBs > 100 IU/L are achieved in most patients and overall, this approach is far less expensive. Gane et al. in a recent study examined a group of 147 patients, of which 85% were HBV DNA positive prior to transplantation (58). These patients received low-dose IM HBIG (400 IU) daily for 1 week and monthly thereafter, combined with daily lamivudine. Five-year survival and HBV reinfection rates were 88% and 4%, respectively, very comparable to results achieved with intravenous HBIG. Discontinuation of Therapy Several studies have examined the effect of discontinuing HBIG. In a study of 21 patients, HBIG was discontinued at a median of 26 months
386
Shetty
after LT; lamivudine and/or adefovir was continued (59). At 48 weeks after HBIG cessation, two patients developed HBV recurrence, one of whom was noncompliant with the oral antiviral agent. This small study suggests that HBIG discontinuation with ongoing maintenance therapy using oral antivirals may be effective in preventing HBV recurrence. However, there is a lack of high-quality controlled data examining this issue, and no current guidelines exist in terms of discontinuing post-LT HBIG prophylaxis. 4.2.2. T REATMENT OF R ECURRENT H EPATITIS B P OST-LT Post-LT hepatitis B infection is defined as the detection of HBsAg, measurable HBV DNA, and elevated ALT. Retransplantation in hepatitis B is associated with high mortality if graft failure is caused by recurrent viral disease, rather than other etiologies (60). It is therefore important to treat recurrent hepatitis B aggressively before graft failure occurs. Lamivudine has been used in this setting for several years with excellent efficacy and safety profile (61–63). In a large multicenter trial involving 52 recipients with recurrent HBV, the use of lamivudine for 1 year led to HBV DNA suppression and HBeAg loss in 60% and 30% of cases, respectively (63). Unfortunately, YMDD mutations developed in 27–30% of recipients as early as 7 months after treatment initiation. Adefovir has been shown to be effective against lamivudine-resistant HBV. Successful rescue therapy with the addition of adefovir to lamivudine has been shown to reverse acute graft failure and severe fibrosing cholestatic hepatitis due to lamivudine- and HBIG-resistant HBV (64, 65). Entecavir may be useful in adefovir-resistant and lamivudineresistant HBV, but due to its cross-resistance with lamivudine is not optimal. Tenofovir has shown excellent potency against wild-type lamivudine- and adefovir-resistant HBV. However, scanty data exist regarding the role and efficacy of both entecavir and tenofovir in the post-transplant setting. An early report raised concerns of interferoninduced allograft rejection in this population, and interferon is not commonly used, given the variety of alternative therapeutic choices (66).
5. LIVER TRANSPLANTATION FOR VIRAL HEPATITIS C Based on current estimates, the incidence of HCV-related cirrhosis and hepatocellular carcinoma is expected to peak by the year 2008, leading to an increased demand for transplantation in HCV-infected individuals (67, 68). Unfortunately, reinfection of the hepatic allograft by hepatitis C is unavoidable, with a high incidence of accelerated liver injury and subsequent graft failure. The management of recurrent HCV
Chronic Viral Hepatitis and Liver Transplantation
387
is one of the most daunting challenges faced by those who care for LT recipients.
6. POST-LT RECURRENCE OF HCV 6.1. Natural History of Recurrent Hepatitis C Individuals who are viremic at the time of transplantation experience universal virological recurrence of disease. Some evidence of histologic recurrence seems inevitable but the natural history of recurrent HCV is variable and incompletely understood. One-third of patients will have minimal hepatic fibrosis at 5 years of follow-up. In others, progression of liver injury is alarmingly rapid, with cirrhosis developing in 10–25% within 5 years (69). Fibrosis progression in recurrent hepatitis C appears to be more rapid than in nontransplant patients and is nonlinear. Patients with high histologic activity within the first year post-transplant are at greatest risk of progressive fibrosis and cirrhosis (70). Most of those with cirrhosis develop decompensation and death within 1 year. In contrast, only 20% of immune-competent patients develop cirrhosis after 20 years of HCV infection, and only 3–6% of these decompensate each year. The negative impact of recurrent HCV on post-LT survival has been illustrated in a retrospective cohort study of over 11000 transplant recipients (71).
6.2. Kinetics of Post-Transplant HCV Infection Negative-strand HCV RNA, the most reliable indicator of HCV replication, has been detected in the first week following liver transplantation. A detailed report of HCV kinetics found that HCV RNA concentrations dropped dramatically during the anhepatic phase and again 8–24 h after reperfusion (72). Viral levels increased at 24–72 h post-transplant and peaked between months 1 and 4. At 1-year post-LT, HCV RNA levels were 1–log10 higher than pre-transplant levels.
6.3. Patterns of Recurrent hepatitis C Approximately 70% of patients develop acute hepatitis, usually in the first 3–6 months after LT, which then evolves to chronic hepatitis. Chronic hepatitis without a preceding acute hepatitis occurs in about 20% of patients and has a less aggressive course. A severe and rapidly progressive form of the disease is denoted as the fibrosing cholestatic variety (73), characterized by histological features of ballooned hepatocytes, confluent necrosis, bile duct proliferation, and cholestasis. While fibrosing cholestatic hepatitis C has been historically associated with
388
Shetty
dismal outcomes, recent studies have suggested prolongation of survival with the use of antiviral agents.
6.4. Factors Affecting HCV Recurrence A number of studies have attempted to identify the factors that impact on the severity and timing of HCV recurrence (Table 2). These may broadly be classified as follows: 1. Viral Factors: Pre-transplant viral titers have been associated with compromised patient and graft survival (74). Multiple studies have, however, demonstrated a lack of correlation between post-transplant viral titers and histologic severity of disease. HCV genotype and quasispecies have a variable effect on recurrence. 2. Recipient Factors: Several recipient variables have been associated with more severe recurrence. The most reliable of these include advanced recipient age and non-Caucasian race (75). 3. Donor Factors: Those associated with negative outcome include donor age >50 years (75) and high donor fat content. Prolonged warm and Table 2 Factors Associated with Severity of Recurrent HCV Factor
Association
Recipient-related factors Female gender Age Non-Caucasian race Severity of illness (pre-OLT)
Established (survival) Established (survival) Established (survival, severity) Established (survival, severity)
Donor-related factors Age > 50 years Allograft fat content Cold/warm ischemic time Living donor
Established (severity, survival) Established (severity) Unknown, insufficient data Controversial
Viral factors Pre-OLT viral load Genotype 1b Diversity of quasispecies
Established (severity) Controversial Controversial
Clinical factors CMV infection Treatment of acute rejection (OKT3, corticosteroids)
Established (severity) Established (severity)
Chronic Viral Hepatitis and Liver Transplantation
389
cold ischemic time may be risk factors for early recurrence but are not well established. The utilization of living donors for HCV-infected recipients is controversial. Theoretically, living donors may offer significant advantages including the opportunity for pre-transplant antiviral therapy, shortened liver allograft cold ischemic time, and younger donor age. However, biological mechanisms that may potentiate adverse outcomes in this setting include enhanced HCV proliferation due to rapidly regenerating hepatocytes, histocompatibility leukocyte antigen homology between donor and recipient, and a higher rate of biliary complications, which may act synergistically to damage the allograft. While two studies (76, 77) suggest that living donation may be associated with more rapid HCV recurrence, the majority of studies point to no differences in graft and patient survival or histological findings (78, 79). Emerging data from the multicenter NIH-sponsored study of living donor liver transplantation (LDLT) suggest a neutral effect on allograft survival (80). In an era marked by a shortage of donor organs, LDLT should not be withheld from potential HCV-positive recipients until the outcome data are better defined. 4. Clinical Factors: (a) CMV infection has been strongly associated with increased severity of recurrence (81) (b) Impact of immunosuppression (i) Corticosteroids: if used for acute cellular rejection, steroids are associated with a significant rise in HCV RNA levels and with increased mortality/graft loss (relative risk = 2.7–2.9, p = 0.04) (82). (ii) Calcineurin Inhibitors: there appear to be no significant differences in the severity of histological recurrence of hepatitis C among recipients receiving tacrolimus when compared to those receiving cyclosporine (83). (iii) Mycophenolate mofetil (MMF): a recent analysis of over 1100 liver transplant recipients demonstrated that MMF triple therapy at discharge was associated with a reduced risk of death, graft loss, acute rejection, and death from infectious complications (84). While other smaller studies have suggested a slightly higher risk of HCV recurrence associated with MMF, the overall impact of MMF appears to be neutral or beneficial. (iv) T-cell Depleting Therapies: steroid-resistant rejection and OKT3 administration appear to be significant risk factors for the rapidity and severity of histological recurrence of HCV (85). Data on the impact of thymoglobulin on HCV recurrence are lacking but this agent should probably be used with great caution in this setting. Interleukin-2 receptor antibodies have been reported to be associated with more severe HCV recur-
390
Shetty
rence in small single-center studies. Long-term results from a large randomized controlled study of these agents in HCVinfected recipients are awaited.
7. ANTIVIRAL THERAPY The current standard of therapy for chronic hepatitis C is pegylated interferon (PEG-IFN) weekly and daily ribavirin (RBV) orally. Unfortunately, this therapy is poorly tolerated even in the nontransplant patient and offers many challenges in a transplant population. Interferon is associated with bone marrow depression, increased susceptibility to infection, and may precipitate acute rejection. RBV causes hemolytic anemia, which may be severe if dose adjustment is not made for renal disease. However, given the absence of alternative therapies, and the recognized impact of HCV recurrence on graft and patient survival, interferon-based therapies have been utilized in a number of different strategies as outlined in the following section. Therapeutic intervention may be offered at three specific time points (Fig. 2).
7.1. Prior to LT (Pre-Transplant Antiviral Therapy) It aims to eradicate or suppress virus prior to engraftment. Pre-Transplant Antiviral Therapy: A pilot study of the tolerability and efficacy of pre-transplant antiviral therapy (86) randomized patients with HCV cirrhosis to varying doses of nonpegylated interferon, combined with RBV. Of the 15 who were randomized, none achieved a sustained virological response (SVR). The majority (86%) experienced side effects, and the study was terminated prematurely due to the unac-
Fig. 2. Time points for therapeutic intervention in HCV patients undergoing LT.
Chronic Viral Hepatitis and Liver Transplantation
391
ceptably high occurrence of serious adverse events, including a fatal infection. A larger single-center study from the University of Colorado (87) utilized the principle of a low accelerated dose regimen (LADR). SVR was achieved in only 11% of patients infected with genotype 1, and two deaths were noted during the treatment period. Encouragingly, of 10 patients who underwent LT after achieving SVR, none experienced recurrent HCV. These studies offer several important insights into antiviral therapy directed at those with HCV cirrhosis. Those with advanced liver disease are at risk for life-threatening complications including accelerated liver failure and severe infections. Suitable candidates for therapy therefore include patients with adequately compensated liver disease (Child-Pugh class A or B, MELD score 18). These patients often require hematopoietic growth factors in order to maintain full dose therapy. Close attention should be paid to renal function which if compromised, may contribute to RBV toxicity.
7.2. Treatment of LT Recipients (i) Preemptive Therapies: administered immediately post-OLT to prevent infection of the allograft. (ii) Prophylactic Therapies: administered in an attempt to neutralize the infection of the allograft. (iii) Therapy of recurrent disease: instituted after documentation of established disease.
(i) Preemptive Therapy: this refers to the initiation of therapy in the early post-transplant period when HCV viral loads are lower than pre-transplant levels, and histologic disease is absent or minimal. Even though there is a theoretical advantage to such an approach, tolerability is a marked limitation. An uncontrolled Italian trial utilizing combination standard IFN alpha-2b and RBV within 3 weeks after transplantation and continuing for 52 weeks reported an SVR of 33% (88). Two randomized controlled US studies have examined the use of preemptive pegylated interferon therapies. Shergill et al. utilized standard IFN 3 MU thrice weekly or PEG-IFN alpha-2b 1.5 mcg/kg/wk alone or in combination with RBV and continued treatment to a total of 48 weeks (89). Chalasani and associates studied PEG-IFN alpha-2b 180 mcg weekly for 12 months. SVR was noted in only 8–9%, with dose reductions and discontinuations required in 85% and 37% of those treated (90). LDLT recipients offer an attractive group within which to offer preemptive therapy, as they often have relatively well-preserved liver dis-
392
Shetty
ease. One uncontrolled study (91) of 21 HCV-infected LDLT recipients demonstrated an SVR of 43% on combination therapy with IFN alpha2b and RBV. Overall, it is not clear as to whether preemptive therapy of recurrent HCV offers improved outcomes. Proponents of such an approach argue that HCV recurrence should and can be treated before graft damage has occurred. Efficacy is believed to be enhanced by treatment at an early stage. However, opponents of early treatment express concern that the risk of graft rejection may be increased and that early treatment does not permit segregation of patients into those with mild versus those with more aggressive graft reinfection. (ii) Prophylactic Therapies: Preclinical and retrospective cohort studies suggest that HCV antibodies have neutralizing effects and may attenuate the risk of HCV infection. Studies in chimpanzees using polyclonal anti-HCV-enriched immune globulin have demonstrated delay or prevention of acute infection when administered to the animal before inoculation of an infectious isolate (92). In humans, the neutralizing antibodies generated in individual patients are isolate-specific and are directed against epitopes encoded within the hypervariable region of the HCV envelope gene. Two prospective studies have tested the efficacy of a polyclonal immune globulin preparation enriched in anti-HCV. A preliminary report of the Canadian hepatitis C immunoglobulin (HCIG) study found no benefit, with similar levels of viremia and histologic disease between treated and untreated groups (93). A second multicenter trial in the United States (94) evaluated 18 patients – 6 received high-dose HCIG (Cicavir), 6 received low-dose therapy, and 6 were untreated. No difference in serum HCV RNA was noted between the groups, although a decrease in hepatic HCV RNA post-LT was observed in the group treated with high-dose HCIG. A third study utilizing a fully human monoclonal antibody that binds to the E2 envelope protein of HCV (HCV-AbXTL68) has also been reported (95). In this multicenter, randomized phase 2 study, 24 HCVpositive patients were administered varying-dose infusions initiated immediately post-LT. None of the patients achieved complete viral suppression, although high-dose therapy did produce a transient median decline from the baseline viral load. The lack of a meaningful clinical effect in any of the HCIG studies suggests the need for further refinement of what may prove to be a promising approach. (iii) Antiviral Therapy for Established Recurrent HCV: Potential advantages of waiting to treat HCV until documented histological or clinical disease include the following: lower doses of immunosuppression, improved tolerance of therapy, lower risk of acute rejection, and cost savings.
Chronic Viral Hepatitis and Liver Transplantation
393
Results of antiviral therapy for established recurrence have been disappointing with SVR rates significantly lower than in nontransplant populations. Most studies evaluating IFN-based therapies are uncontrolled, use variable doses and duration of IFN and RBV therapy, and are of a sample size too limited to perform multivariate analyses to identify predictors of response. Adverse events are common with treatment withdrawal required in about 50% of patients. In the trials enrolling more than 20 patients evaluating the efficacy of pegylated interferon with RBV in liver transplant recipients, SVR rates have ranged from 12 to 45% (90, 96–103). Carrion et al. reported an important randomized controlled trial, which was the first to assess the impact of combination therapy on the development of fibrosis and hepatic venous pressure gradient (HVPG) (102). The only variable independently associated with fibrosis improvement/stabilization was treatment (odds ratio [OR] =3.7, 95% confidence interval [CI] 1.3–10, P = 0.009). This data demonstrates that antiviral therapy slows disease progression (particularly in sustained virological responders), as shown by its effects on liver histology and on HVPG. Berenguer et al. (103) have demonstrated that SVR was associated with enhanced survival. Several important lessons may be learned from these studies. As in the nontransplant setting, PEG-IFN with RBV achieves higher response rates than PEG-IFN monotherapy or standard IFN with RBV. At least one retrospective study suggests that the presence of fibrosis in the transplant population does not significantly reduce the likelihood of virologic response (100), and so an approach of waiting for progression is appropriate. Whether empiric use of growth factors should be used initially to allow full dosing from the start requires further analysis. As reduced doses of PEG-IFN are not associated with reduced efficacy in the nontransplant setting, it seems reasonable to start liver transplant recipients at these lower doses. RBV dosing is much more difficult. Since RBV levels are likely to be more important than doses and are the determinants of response, dose adjustments of RBV according to levels seems logical, although not always clinically feasible.
7.3. IFN and the Risk of Rejection in Liver Transplant Recipients A potentially serious and somewhat controversial complication of antiviral therapy in transplant patients is rejection. Two uncontrolled treatment trials (104, 105) of recurrent disease showed acute cellular rejection rates between 11 and 30%, much higher than in randomized controlled trials. This data suggests that interferon therapy may be a risk factor for rejection, an issue which requires further study. Data
394
Shetty
from the University of Colorado (106) suggest that close monitoring of calcineurin inhibitor levels is necessary during antiviral therapy as a greater proportion of antiviral responders experience rejection than nonresponders, presumably since improved hepatic function leads to enhanced biotransformation and lower immunosuppression levels. Retransplantation for recurrent hepatitis C virus: The only definitive treatment for graft failure is retransplantation. At present, retransplants account for 8–9% of all LTs, with recurrent HCV infection comprising approximately 40% of retransplant volumes. Outcomes of single-center studies comparing re-LT outcomes demonstrate inferior rates of success for HCV-associated retransplants, as compared to retransplantation for other indications (107, 108). Predictors of poor outcome after retransplanation include recipient age over 50 years, serum creatinine >2.0 mg/dL, serum bilirubin >10 mg/dL, and poor physical condition. Additionally those with a longer period of time from first to second transplant seem to have a better outcome. Retransplantation for recurrent HCV disease remains a controversial issue. Most transplant programs use a selective approach in limiting this option to patients with favorable clinical characteristics.
8. THE USE OF VIROLOGICALLY COMPROMISED ORGANS IN LIVER TRANSPLANTATION The emergence of LT as the standard of care in complicated cirrhosis has predictably resulted in a widening disparity between organ availability and demand. In an effort to expand the pool of utilizable organs, many centers will use less than perfect or extended donor criteria organs. Among other criteria, these include organs from patients infected with HCV or exposed to HBV.
8.1. Use of HCV-Infected Grafts Several studies (109–111), including analyses of the UNOS database, have confirmed that the use of HCV-positive grafts in HCV-infected recipients has similar outcomes as compared to the transplantation of HCV-negative grafts. The analysis of donor liver histology is mandatory and only organs with little or no fibrosis are utilized.
8.2. Use of Anti-Hepatitis B Core (Anti-HBc-Positive) Grafts This has become an accepted clinical option, but the selection of recipients for these potentially infectious organs deserves close attention. Those undergoing LT for HBV cirrhosis should, of course, receive primary consideration for such organs since the post-LT immuno-
Chronic Viral Hepatitis and Liver Transplantation
395
prophylaxis that they receive would prevent de novo HBV infection. Recipients who are anti-HBc-positive, with or without anti-HBs, are at low risk of de novo HBV (range 0–13%), as are recipients who are anti-HBc-negative, anti-HBs-positive (range 0–11%) (112–115). The highest risk of de novo HBV occurs in those who are negative for both anti-HBc and anti-HBs (116–118) and these patients should be offered anti-HBc-positive organs only in case of extenuating circumstances such as HCC or limited life expectancy without LT. There is a variability in prophylactic practices across transplant centers. Several centers utilize nucleoside/nucleotide analogues along with HBIG in high-risk recipients (119). However, the optimal regimen has not yet been established.
9. LIVER TRANSPLANTATION IN HIV COINFECTED INDIVIDUALS Patients coinfected with HIV and either HCV or HBV are living longer due to the beneficial effects of highly active antiretroviral therapy (HAART). Unfortunately, complications of end-stage liver disease now account for a large proportion of deaths in this group (120). While HIV was initially considered a contraindication for LT, a pilot study by Stock was pivotal in reassessing the role of LT in this population (121). A recent analysis of the UNOS database suggested that patients with HIV and viral coinfections (especially HCV) had compromised survival as compared to HIV-negative individuals (122). Currently the National Institutes of Health is sponsoring a prospective multicenter trial to analyze outcomes by enrolling 125 recipients who satisfy strict listing criteria at 20 transplant centers in the United States (www.HIVTransplant.com). Until results from this study are available, HIV-coinfected patients should not be denied LT unless other clear contraindications exist.
10. CONCLUSIONS Liver transplantation is a life-saving option in those with complications of chronic viral hepatitis. However, recurrent viral infection in the allograft is a significant concern and impacts on postLT outcomes and graft function. The use of immunoprophylaxis and oral antiviral agents has dramatically altered the treatment paradigm in patients transplanted for HBV, and this entity is now associated with excellent post-LT outcomes. Future efforts will have to focus on the optimal duration and dosing of immunoprophylaxis, prevention and management of multidrug-resistant HBV. Unfortunately, HCV
396
Shetty
recurrence continues to be a significant clinical burden, associated with compromised post-LT outcomes. The role of hepatitis C immunoglobulin and protease/polymerase inhibitors has not yet been established in this population. Future challenges include an urgent need to gain insight into the pathogenesis of recurrent HCV and formulate effective and safe therapies. We will then be in a position to offer these patients liver transplantation not just as a temporizing measure but as a definitive therapy for their liver disease.
REFERENCES 1. World Health Organization: Hepatitis B – World Health Organization fact sheet 204. Available at http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed January 2008. 2. World Health Organization Hepatitis C – World Health Organization fact sheet 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed January 2008. 3. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: 693–699. 4. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96. 5. Roberts MS, Angus DC, Bryce CL, Survival after liver transplantation in the United States: a disease specific analysis of the UNOS database. Liver Transpl 2004;10:886–897. 6. Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B virus and Cirrhosis. Hepatology 1995;21:77–82. 7. Todo S, Demetris AJ, Van Thiel D, et al. Orthotopic liver transplantation for patients with hepatitis B virus related liver disease. Hepatology 1991;13: 619–626. 8. O’Grady JG, Smith HM, Davies SE, et al. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14:104–111. 9. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (2). N Engl J Med 1989;321:1092–1099 10. Kim WR, Poterucha JJ, Kremers WK, et al. Outcome for liver transplantation for hepatitis B in the United States. Liver Transpl 2004;10:968–974. 11. Han Y, Lee S , Joh J, et al. Outcomes of Hepatitis B Virus Recurrence After Liver Transplantation. Transplantation Proceedings 2006;7:2123–24. 12. Tur-Kaspa R, Shaul Y, Moore DD, et al. The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology 1988;167:630. 13. Brind A, Jiang J, Samuel D, et al. Evidence for selection of hepatitis B mutants after liver transplantation through peripheral blood mononuclear cell infection. J Hepatol 1997;26:228–35.
Chronic Viral Hepatitis and Liver Transplantation
397
14. Yoffe B, Bruns DK, Bhatt HS, et al. Extrahepatic hepatitis B virus DNA sequences in patients with acute hepatitis B infection. Hepatology 1990;12: 187–192. 15. Kim KH, Lee KH, Chang HY, et al. Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immunoglobulin prophylaxis and lamivudine therapy. J Med Virol 2003;71: 367–375. 16. Protzer-Knolle U, Naumann U, Bartenschlager R, et al. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology 1998;1:254–263. 17. Ghany MG, Ayola B, Villamil FG, et al. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 1998;27:213–222. 18. Wong SN, Chu CJ, Wai CT, et al. Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy. Liver Transpl 2007;13:374–381. 19. Roche B, Samuel D. Evolving strategies to prevent HBV recurrence. Liver Transpl 2004;10:S74–S85. 20. Davies SE, Portmann BC, O’Grady JG, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13:150–157. 21. Marzano A, Gaia S, Ghisetti, V, et al. Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. Liver Transpl 2005;11: 402–409. 22. Mutimer D, Pillay D, Dragon E, et al. High pre-treatment serum hepatitis B virus titer predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatol 1999;30:715–721. 23. Faria LC, Gigou M, Roque-Afonso et al. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation. Gastroenterology 2008;134:1890–99. 24. Konig V, Hopf U, Neuhaus P, et al. Long-term follow-up of hepatitis B virus-infected recipients after orthotopic liver transplantation. Transplantation 1994;58:553–559. 25. Wu LM, Xu X, Zheng SS. Hepatitis B virus reinfection after liver transplantation: related risk factors and perspective. Hepatobiliary Pancreat Dis Int 2005;4: 502–508. 26. Sharma P, Lok A. Viral hepatitis and liver transplantation. Semin Liv Dis 2006;26:285–297. 27. So SK, Esquivel CO, Imperial JC, et al. Does Asian race affect hepatitis B virus recurrence following liver transplantation for hepatitis B cirrhosis? J Gastro Hep 1999;14:S48–52. 28. Ho BM, So SK, Esquivel CO, et al. Liver transplantation in Asian patients with chronic hepatitis B. Hepatology 1997;25:223–25. 29. Lok AS, McMahon BJ, Chronic hepatitis B. AASLD practice guidelines. Hepatology 2007;45:507–39. 30. Keeffe EB, Dietrich DT, Han SB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol 2006;4:936–62.
398
Shetty
31. Fontana R, Hann H, Perrillo R, Vierling JM, Wright T, Rakela J, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002;123:719–27. 32. Perrillo RP, Wright T, Rakela J, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33:424–32. 33. Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: A comparative study using a matched, untreated cohort. Hepatology 2001;34:411–4. 34. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125:1714–22. 35. Andreone P, Biselli M, Gramenzi A, et al. Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B awaiting liver transplantation. Transplantation 2002;74:1119–24. 36. Villeneuve JP, Conderay LD, Willem B, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000;31: 207–10. 37. Marcellin P, Chang TT, Lim GS, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808–16. 38. Perrillo R, Schiff E, Yoshida E, Staler A, Hirsch K, Wright T, et al. Adefovir dipivoxil for the treatment of Lamivudine–resistant hepatitis B mutants. Hepatology 2000;32:129–34. 39. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and postliver transplantation patients. Hepatology 2003;38:1419–27. 40. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre-and post-liver transplantation patients with lamivudine resistant hepatitis B: final long-term results. Liver Transpl 2007;13:349–360. 41. Rapti I, Dimou E, Mitsoula P, et al. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HbeAg-negative chronic hepatitis B. Hepatology 2007;45:307–313. 42. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–10. 43. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576–88. 44. Marcellin P, Jacobson I, Habersetzer F, et al. Tenofovir disoproxil fumarate (TDF) for the treatment of HBeAg-negative chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 102) [abstract]. J Hepatol 2008;48:S26. 45. Lim SG, Ng TM, Kung N, et al. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med 2006; 166:49–56. 46. Samuel D, Muller R, Alexander G, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993;329:1842–7. 47. Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology. 2000;32:1189–95.
Chronic Viral Hepatitis and Liver Transplantation
399
48. McGory R, Ishitani M, Oliveira W, et al. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation 1996;61:1358–1364. 49. Devlin J, Smith H, O’Grady J, et al. Impact of immunoprophylaxis and patient selection on outcome of transplantation for HBsAg-positive liver recipients. J Hepatol 1994;21:204–210. 50. Terrault NA, Zhou S, Combs C. et al. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin. Hepatology 1996;24:1327–1333. 51. Schreibman I, Schiff E. Prevention and treatment of recurrent Hepatitis B after liver transplantation: the current role of nucleoside and nucleotide analogues. Annals of Clinical Microbiology and Antimicrobials 2006, 5:8. (http://www.annclinmicrob.com/content/5/1/8. 52. Terrault NA, Zhou S, McCory RW, et al. Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. Hepatology 1998;28:555–561. 53. Sawyer RG, McGory RW, Gaffey MJ, et al. Improved clinical outcomes with liver transplantation for hepatitis B induced chronic liver failure using passive immunization. Ann Surg 1998;227:841–850. 54. Han SH, Ofman J, Holt C, et al. An efficacy and cost-effectiveness analysis of combination Hepatitis B Immune Globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation, compared with hepatitis B immune globulin monotherapy. Liver Transp 2001;6:741–748. 55. Angus PW, McCaughan GW, Gane EJ et al. Combination low-dose Hepatitis B Immune Globulin and lamivudine therapy provides effective prophylaxis against post-transplantation hepatitis B. Liver Transpl 2000;6:429–433. 56. Loomba R, Rowley AK, Wesley R, Smith KG, Liang TJ, Pucino F, Csako G. Hepatitis B immunoglobulin and Lamivudine improve hepatitis B-related outcomes after liver transplantation: meta-analysis. Clin Gastroenterol Hepatol 2008;6(6):696–700. 57. Lo CM, Li CL, Lau GK, et al. Liver transplantation for chronic hepatitis B with lamivudine-resistant YMDD mutant using add-on adefovir dipivoxil plus lamivudine. Liver Transplantation 2005;11:807–13. 58. Gane EJ, Angus PW, Strasser S, et al. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology 2007;132:931–7. 59. Wong SN, Chu CJ, Wai CT, et al. Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy. Liver Transpl 2007;13:374–381. 60. Crippin J, Foster B, Carlen S, et al. Retransplantation in hepatitis B – a multi center experience. Transplantation 1994;57:823–826. 61. Ben-Ari Z, Shmueli D, Mor E, et al. Beneficial effect of lamivudine in recurrent hepatitis B after liver transplantation. Transplantation 1997;63:393–396. 62. Ben-Ari Z, Shmueli D, Mor E, et al. Beneficial effect of lamivudine pre-and post-liver transplantation for hepatitis B infection. Transplant Proc 1997;29: 2687–2688. 63. Perrillo R, Rakela J, Dienstag J, et al. Lamivudine Transplant Group: multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Hepatology 1999;29:1581–6.
400
Shetty
64. Beckebaum S, Malago M, Dirsch O, et al. Efficacy of combined lamivudine and adefovir dipivoxil treatment for severe HBV graft reinfection after living donor liver transplantation. Clin Transplant 2003;17:554–9. 65. Walsh KM, Woodall T, Lamy P et al. Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus. Gut 2001;49:436–40. 66. Terrault NA, Holland CC, Ferrell L, et al. Interferon alfa for recurrent hepatitis B infection after liver transplantation. Liver Transpl Surg 1996;2:132–138. 67. Organ Procurement and Transplantation Network(OPTN)database. Available at http://www.optn.org. Last accessed April 30, 2008. 68. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting the future healthcare burden from hepatitis C in the United Stages. Liver Transpl 2003;9:331–8. 69. Berenguer M, Prieto M, Rayon JM, Mora J, Pastor M, Ortiz V, et al. Natural history of clinically compensated HCV-related graft cirrhosis following liver transplantation. Hepatology 200;32:852–8. 70. Berenguer M, Ferrell L, Watson J, et al. HCV-related fibrosis progression following liver transplantation : increase in recent years. J Hepatology 2000;32:673–84. 71. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889–96. 72. Garcia-Retortillo M, Forns X, Feliu, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 2002;35:680–687. 73. Schluger LK, Sheiner PA, Thung SN, Lau JY, Min A, Wolf DC et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 1996;23(5):971–76. 74. Charlton M, Seaberg E, Wiesner R, et al. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology 1998;28:823–830. 75. Neumann U, Berg T, Bahra M, et al. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J. Hepatol 2004;41:830–836. 76. Thuluvath P, Yoo H. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl 2004;10:1263–1268. 77. Garcia-Retortillo M, Forns X, Llovet J, et al. Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation. Hepatology 2004;40:699–707. 78. Russo M, Galanko J, Beavers K, et al. Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States. Liver Transpl 2004;10:340–346. 79. Schiffman M, Stravits T, Contos M, et al. Histologic recurrence of chronic hepatitis C in patients after living donor and deceased donor liver transplantation. Liver Transpl 2004;10:1248–55. 80. Terrault NA, Shiffman ML, Lok AS, et al. Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation. Liver Transpl 2006;13:122–129. 81. Mukherjee S, Sorrell MF. Controversies in liver transplantation for hepatitis C. Gastroenterology 2008;134:1777–1788. 82. Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and
Chronic Viral Hepatitis and Liver Transplantation
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96. 97.
98.
401
Digestive and Kidney Diseases Liver Transplantation Database. Liver Transplantation and Surgery 1999;5(4:suppl 1):107–14. Zervos XA, Weppler D, Fragulidis GP, Torres MB, Nery JR, Khan MF, et al. Comparison of tacrolimus with microemulsion cyclosporine as primary immunosuppression in hepatitis C patients after liver transplantation. Transplantation 1998;65(8):1044–6. Wiesner RH, Steffen BJ, David KM, Chu AH, Gordon RD, Lake JR. Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients. Am J Transplant 2006 Jul;6(7):1609–16. Rosen HR, Shackleton CR, Higa L, Gralneck IM, Farmer DA, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol 1997;92(9)1453–1457. Crippin JS, McCashland TM, Terrault NA, Sheiner PA et al. A pilot study for the tolerability and efficacy of antiviral therapy in hepatitis C virus infected patients awaiting liver transplantation. Liver Transplant 2002;8(4):350–5. Everson GT, Trotter J, Forman L, Kugelmas M, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005;42:255–262. Mazzaferro V, Tagger A, Schiavo M, et al. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment. Transplant Proc 2001;33:1355–1357. Shergill A, Khalili M, Bellinger K, et al. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C infected patients undergoing liver transplantation. Am J Transplant 2005;5:118–124. Chalasani N, Manzarbeitia C, Ferenci P, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 2005;41:289–298. Sugawara Y, Makuuchi M, Matsui Y, et al. Preemptive therapy for hepatitis C virus after living donor liver transplantation. Transplantation 2004;78: 1308–1311. Krawczynski K, Alter M, Tankersley D, et al. Effect of immune globulin on the prevention of experimental hepatitis C virus infection. J Infect Dis 1996;173:822–828. Willems B, Marotta P, Greig PD, et al. Anti-HCV immunoglobulins for the prevention of graft infection in HCV-related liver transplantation. J Hepatol 2002;36:S96A. Davis GL, Nelson DR, Terrault NA, et al. A randomized open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Cicavir) in liver transplant recipients. Liver Transpl 2005;11:941–949. Schiano TD, Charlton M, Younossi Z, Galun E, et al. Monoclonal antibody HCVAb XTL 68 in patients undergoing liver transplantation for HCV: results of a phase 2 randomized study. Liver Transpl 2006 Sep;12(9):1381–9. Mukherjee S. Pegylated interferon alfa-2a and RBV for recurrent hepatitis C after liver transplantation. Transpl Proc 2005;37:4403–4405. Oton E, Barcena R, Garcia-Garzon S, Moreno-Zamora A, et al. Pegylated interferon and RBV for the recurrence of chronic hepatitis C genotype 1 in transplant patients. Transpl Proc 2005;37:3963–3964. Biselli M, Andreone P, Gramenzi A, Lorenzini S, et al. Pegylated interferon plus RBV for recurrent hepatitis C infection after liver transplantation in na¨ıve
402
99.
100.
101.
102.
103.
104.
105. 106.
107.
108.
109.
110. 111.
112.
113. 114. 115.
Shetty and non-responder patients on a stable immunosuppressive regimen. Dig Dis Sci 2005;27–32. Dumortier J, Scoazec JY, Chevallier P, et al. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 2004;669–694. Mukherjee S, Rogge J, Weaver L, et al. Pilot study of pegylated interferon alfa2b and RBV for recurrent hepatitis C after liver transplantation. Transpl Proc 2003;3042–4. Berenguer M, Palau A, Fernandez A, Benlloch S, et al. Efficacy, predictors of response and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2006;12:1067–76. Carri´on JA, Navasa M, Garc´ıa Retortillo M, Garc´ıa–Pagan JC, Crespo G, Bruguera M, Bosch J, Forns X. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746–56. Berenguer M, Palau A, Aguilera V, Rayon J-M, Juan FS, Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transpl 2008;8:679–87. Stravitz T, Shiffman M, Sanyal A, et al. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 2004;10:850–8. Saab S, Kalmaz D, Gajjar N, Hiatt J, et al. Outcomes of acute rejection after interferon therapy in liver transplant recipients. Liver Transpl 2004;10:859–67. Kugelmas M, Osgood MJ, Trotter JF, et al. Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection. Liver Transpl 2003;9:1159–1165. Carmiel-Haggai M, Fiel MI, Gaddipati HC, Abittan C, et al. Recurrent hepatitis C after retransplantation: factors affecting graft and patient outcome. Liver Transpl 2005 Dec;11(12):1567–73. Neff G, O’Brien C, Nery J, et al. Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection. Liver Transpl 2004;10:1497–503. Vargas HE, Laskus T, Wang LF, et al. Outcome of liver transplantation in hepatitis C virus-infected patients who received hepatitis C virus-infected grafts. Gastroenterology 1999;117:149–53. Velidedeoglu E, Desai NM, Campos L, et al. The outcome of liver grafts procured from hepatitis C positive donors. Transplantation 2002;73:582–87. Marroquin CE, Marino G, Kuo PC, et al. Transplantation of hepatitis C-positive livers in hepatitis C-positive patients is equivalent to transplanting hepatitis C negative livers. Liver Transpl 2001;7:762–8. Ikegami T, Taketomi A, Ohta R, et al. The risks of HBV infection after liver transplatation from HBc antibody donor to HBs antibody recipient. Hepatogastroenterology 2008;55:2162–5. Roche B, Samuel D, Gigou M, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. J Hepatol 1997;26:517–26. Manzarbeita C, Reich DJ, Ortiz JA, et al. Safe use of livers from donors with positive hepatitis B core antibody. Liver Transp 2002;8:556–61. Holt D, Thomas R, Van Thiel D, et al. Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation. Arch Surg 2002;137:572–5.
Chronic Viral Hepatitis and Liver Transplantation
403
116. Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission of hepatitis B from HbsAg(–), HbcAb(+), HBIgM(–) organ donors. Transplantation 1995;59:230–234. 117. Douglas DD, Rakela J, Wright TL, et al. The clinical course of transplantationassociated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3:105–111. 118. Joya-Vazquez PP, Dodson FS, Dvorchik I, et al. Impact of anti-hepatitis Bcpositive grafts on the outcome of liver transplantation for HBV-related cirrhosis. Transplantation 2002;73:1598–602. 119. Uemoto S, Sugiyama K, Marusawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998;65:494–9. 120. Rosenthal E, Poiree M, Pradier C, et al. GERMIVIC Joint Study Group. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France. AIDS 2003;17:1803–9. 121. Stock PG, Roland ME, Carlson L, et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 2003;76:370–5. 122. Mindikoglu AL, Regev A, Magder LS. Impact of human immunodeficiency virus on survival after liver transplantation: analysis of United Network for Organ Sharing database. Transplantation 2008;85(3):359–68.
Treatment of Viral Hepatitis in Children – 2008 Zachary R. Schneider and Parvathi Mohan CONTENTS H EPATITIS B: I NTRODUCTION NATURAL H ISTORY S CREENING AND P REVENTION T REATMENT I MMUNOMODULATORY T HERAPY S UMMARY AND R ECOMMENDATIONS H EPATITIS C: I NTRODUCTION NATURAL H ISTORY S CREENING AND P REVENTION T REATMENT R EFERENCES
Key Principles
• Chronic hepatitis B and C are still detected in infants and children despite widespread screening of blood donors, high-risk groups, and pregnant women. • Incidence of hepatitis B has reduced significantly since the implementation of universal vaccination. • Children with chronic hepatitis B and C are relatively asymptomatic, but may occasionally present with severe sequelae such as liver failure.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 16, C Humana Press, a part of Springer Science+Business Media, LLC 2009
405
406
Schneider and Mohan
• A high degree of suspicion and careful evaluation are essential for the diagnosis and management of these children. • Treatment options are limited, suboptimal, and should be considered on a case-by-case basis. • Short- and long-term follow-up of infected children are needed to detect early signs of progression and decompensation of liver disease. • Availability of newer drugs for more optimal and safer therapy, especially through clinical trials, is the best hope for the immediate future.
1. HEPATITIS B: INTRODUCTION A 12-year-old girl presented at my institution with a history of recent jaundice and detection of elevation of liver functions. The mother had died of complications of hepatitis B and the child was recently found to be hepatitis B positive, but remained asymptomatic. Further testing including a sonographic study of the liver showed a large mass in the liver with extension to the inferior vena cava and an alpha fetoprotein (AFP) of over 20,000 ng/ml. The tumor was inoperable and the caregiver refused any diagnostic testing or treatment. The patient was lost to follow-up for 4 months, returned in profound multi-system failure and died shortly afterward. The total period of illness from the onset of jaundice to her demise was about 8 months. This case illustrates an unfortunate, but fortunately rare scenario in a child with perinatally acquired hepatitis B (HBV) infection leading to devastating sequel. Hepatitis B, a small enveloped DNA virus from the family hepadnaviridae, causes acute and chronic liver disease in children just as in adults. Childhood infection appears to differ from that in the adult in terms of epidemiology, clinical features, and natural progression. The age of acquisition of the primary infection determines the propensity to develop chronic liver disease or a carrier state, and therefore, infants and children are at greater risk of a protracted course than adults. Transmission characteristics also differ by population and geographic regions of the world (1, 2, 3). In highly endemic areas of Asia and Africa, majority of infection occurs via vertical or perinatal transmission whereas in countries such as the United States, it is mainly by horizontal transmission through contact with body fluids, as among household contacts or institutionalized children, and sexual contact and intravenous drug use, particularly in the adolescents. HBV infection is preventable by vaccination and universal vaccination is becoming a worldwide priority. Thus, there has been a steady decrease in the incidence of HBV infection (from 1982 to 1998) with a 73% decline in
Treatment of Viral Hepatitis in Children – 2008
407
the adolescents (3). The incidence of acute infection has decreased to about 8–10% of new cases per year among children from 0 to 20 years. This has been achieved through routine screening of pregnant women, increasing use of vaccination, and improving practices among intravenous drug users (IVDU) (4). Nonetheless, HBV infection continues to be a major public health problem in endemic areas with a carrier rate approximating 15–20% and adds to the incidence of new cases in the United States through infected immigrants or adoptees from those areas (5, 6). The risk of developing hepatocellular carcinoma (HCC) is high in hyperendemic areas such as Southeast Asia and the Pacific islands although HCC develops frequently only in the presence of cirrhosis. Effective vaccination has controlled the incidence of HCC even in those areas and the annual incidence of HCC in children below 10 years has dropped from 0.7 per 100,000 to 0.36 per 100,000 between 1986 and 1990 (7).
2. NATURAL HISTORY About 90% of perinatally infected infants develop chronic HBV infection and the rate of infection drops to 25–50% in toddlers and to 6–10% in older children, i.e., the younger the age of infection the higher the propensity for chronic infection (3, 4, 8). Transmission occurs mostly during birth, but is not related to the mode of delivery and is higher (90%) if mother is hepatitis B antigen (HBeAg) positive or if infected in the third trimester; this may be related to high maternal viral load and immaturity of the neonatal immune system (5, 6). The natural course of HBV infection is now recognized to consist of four phases: (a) an immune tolerant phase (presence of HBeAg, high HBV viral load, normal aminotransferase, and minimal liver disease); (b) an immune clearance phase (HBeAg positive chronic liver disease); (c) inactive HB surface antigen (HBsAg) positive carrier state (HBeAg negative, low HBV DNA, normal aminotransferases, and minimal liver histology changes); and (d) reactivation/HBeAg-negative chronic hepatitis B (negative HBeAg and positive HBe antibody (HBeAb), detectable HBV DNA and active liver inflammation with elevated aminotransferases) (8). The first phase may last for a varying period of time, even into adulthood unless the infection is acquired later in life, beyond infancy. Although sero-convertion to HBeAb is rare during this phase, children do well with minimal liver involvement, but treatment may not be effective in the face of normal or near normal aminotransferases (1, 8). HBeAg negative hepatitis is very rare in children. Children with chronic HBV infection are generally asymptomatic and may be unaware of their infected status which increases the risk
408
Schneider and Mohan
of horizontal transmission. Liver disease is relatively mild during childhood and biopsies show mild inflammation and fibrosis although bridging fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC) have been reported in pre-teen children (9, 10, 11) Progression to HCC usually occurs over 30 years in 10–40% of those with HBV-related cirrhosis (12). In a study from Taiwan, rapid development of cirrhosis and HCC was found to occur early in life even in HBV carriers with low-positive levels of HBeAg and HBC antibody indicating an early seroconversion to HBeAb (13). Natural seroconversion may vary from 10 to 20% depending on host factors, but is found only in about 2–5% infants and children in endemic areas (7, 13, 14, 15).
3. SCREENING AND PREVENTION Age at acquisition of HBV infection, is therefore, a major determinant of chronicity and, thus, early identification, appropriate prevention, therapy, and counseling are vital. Over the past two decades, this has been achieved through implementation of active immunization strategies in the United States spearheaded by the Center of Disease Control (CDC). Universal immunization of all infants at birth, routine screening of all pregnant women and immuno-prophylaxis of the newborns of infected or potentially infected mothers, routine immunization of children, adolescents, and adults previously not vaccinated have reduced the incidence of chronic HBV and prevented acute HBV infections significantly (16, 17). Groups at high risk for developing HBV infection include individuals born in areas of high or intermediate endemicity, close contacts of HBsAg positive individuals, IVDU, all pregnant women, inmates of correctional facilities, and those on hemodialysis (16, 18). Details of active and passive prophylaxis of HBV are beyond the scope for discussion in this chapter. Management of chronic HBV infection in children should include the following considerations (1): 1. Establish evidence for chronic HBV infection with at least two positive HBsAg testing 6 months apart with a positive HBcAb (core antibody) IgG (may be occasionally a false positive). 2. Establish ALT (alanine aminotransferase) elevations for at least 3–6 months in children over 2 years. 3. Monitor yearly HBeAg and anti-HBeAg positivity in those with normal ALT. 4. A liver biopsy to assess extent of histological disease is desirable but not mandatory. 5. Monitor for clinical evidence of decompensated liver disease. 6. Immunize against hepatitis A.
Treatment of Viral Hepatitis in Children – 2008
409
7. Ensure HBV immunization of household/social contacts. 8. Check serum alpha-fetoprotein and liver sonogram yearly as screening tools for HCC. 9. Monitor for a period of time to ensure that there is no spontaneous seroconversion to HBeAb which precludes need for treatment.
4. TREATMENT Treatment strategies for children with chronic HBV should aim to inhibit the viral replication, prevent active liver disease, and induce HbeAg seroconversion, and ideally, to eradicate the HBsAg. Children with chronic HBV infection can develop active liver disease at any time with potentially severe sequelae later in life and the currently available therapies, while not totally effective in eradicating the virus, may still contain or reduce the progression. But, children in the early immune tolerant phase typically maintain a high serum viral load and normal aminotransferases which are factors against successful outcome of treatment. The antiviral therapy is effective only in <5% in those with normal aminotransferases, 5–10% in those with ALT >1.5–2 times the upper limit of normal (ULN), and 25% if ALT is above 5 × ULN (5, 18). Currently, there are only a few options to treat HBV in children and they have major limitations and dubious success. Patients who develop chronic infection need to be evaluated individually and a strategy to treat should be developed based on age, laboratory values, and the phase of immunity as detailed above (1). Drugs approved for therapy in children, namely interferon (IFN), lamivudine (LAM), and recently, adefovir (ADV) do not consistently fulfill the goals of therapy; therefore, appropriate patient selection is critical to the success of the treatment. For the physician and the parent, it is often a complex and difficult decision to make, to treat or not to treat, especially if the practice of medicine should be based on the principle – “Physician! Do no harm”. This chapter discusses the key studies on treatment of hepatitis B infected children, the main concerns/questions and future directions in this area. Through the years several guidelines have been developed which are helpful to the practicing pediatricians and hepatologists in making a decision to treat a child with chronic HBV (1, 5, 12). In 1999, a series of consensus statements were released by 18 researchers from Europe who pooled their experience in treating a large group of HBVinfected children. They agreed that (1) children with HBV DNA and HBeAg positivity should be considered for treatment to accelerate the clearance of HBeAg; (2) only children above 2 years should be treated because of potential growth retardation from IFN; (3) children should
410
Schneider and Mohan
maintain elevated ALT levels indicative of active hepatitis in order to have a good response to treatment; (4) the viral load should be low or intermediate; (5) a liver biopsy should be considered as an important tool to assess severity of inflammation and fibrosis; (6) treatment is contraindicated in children with decompensated liver disease, cytopenia, severe renal cardiac, or significant autoimmune diseases; hepatitis C and HIV were not excluded; and (7) A standard dose of 5 MU/m2 of interferon three times weekly for 6 months should be used (12). Some of these principles are still applicable when considering treatment with newer, safer oral therapies.
5. IMMUNOMODULATORY THERAPY 5.1. Interferons Interferon (IFN) alfa was the first drug used to treat chronic HBV in both adults and children. It has antiviral, anti-tumor, and immunomodulatory activities (6). Review of published data on treatment of HBV patients with IFN reveals a positive response in up to 58% of treated adult and pediatric patients in the western hemisphere whereas the response rate is much lower at 3–17% in the Asian continent which may be due to genetic and racial factors (4, 18). Elevated aminotransferases seem to reduce the racial differences in response to therapy and offer about 20–25% seroconversion even in endemic areas, when coupled with a younger age at treatment and low HBV DNA levels. Seroconversion may occur during or up to 12 months of completion of treatment. Doses ranging from 5 to 10 MU/m2 (high) to 3–6 MU/m2 (low) three times a week for 6–12 months have been used in various published reports and response rates are similar in children and adults and vary from 8 to 50% (Table 1). Response may be affected by the route of acquisition, ethnic origin, histological activity in the liver, and viral factors (Table 2). IFN may occasionally cause flares of hepatitis or elevated aminotransferases during treatment which should not be an indication to stop therapy (20). Data derived from the various studies on IFN therapy in children are conflicting and not reassuring. One of the earlier, notable studies was a large multinational randomized controlled trial in 149 HBV infected children from 18 centers in Europe and the North American continent (23). Children between 1 and 17 years who had ALT levels X 2 ULN were treated with IFN alpha for 24 weeks. At the end of the study period, there was loss of HBeAg and DNA in 26% vs. 11% untreated controls and loss of HBsAg in 10% vs. 1 % of controls; baseline ALT levels, viral load, or liver histology did not affect the response. Torre
∗
50 9 127 70 107 30 37 21
Treated #
No placebo control group reported.
Ruiz-Moreno 1995 Narkewitz 1995 Torre 1996 Sokal 1998 Bartolloti 2000 Gurakan 2000 Diem 2005 Hsu 2008
Author/year
Dose million U/m2 (TIW) 3.6–7.2 5–6 3–10 6 3–7.5 5–10 6 3
Age in years range/mean 9±3 5.7 1.5–17 1–17 8.5 10.6 ± 3 5.2 ± 3.8 14 12–24 16–24 12–48 24 12–24 24 16–24 24
Duration (weeks) 36/10 26/11 23/10 26/11 32/29 33–60 (2 doses)/..∗ 47/33 86/89
HBe conversion Rx/control (%)
Table 1 Treatment of Hepatitis B in Children – Key Studies
—10/1 1.6/0 10/1 25/0 7/. . .∗ 9/4 9.5/4.8
HBsAg loss Rx/control (%)
21 22 24 23 25 26 27 28
Ref. No.
412
Schneider and Mohan
Table 2 Variables Associated with Treatment Success in Children with Chronic HBV Infection (Modified with permission from Elisofon et al. (1)) Agent
Factors offering a higher response
Factors not affecting response
Interferon
ALT > twice normal for age Female gender HBV viral load >105 copies/mL Younger age at treatment (<5 years) (29) Older age at acquisition of infection Active inflammation on liver biopsy HBV genotype (19) Elevated ALT 9 > twice normal for age Active inflammation on baseline liver biopsy (high HAI score)
Ethnicity Body surface area
Lamivudine
Adefovir (43)
Age >12 years Elevated ALT >2.3 times normal for age HBV DNA < 8.8 log10 copies/ml
Baseline Viral load Race/ethnicity/age/ gender Baseline BMI/weight Previous interferon treatment
and Tambini performed a meta-analysis of six randomized controlled clinical trials involving 240 children from Europe and concluded that prolonged therapy over 6 months, a higher baseline ALT, but not a higher dose of IFN, led to a favorable response (24). In contrast, a higher dose of IFN was found to offer a higher response rate in another smaller study (26). In another large study of 107 children treated for 3–6 months and followed for 69 months, there was a high rate of HBeAg seroconversion (32% total, 15% during therapy and 17% in the follow-up period) indicative of short-term benefit from therapy, but no long-term benefits were observed in maintaining HBe seroconversion as compared to untreated children (25). Kobak et al. reported a favorable response from IFN therapy in clearing the HBsAg and HBeAg in children below 5 years (29). In a retrospective study on 22 children by chart review, 78% under 5 years vs. 23% over 5 years of age responded to therapy and aminotransferase levels did not affect the out-
Treatment of Viral Hepatitis in Children – 2008
413
come. Steroid priming has not been found to be effective (30). Recently Hsu et al. studied the short- and long-term effects of IFN therapy in young children with early acquisition of HBV infection. They found that the cumulative rate of virologic response at 1 year and 6 years after the end of treatment (with and without steroid priming) did not differ between treated and untreated patients. A lower pre-treatment viral load seemed to provide some beneficial effect on therapy (28). Overall, response to IFN alone has been disappointing.
5.2. Limitations Limited efficiency and adverse effects restrict use of IFN in the treatment of children. The profile of adverse events is similar in children and adults. Side effects include, fever, flu-like symptoms, myalgia, headaches, and more serious ones such as neutropenia, thyroiditis, retinal changes, seizures, and depression. There is potential danger of worsening autoimmune disorders and compensated cirrhosis. The use of IFN in younger children has been of concern due to its potential effect on growth, although growth failure is reversible, but use of IFN under 2 years of age is not advisable (1, 31). Contraindications to the use of IFN include decompensated cirrhosis, renal disease, neutropenia, seizures, cardiac disease, autoimmune disease, and clinical depression – patients with these concomitant conditions should be either excluded from IFN treatment or should be treated with very close monitoring.
5.3. Oral Antiviral Agents More recent antiviral agents many of which are already approved for use in adults with HBV infection are being considered for treatment of children with HBV, either as approved drugs or through multicenter-controlled studies. They include nucleoside and nucleotide analogues. These drugs are phosphorylated into their active forms within the infected cells and are incorporated into HBV-infected hepatocyte inhibiting viral multiplication (19). These include lamivudine (LAM) and adefovir (ADV) with an attractive safety profile and ease of administration, but with significant deficiencies in the long-term outcome of treatment.
5.4. Lamivudine Lamivudine (LAM) is a pyrimidine nucleoside analogue which prevents replication of HBV in the hepatocyte, leading to chain termination and thereby inhibition of viral reverse transcription, with a rapid decrease in viral load in the early phase of treatment. Histological improvement has been noted on LAM therapy in various trials in adults
414
Schneider and Mohan
(32, 33). LAM is now approved for use in children by the Federal Drug Administration (FDA) in the United States, at an oral dose of 3 mg/kg (a maximum of 100 mg/day). This was supported by the outcome of a large multi-center double blind, placebo-controlled trial for 52 weeks which was initiated in 2002 in the United States and Europe in which 288 children participated (34). Children who were HBsAg positive for 6 months or more, with HBeAg and DNA positivity and elevated ALT >1.3 times the ULN, but lower than 500 IU/L and histological evidence for chronic liver disease, were given LAM 3 mg/kg or placebo. Twentythree percent of children cleared HBeAg and HBV DNA at 52 weeks as compared to 13% of untreated children. The response rate was higher, 35% in those with ALT >2 X ULN. Non-responders, treated with openlabel LAM showed a cumulative virologic response in 35% over a 3year period. But loss of HBeAg occurred only in 3%. A minimum of 1 year of treatment with LAM is now recommended and should continue for at least 6 months after clearance of HBeAg (3). In a follow-up study, 19% children showed LAM resistance (YMDD mutant) within the first year of treatment which increased over time if treatment was continued beyond 1 year, resulting in lower response rates (35). Viral response (VR) was maintained in most patients who had initially responded to LAM in the first 12 months. One hundred and fifty one children from this study were followed for 2 more years (36). Durable VR in the form of HBeAg clearance was seen in 82% and over 90% in those who was treated for 52 weeks and at least 2 years, respectively. Hom et al. reported that higher baseline ALT, higher HAI score, and lower DNA levels may be predictive of a positive viral response, but age or ethnicity did not have any impact on the result of therapy, whereas Choe et al. reported a better response in young school age children when treated with LAM as compared to IFN (37, 38). Thus, cumulative data from various studies point to varying durability of HBe seroconversion, rare HBsAg clearance, and concerns regarding the development of LAM resistance on long-term use (37, 38, 39).
5.5. Combination Therapy Combination therapy with IFN and LAM is an attractive idea and has been used in a limited number of pediatric studies (4). No improved outcome has been reported. But, a more recent pilot study holds promise especially in children with normal aminotransferases. Twenty-three children infected as infants, most of them with normal transaminases, were treated with LAM alone for 8 weeks followed by LAM and interferon alpha 5 MU/m2 for 10 months. Seventy percent children cleared HBV at the end of treatment with a 22% seroconversion to HBeAb with
Treatment of Viral Hepatitis in Children – 2008
415
17% achieving sustained HBsAg clearance after 40 months (40). Diciki et al. reported 30 children who were treated simultaneously with large doses of both drugs (IFN 10 million units) (LAM 4 mg/kg) for 6 months vs. 12 months; 60% of those treated for 12 months and 30% of those treated for 6 months achieved HBeAg clearance (41).
5.6. Limitations Although the safety profile of LAM is excellent, relapse following cessation of treatment and development of resistance due to viral mutations limit the use of LAM and defines a possible role in combination therapies with either IFN or other nucleoside/nucleotide analogues (19).
5.7. Adefovir Adefovir dipivoxil (ADV) is another nucleoside analogue currently approved for use in adults with chronic HBV infection. The mechanism of action includes inhibition of HBV DNA reverse transcriptase and DNA polymerase activity, with efficacy against both the wild- and LAM-resistant mutant type of the virus (1, 42). Viral resistance has been much less as compared to LAM (about 3% in 3 years). A recent multi-center, randomized, double-blind, placebo-controlled study conducted in the United States and Europe explored the safety, efficacy, and pharmacokinetics of ADV in 173 treatment na¨ıve and previously treated children with chronic HBV infection, stratified based on age to three categories (2–7, 8–12, 12–18 years). ADV was given at doses of 0.3 mg/kg, 0.25 mg/kg, and 10 mg daily, respectively, vs. placebo (2:1) for 48 weeks (43). The racial distribution was similar for both Caucasian vs. Asian. The primary end point was serum HBV DNA <1000 copies/mL and normal ALT at week 48. This was achieved in 23% of patients between 12 and 17 years on ADV vs. 0% in controls (p <0.009), similar to its efficacy in adult patients. There was no difference in viral clearance between treated and untreated younger patients. Across all age groups, there was a greater number of patients on ADV who seroconverted to HBeAb (15.9% vs. 5.3%) although this was not statistically significant. No patient developed an ADV-associated mutation (rtN236T or rtA181V). The drug was safe and well-tolerated by all age groups. Treatment-related adverse effects were unusual and included asymptomatic elevations of creatinine and elevation of hepatic enzymes in a few patients. The relative lack of response of younger children could not be explained. Overall, the study indicated that higher ALT and lower HBV DNA at baseline were associated with better outcome with the primary endpoints (43).
416
Schneider and Mohan
5.8. Newer Therapy Entecavir is an oral guanosine nucleoside analogue which inhibits HBV polymerase activity at various steps and is now licensed for use in adults in the United States since 2005. A pharmacokinetic and safety/efficacy study in children is being initiated in Europe and the United States (1). Tenofovir has just been licensed for use in adults and clinical trials in children are anticipated. Pegylated interferon-␣ 2a (PEG-IFN) is now approved for treatment of adults with HBeAg positive and negative infection and promises to offer a better virologic and histological response as a single agent or in combination with LAM. While there was a 7% loss of HBsAg with PEG alone there was no benefit from combined therapy with LAM (1). PEG-IFN is not yet approved for use in children. Other drugs in trials in adults are telbivudine, emtricitabine, and tenofovir especially in the setting of HIV co-infection, but there are no data on their use in children.
6. SUMMARY AND RECOMMENDATIONS Infants affected perinatally have a greater propensity to develop chronic HBV infection. These children do not seem to benefit from therapy with interferon or the newer oral nucleoside or nucleotide analogues which are generally ineffective in those with low ALT and high viral loads. Indefinite treatment is costly and may prompt the development of resistant strains. Interferons, despite their side effects, offer the best chance of clearance of HBsAg or seroconversion to HBeAb and a finite duration of therapy in those with elevated aminotransferases and abnormal liver histology. Careful selection of pediatric patients for treatment should be based on the capability for close monitoring and regular follow-up, considerations such as co-morbidity, progression or active liver disease, familial, social and compliance issues, and definite end points in treatment. During treatment with any agent, patients should be assessed for markers of viral activity and immune-mediated liver injury. Patients’ growth, weight, body mass index (BMI), and liver functions should be closely monitored and health-related quality of life and psychological factors should not be ignored.
7. HEPATITIS C: INTRODUCTION Hepatitis C virus (HCV) is a small, single-stranded RNA virus belonging to the family Flaviviridae which has become the most significant cause of chronic liver disease of infectious etiology in the United States. Data from the Centers for Disease Control and Prevention
Treatment of Viral Hepatitis in Children – 2008
417
(CDC) have shown the seroprevalence of HCV infection is 1.8% in the general population of the United States (44). Among children, the seroprevalence is 0.2% for those <12 years of age and 0.4% for those 12–19 years of age. In adults, the highest rates of HCV antibody are found among those with repeated percutaneous exposures (IVDU) and patients with hemophilia who have received multiple blood transfusions (60–90%). This is followed by hemodialysis patients (20%) and even lower rates among parenteral or mucosal exposures such as patients with high-risk sexual behaviors, household contacts of infected persons, and health-care workers (1–10%) (17, 44). Before 1986, transfusionassociated hepatitis occurred in 5–13% of recipients. Following the introduction of HCV antibody screening in 1992 and development of a more sensitive second generation test in 1992, the rate of transmission decreased to 0.001% per unit transfused. Some transfusion-related infections continue to occur due to the failure of the second generation assay to detect anti-HCV in approximately 5% of infected persons and rare cases of blood donations made between the time of acquisition of infection and seroconversion – the “ window period” (4, 44, 45). Subsequent to the introduction of HCV screening techniques, vertical transmission has become the leading source of infection for children (45). Seroprevalence among pregnant women in the United States has been estimated at 1–2% with the risk of perinatal transfer from viremic mothers averaging 5–6% (16). Maternal co-infection with immunodefficiency virus (HIV) and maternal IVDU have been associated with an increased risk of perinatal transmission of HCV (46). Breastfeeding and the mode of delivery (esarean section or vaginal delivery) do not show any difference in transmission rates. Viral factors such as genotype and viral load have not been consistently measured across studies and, therefore, their roles as risk factors in mother-to-infant HCV transmission remain to be proven (46).
8. NATURAL HISTORY Perinatal acquisition of HCV has been shown to lead to a high incidence of viremia and relatively high ALT levels during the first few years of life which subsequently normalize in a significant percentage of patients. In one prospective study of 70 infants born to HCV-infected women in five European centers between 1990 and 1999, 93% were shown to have a wide range of ALT elevations in the first year of life with subsequent normalization of ALT and HCV RNA clearance in 19% by 30 months of age (47). Vogt et al. reported a greater prevalence of HCV RNA clearance in 30 of 67 (45%) children with posttransfusion HCV 20 years after cardiac surgery. However, Vogt et al.
418
Schneider and Mohan
did not report the timing of HCV RNA clearance, so that it is difficult to determine the proportion of children expected to clear viremia later in life (48). In a second retrospective study of 200 HCV-infected children (45% HCV perinatally acquired) in seven European centers, followed for 1–17.5 years, 6% achieved sustained viral clearance and normalization of the ALT level (49). Overall, persistent infection develops in at least 85% of infected newborns even in the absence of biochemical evidence (44). Most studies indicate that spontaneous clearance of HCV virus is rare beyond infancy. Chronic HCV infection is generally asymptomatic. Most children are detected to have chronic HCV infection by history of transfusion, perinatal HCV positivity, or occasionally elevated ALT and its silent nature lends itself to failure of detection of the infection in a large number of patients. Of obvious concern are the long-term effects of chronic HCV on children. Children generally show mild histological changes on liver biopsy even in their late adolescence; however, significant fibrosis, cirrhosis, and HCC have been reported (50, 51, 52). In a study of 60 HCV-infected children (68% transfusion acquired, 13% perinatally acquired), followed for 13 years after infection, patients were mostly asymptomatic with fatigue and diffuse abdominal pain being the most frequent reported symptoms. Overall, 42 liver biopsy specimens were examined and the majority (71%) showed only mild inflammatory changes. Fibrosis was mild or absent in 88% and bridging fibrosis seen in 12% by 13 years (51). Although ALT appeared to be an excellent correlate to liver histology based on this study, discrepancies still existed attesting to the continued value of liver biopsy (51). The need for a liver transplantation for complications of chronic HCV infection is fortunately rare during childhood since the outcome is rather poor, due to the strong possibility of recurrence of HCV in the allograft, according to the Study of Pediatric Liver Transplantation (SPLIT) Registry (53).
9. SCREENING AND PREVENTION The American Academy of Pediatrics (AAP) recommends screening of infants born to HCV-infected mothers and persons with risk factors for HCV infection as shown below; at this time routine screening of pregnant women is not recommended (4, 44). Among infants born to anti-HCV positive mothers, passively acquired antibodies may persist up to 18 months. In these cases assays for HCV RNA detection (HCV PCR) may be used to detect active infection in the infant rather than passive transfer of antibodies from the mother (16).
Treatment of Viral Hepatitis in Children – 2008
419
Current recommendations for screening for HCV infection (16):
Children born to HCV-positive mother Transfusion/solid organ transplantation before 1992 Recipient of clotting factors before 1992 Chronic hemodialysis After known parenteral exposure Persistently high ALT History of drug use Adoptees from endemic areas
HCV exhibits substantial heterogeneity as a result of mutations occurring during viral replication. This rapid mutation appears to be the mechanism by which the virus escapes immune surveillance and the largest stumbling block in the creation of an effective vaccine. In addition, since antibodies created against one HCV genotype do not recognize other viral genotypes, previous infection does not protect against re-infection with the same or different genotype of the virus (44). Currently, there is no evidence of clinical efficacy from the use of immune globulin for post-exposure HCV prophylaxis of HCV. Due to the lack of a vaccine and immuno-prophylaxis, general precautions and prevention techniques such as blood product screening have a critical role in prevention of propagation of HCV infection. Patients should be advised to abstain from IV drug use, alcohol, and risky sexual behaviors. Current guidelines of the CDC and AAP do not consider maternal HCV infection a contraindication to breastfeeding (16). Also, routine serologic testing of adoptees is not recommended though advised, unless the biological mother has an increased risk for HCV.
10. TREATMENT The decision to treat a child with HCV infection is complex because of the lack of predictable success, the presence of significant toxicity related to currently available therapies, and the relatively benign nature of the disease in childhood and adolescence. Children infected with HCV tend to have a milder degree of liver disease with minimal fibrosis. This presumably can be attributed to the shorter duration of infection and the absence of co-morbid conditions such as HIV-infection, alcohol abuse, or autoimmune disorders that would complicate treatment (17). In contrast, by virtue of their longer life expectancies, there is a likelihood of development of complications from HCV later in life. The
420
Schneider and Mohan
decision to treat may have to be based on several factors such as clinical assessment, laboratory parameters especially synthetic functions of the liver, viral genotype, evidence of portal hypertension, liver biopsy findings, and any contraindication to treatment (1). Before considering therapy: 1. Infection should be confirmed via HCV RNA PCR and laboratory tests determining HCV genotype. 2. Liver function tests should be done to assess inflammation and to rule out other types of liver diseases, such as autoimmune hepatitis and Wilson’s disease. 3. Patients should be monitored for complications such as portal hypertension and hepatic decompensation. 4. Prior to a decision to treat, a liver biopsy to assess the extent of histological disease is suggested, except in those infected with genotype 2 or 3 due to their excellent response rate to treatment and associated mild liver disease (1). 5. Additionally, the presence of other co-morbidities such as obesity and alcohol use in adolescents should be investigated to determine their effect on treatment outcomes. 6. Optimal timing of therapy should also take into consideration agerelated limitations, growth, social, and psychological factors.
Treatment of HCV infection may be considered in the following settings: 1. Children with genotypes 2, 3 because of excellent response and shorter duration of treatment (1). 2. Children with evidence for advancing disease, compensated cirrhosis, or moderate to severe fibrosis on biopsy require close monitoring for sudden hepatic decompensation. 3. Treatment in the setting of clinical trials involving therapeutic options not currently approved for use in children. 4. Availability of newer therapies.
10.1. Interferon Alpha Interferon alpha (IFN) monotherapy has been extensively studied in adults and was shown to result in sustained virologic response (SVR) 6 months after completion of therapy in approximately 8% of patients (54). To date, no large multi-center trials have studied sustained response rates, predictors of response to therapy, or safety of and tolerance of IFN monotherapy in children with chronic hepatitis C. One of the earliest studies involving children came from Japan in 1997 in which 22 children with transfusion acquired HCV infection
Treatment of Viral Hepatitis in Children – 2008
421
were treated with IFN and 11 children (50%) reached sustained viral response with 1–2 rounds of treatment (55). Furthermore, Jacobson et al. attempted to answer these questions by doing a meta-analysis of 19 trials involving 366 IFN treated and 105 untreated children aged 2–21 (56). Initial treatment trials using a dose of 3 MU/ m2 of IFN three times weekly showed that children had a much better response rate of about 35–40% compared to adults; genotypes other than 1 responded better (70% vs. 27%) (54, 56, 57). No differences were noted among the studies with regard to the duration of treatment or dosage. The most commonly reported adverse events in children were influenza-like symptoms including fever, weight loss during treatment (with subsequent resolution), neutropenia, and alopecia (56). High-dose IFN alpha (10 MU/m2 ) was studied by Marcellini et al. and was not found to be superior to the standard dosage (58).
10.2. Interferon-Alpha and Ribavirin Ribavirin (RBV) is a synthetic nucleoside which has some in vitro antiviral activities providing synergy when used in combination with IFN, but has no direct antiviral effect if used as a single agent. However, superiority of combination therapy with standard interferon over interferon monotherapy was established in adults by several studies in 1998 (59). In 2000, a cohort study consisting of 12 children and adolescents with chronic hepatitis C and previous malignancy were treated with recombinant IFN alpha-2a (6 MU/m2 body surface area, three times a week, subcutaneously) combined with RBV (15 mg/kg body weight/day, orally) for 12 months (60). All of the patients had HCV subtype 1 and none had previously been treated with IFN. Sustained response as defined by normalization of aminotransferases and negativity of HCV RNA at the end of treatment and >6 months after withdrawal of therapy was seen in 50% of participants 12 months after withdrawal of therapy, the majority of which had achieved HCV RNA negativity within 1–3 months of treatment (60). A second study published in 2000 consisted of 11 children with chronic hepatitis C and malignancy in remission being treated with IFN and RBV for 48 weeks with a 12-month follow-up period (61). At the 12-month follow-up, 64% had sustained virologic and biochemical responses with undetectable HCV RNA and normal ALT levels; all those with genotype 3 sustained SVR (61). In a larger study involving 40 HCV-infected children, patients were treated with IFN-alpha at a dose of 3 or 5 MU/m2 3 times weekly in combination with oral RBV 15 mg/kg/d for 12 months. Twenty-five patients (61%) were HCV RNA negative at the end of treatment and remained negative at the 6-month follow-up
422
Schneider and Mohan
with normalization of ALT levels. Sustained viral response (SVR) was achieved in 53% of patients with HCV subtype 1 and 100% of patients with either subtype 2 or 3 (62). The most notable study to date was published in 2005 by the International Pediatric Hepatitis C therapy group (63). This phase 3 study encompassed 48 weeks of treatment followed by 24 weeks of observation, conducted in 29 centers in the United States and Europe, and enrolled 118 children between 3 and 17 years. They were treated with IFN-alpha-2b 3 million IU/m2 subcutaneously three times a week in combination with RBV at 15 mg/kg PO. The eligibility criteria included serum positivity for HCV by quantitative PCR and a liver biopsy consistent with chronic HCV. The study excluded children with anemia, thrombocytopenia, positive ANA ≥160 and abnormal synthetic liver functions, other viral infection and systemic illnesses. In all, 46% attained SVR at follow-up, and SVR was higher in those infected with genotype 2 or 3 (84%) vs. genotype 1 (36%). This study concluded that HCV genotype 2 or 3 and a viral load below 2 million copies/mL for HCV genotype 1 were favorable factors for SVR. Side effects included anemia, neutropenia leading to dose modifications in 31% and discontinuation in 7%. A notable aspect of this trial was the impact of therapy on growth. The linear growth and weight gain were temporarily inhibited during the study which was partially compensated during the observation period (63). Additionally, the teratogenic properties of RBV was considered as a serious side effect and RBV was used with extreme caution in both adolescent males and females of childbearing potential (63, 64). Overall, baseline ALT, mode of acquisition of HCV, ethnicity, gender, and the duration of infection did not seem to affect the SVR in any of these studies. In 2003, the Food and Drug Administration approved the combination of standard IFN and RBV for the treatment of chronic hepatitis C in children between 3 and 17 years of age and this remains as the only FDA approved treatment to date.
10.3. Pegylated Interferon (PEG-IFN) Monotherapy The limited attainment of SVR, the need for frequent injections and the side effect profile were recognized as the major obstacles or disadvantages in the use of standard intereferons. The use of PEG-IFN once a week seemed to improve response rate and was more acceptable to patients. Pegylation of IFN, i.e., covalent linking of a protein molecule to polyethylene glycol was found to provide a longer half-life and reduced clearance allowing for less frequent dosing. Three large trials in adults addressing the end of treatment response (ETR) and sustained
Treatment of Viral Hepatitis in Children – 2008
423
virologic response (SVR) using a dose of 180 g/kg or a randomized weight-based dosing of 0.5, 1, 1.5 g/kg of body weight once weekly showed an ETR (end of treatment response) of 33–69 % and SVR of 23–39% (65). Subsequently, the safety and efficacy of PEG-IFN monotherapy was evaluated in a pharmacokinetic study in 14 children infected with HCV 1 genotype from 2 to 8 years (66). PEG-IFN was given subcutaneously at a dose of 180 g/1.73 m2 once a week for 48 weeks (66). The primary efficacy end point, defined as HCV RNA level of <50 IU/mL at 24 weeks after the end of therapy, was attained in 43% (6/14) patients (46% for genotype 1). Side effects were milder than reported in adults and included fever, headache, fatigue, vomiting, and rarely irritability and need for dose adjustment, but weight loss was not reported (66).
10.4. Peginterferon and Ribavirin Combination Therapy Peginterferon (PEG-IFN) and RBV combination is currently being used as standard therapy for chronic HCV infection in adults, but has not yet been approved by FDA for use in children. Studies have shown that this combination therapy has significantly improved rates of SVR when compared to thrice-weekly IFN and RBV therapy (54–56% vs. 44–47%) (67, 68). Additionally, the combination therapy in adults has also been associated with a decrease in hepatic inflammation and a decrease in relapse rates especially in patients with genotype 1 (42% vs. 29–33%) (68). To date, there are very few reports of PEG-IFN and RBV combination therapy in children. In 2005, an open-label uncontrolled pilot study evaluated this therapy in 62 children and adolescents aged 2–17 years (69). The patients were treated with subcutaneous PEGIFN-alpha-2a at a dose of 1.5 micrograms/kg body weight once per week plus oral RBV at 15 mg/kg/day for 48 weeks. SVR was documented in 59% at the 6 month follow-up after therapy cessation. All 13 patients with genotype 2 or 3 achieved SVR, while 22 of 46 (47.8%) of those with genotype 1 achieved SVR, a rate similar to that of the thrice-weekly IFN and RBV therapy. The likelihood of SVR was independent of baseline ALT and mode of acquisition. Overall, treatment was well-tolerated with leukopenia (83%) being the most reported side effect (69). A pivotal multi-center, placebo-controlled study has been underway since 2004 involving 11 centers and 112 patients from the United States evaluating the safety and efficacy of the combination therapy in children between 5 and 18 years (70). Patients received PEG-2a injection (180 micrograms/1.73 m2 ) once a week and either placebo or RBV tablets orally twice daily (15 mg/kg/day with a maximum dose of 1200 mg/day if >75 kg and 1000 mg/day if <75 kg). The purpose
424
Schneider and Mohan
of the study was to assess the safety and efficacy of PEG-2a plus RBV, and to evaluate additional clinical features impacting treatment such as health-related quality of life and growth and body composition before, during, and after chronic HCV treatment. The final results of this crucial study will be presented and published shortly. From Europe, Jara et al. have published a similar study on 30 children between 3 and 16 years treated with PEG-IFN 1.0 g/kg/week and RBV 15 mg/kg/day for 24–48 weeks (71). Overall, a 50% SVR was attained in patients with all genotypes and virologic response at week 12 was predictive of SVR at 24 weeks after cessation of therapy.
10.5. Newer Therapies Several emerging therapies are being considered for treatment of HCV infection, but none has been approved for use by the FDA, particularly in children. Besides alternate forms of interferons such as omega IFN or gamma IFN, RBV substitutes such as viramidine and levovirin have been considered for trials in adults with HCV because of lesser hematologic side effects (1). VX-497 or merimepodib combined with PEG-IFN and RBV has been evaluated in adults as a more effective drug for achieving durable SVR (72). Hepatitis C virus (HCV) NS3/4A protease inhibitors also have potential for treating chronic HCV disease and are being considered for future trials (73).
10.6. Considerations and Recommendations Based on these studies, the following recommendations may be beneficial when considering treatment of HCV in children: 1. All children to be monitored closely for side effects during therapy and dose reduction instituted for serious effects, such as neutropenia, depression, and growth. 2. Those infected with genotypes 2, 3 should be treated for 24 weeks and the others (genotype 1) for 48 weeks. 3. If patients with genotype 1 did not achieve early virologic response or clear HCV by 24 weeks, treatment should be discontinued. 4. Those who complete and clear HCV should be monitored for SVR 6 months after completion (1). 5. Decision to be individualized on a case-by-case basis.
Children who acquire HCV early in life manifest few symptoms and have relatively mild liver involvement, but have the potential to develop more serious sequelae (51). Benefits of early treatment include a better outcome in the absence of co-morbidity such as alcohol use, and avoidance of social stigma. Studies as discussed above have shown that children tolerate treatment with IFN well although they also do not
Treatment of Viral Hepatitis in Children – 2008
425
appear to achieve such optimal sustained viral response rates that would prompt treatment of all infected children. The slow progression and lack of symptoms affecting activity and lifestyle, on the other hand, favor deferment of therapy, given the spectrum of side effects from the therapy especially involving growth. Currently, the combination of PEGIFN and RBV holds the best promise in terms of efficacy and safety and awaits FDA approval. It can be hoped that newer trials involving drugs with less toxicity and a more attractive response profile will be extended to involve not only adults with chronic HCV but children as well.
REFERENCES Hepatitis B 1. Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liv Dis 2006;10:133–48. 2. Zuckerman JN, Zuckerman AJ. The epidemiology of Hepatitis B. Clin Liv Dis 1999;3:179–87. 3. Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43:S56–60. 4. Jonas MM. HBV/HCV C therapy in children. AASLD postgraduate course 2007;106–12. 5. Chang M-H. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int 2008;2:S28–S36. 6. Ng VL, Balistreri WF. Hepatitis B- clinical perspectives in pediatrics. Clin Liv Dis 1999;3:267–90. 7. Chang MH, Chen CJ, Lai MS. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma study group. N Eng J Med 1997;336:1906–7. 8. Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 2006;43:S173–S181. 9. Godra A, Jonas MM, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis B. Mod Pathol 2005;18:346A. 10. Boxell EH, Sira J, Standish RA, Davies P et al. Natural history of hepatitis in perinatally infected carriers. Arch Dis Child Fetal Neonatal Ed. 2004;89(5): F456–60. 11. Fugisawa T, Momatsu H, Inui A, Sogo T et al. Long term outcome of chronic hepatitis B in adolescents and young adults in follow up from childhood. J Pediatr Gastroenterol Nutr 2000;30(2):201–6. 12. Jara P, Bartolloti F. Interferon-␣ treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999;29:163–70. 13. Hsu HC, Wu MZ, Chang MH, Su IJ, Chen DS. Childhood hepatocellular carcinoma develops exclusively in hepatitis B surface antigen carriers in three decades in Taiwan. Report of 51 cases strongly associated with rapid development of liver cirrhosis. J Hepatol 1987;5:260–7.
426
Schneider and Mohan
14. Diem VT. Natural and treatment related history of chronic hepatitis B virus infection. J Pediatr Gastro Nutr 2002;34:A10. 15. Bartolloti F, Jara P, Crivellaro C, et al. Outcome of chronic hepatitis B in Caucasian children during a 2 year observation period. J Hepatol 1998;29:184–90. 16. Red Book. Hepatitis B and C-Report of the committee on infectious diseases. American Academy of Pediatrics. 2006;27:335–61. 17. Jonas MM. Viral hepatitis – from prevention to antivirals. Clin Liv Dis 2000;4:849–77. 18. Lok ASF, McMahon BJ. Chronic hepatitis B- AASLD practice guidelines. Hepatology 2007;45:507–39. 19. Davison S. Chronic Hepatitis. In: Kelly D. Diseases of the liver and biliary system in children, 2nd edition. Blackwell Publishing. 2004;127–61. 20. Lau DTY, Membrano FE. Antiviral Therapy for treatment- na¨ıve hepatitis B virus patients. Gastro Clin N Amer 2004;33:581–99. 21. Ruiz-Moreno M, Camps T, Jimenez J, Lopez R, et al. Factors predictive of response to interferon therapy in children with chronic hepatitis B. J Hepatol 1995;22:540–4. 22. Narkewitz MR, Smith D, Silverman A, Veirling Clearance of chronic hepatitis B virus infection in young children after alpha interferon treatment. J Pediatr 1995;127:815–8. 23. Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, et al. Interferon Alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterol 1998;114:988–95. 24. Torre D, Tambini R. Interferon-␣ therapy for chronic hepatitis B in children: A meta-analysis. Clinic Inf Dis 1996;23:131–7. 25. Bartolloti F, Jara P, Barbera C, Gregorio GV. Long term effect of alpha interferon in children with chronic hepatitis B. Gut 2000;46:715–8. 26. Gurakan F, Kocak N, Ozen H, et al. Comparison of standard and high dose recombinant interferon alpha 2b for treatment of children with chronic hepatitis B infection. Pediatr Infect Dis 2000;19:52–6. 27. Diem HVT, Bourgois A, Bontems P, Goyens P, et al. Chronic hepatitis B infection : Long term comparison of children receiving interferon alpha and untreated controls J Pediatr Gastroenterol Nutr 2005;40:141–5. 28. Hsu H-Y, Tsai H-Y, Wu T-C, Chiang C-L, et al. Interferon – ␣ treatment in children and young adults with chronic hepatitis B: a long term follow-up study in Taiwan. Liver International 2008;1478–3223. 29. Kobak GE, Mackenzie T, Sokol RJ, Narkewicz MR. Interferon treatment for chronic hepatitis: enhanced response in children 5 years old or younger. J Pediatr 2004;145(3):340–345. 30. Giacchino R, Main J, Timitilli A, et al. Dual-center, double blind, randomized trial of lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. Liver 1995;15:143–8. 31. Comanor L, Monor J, Conjeevaram HS, et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth in children. J Viral Hepatol 2001;8:139–47. 32. Leung N. Liver disease- significant improvement with lamivudine. J Med Virol 2000;61:380–5. 33. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998;339: 61–8.
Treatment of Viral Hepatitis in Children – 2008
427
34. Jonas MM, Kelly DA, Mizersky J, Badia IB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Eng J Med 2002;346:1706–13. 35. Sokal EM, Kelly DA, Mizerski J, Badia IB, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006 Feb;43(2):225–32. 36. Jonas MM, Little NR, Gardner SD; International Pediatric lamivudine Investigator Group. Long-term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety. J Viral Hepatol 2008 Jan;15(1): 20–7. 37. Hom X, Little NR, Gardner SD, Jonas MM. Predictors of virologic response to lamivudine treatment in children with chronic hepatitis B infection. Ped Inf Dis J. 2004;23(5):441–4. 38. Choe B-H, Lee JH, Jang YC, Jang CH, et al. Long-term therapeutic efficacy of lamivudine compared with Interferon-{alpha} in children with chronic hepatitis B: the younger the better. J Ped Gastroenterol Nutr 2007;44:92–8. 39. Hartman C, Berkowitz D, Shouval D, Eshach-Adiv O, et al. Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon. Ped Inf Dis J 2003;22(3):224–8. 40. D’Antiga L, Aw M, Atkins MF, Moorat A, et al. Combined lamivudine/interferon (alpha) treatment in immunotolerant children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148(2):228–33. 41. Diciki B, Bosnak M, Kara HI, Dogru O. Lamivudine and interferon-alpha combination treatment of childhood patients with chronic hepatitis B infection. Ped J Inf Dis 2001;20(10):988–92. 42. Marcellin P, Chang T-T, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen positive chronic hepatitis B. N Eng J Med 2003;348:808–16. 43. Jonas MM, Kelly D, Pollack H, Mizerski J, et al. Safety, efficiency and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology 2008;47:1863–71.
Hepatitis C 44. Committee on Infectious Diseases, American Academy of Pediatrics. Hepatitis C virus infection. Pediatrics 1998;101:481–5. 45. Bortolotti F, Resti M, Giacchino R, et al. Changing epidemiologic pattern of chronic hepatitis C virus infection in Italian children. J Pediatr 1998;133:378–81. 46. Yeung LTF, King SM, Roberts EA. Mother-to-Infant transmission of hepatitis C virus. Hepatology 2001;34:223–9. 47. Resti M, Jara P, Hierro L, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. J Med Virol 2003;70:373–7. 48. Vogt M, Land T, Frosner G, Klinger C, et al. Prevalence and clinical outcome of HCV infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999;341:866–70. 49. Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003;36: 275–80. 50. Gonzalez-Peralta R, Langham M, Mohan P, et al. Hepatocellular carcinoma in two adolescents with cirrhosis secondary to hepatitis C virus infection. J Pediatr Gastroenterol Nutr 2003;37:380.
428
Schneider and Mohan
51. Mohan P, Colvin C, Glymph C, Chandra RR, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150(2):168–74. 52. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, et al. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998;28: 1416–23. 53. Futagawa Y, Terasaki PI. An analysis of the OPTN/UNOS Liver Transplant Registry. Clin Transpl 2004:315–29. 54. Carithers RL, Emerson SS. Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials. Hepatology 1997;26:83s–88s. 55. Matsuoka S, Mori K, Nakano O, et al. Efficacy of interferons in treating children with chronic hepatitis C. Eur J Pediatr 1997;156:704–8. 56. Jacobson KR, Murray K, Zellos A, et al. An analysis of published trials of interferon monotherapy in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2002;34:52–8. 57. Bortolotti F, Giacchino R, Vajro P, et al. Recombinant interferon-alfa therapy in children with chronic hepatitis C. Hepatology 1995;22:1623–7. 58. Marcellini M, Kondili LA, Comparcola D, Spada E et al. High dosage alphainterferon for treatment of children and young adults with chronic hepatitis C disease. Pediatr Infect Dis J 1997 Nov;16(11):1049–53. 59. McHutchinson JG, Gordon SC, Schiff ER, Shiffman ML, et al. Interferon alfa2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998 Nov 19;339(21):1485–92. 60. Lackner H, Moser A, Deutsch J, et al. Interferon-␣ and ribavirin in treating children and young adults with chronic hepatitis C after malignancy. Pediatrics 2000;106(4):E53. 61. Christensson B, Wiebe T, Akesson A, et al. Interferon-alpha and ribavirin treatment of hepatitis C in children with malignancy in remission. Clin Infect Dis 2000;30:585–6. 62. Wirth S, Lang T, Gehring S, et al. Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 2002;36:1280–4. 63. Gonzalez-Peralta R, Kelly D, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: Efficacy, safety and pharmacokinetics. Hepatology 2005 Nov;42(5):1010–8. 64. Krilov LR. Safety issues related to the administration of ribavirin. Pediatr Infect Dis J 2002 May;21(5):479–81. 65. Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C- National institutes of health consensus statement. Hepatology 2002 Nov;36(5 Suppl 1):S121–7. 66. Schwarz K, Mohan P, Narkewicz M, Molleston JP, et al. Safety, efficacy and pharmacokinetics of peginterferon [alpha] 2a (40kd) in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2006;43(4):499–505. 67. Fried MW, Shiffman ML, Reddy KJ, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. 68. Manns MP. McHutchinson JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65.
Treatment of Viral Hepatitis in Children – 2008
429
69. Wirth S, Pieper-Boustani H, Lang T, et al. Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatology 2005;41:1013–18. 70. Murray KF, Rodrigue JR, Gonzalez-Peralta R, et al. Design of the PEDS-C trial: pegylated interferon +/– ribavirin for children with chronic hepatitis C viral infection. Clinical Trials 2007;4:661–73. 71. Jara P, Hierro L, dela Vega A, Diaz C, et al. Efficacy and safety of peginterferonalpha2b and ribavirin combination therapy in children with chronic hepatitis C. Pediatr Infect Dis J. 2008;27(2):142–8. 72. Marcellin P, Horsmans Y, Nevens F, Grange JD, et al. Phase 2 study of the combination of merimepodib with peginterferon-alpha2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C. J Hepatol 2007 Oct;47(4):476–83. 73. Thomson JA, Perni RB. Hepatitis C virus NS3-4A protease inhibitors: countering viral subversion in vitro and showing promise in the clinic. Curr Opin Drug Discov Devel 2006 Sep;9(5):606–17.
Viral Hepatitis and Hepatocellular Carcinoma Jorge A. Marrero, MD, MS CONTENTS I NTRODUCTION E PIDEMIOLOGY D IAGNOSTIC E VALUATION T REATMENT P REVENTION R EFERENCES
Key Principles
• Hepatocellular carcinoma (HCC) usually occurs in patients with chronic liver disease, commonly due to viral hepatitis. • Surveillance of patients with cirrhosis of the liver can lead to the detection of HCC at early stages. • The diagnosis of HCC is made by histopathology or by MRI/CT scan showing a hypervascular lesion with washout in the delayed phases. • The Barcelona staging system is the preferred staging system as it combines hepatic function, performance status, and tumor burden, and it is linked to an evidence-based treatment strategy.
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 17, C Humana Press, a part of Springer Science+Business Media, LLC 2009
431
432
Marrero
1. INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related death worldwide (1). Approximately 560,000 people develop liver cancer each year with an almost equal number of mortalities. Thus, it is a tumor with a significant burden worldwide. We herein will discuss the epidemiology, risk factors, surveillance, diagnosis, and prevention of HCC as it pertains to individuals with viral hepatitis.
2. EPIDEMIOLOGY 2.1. General The largest concentration of cases of liver cancer in the world is in Asia, followed by Africa, Europe, and North and South America (2). The incidence of HCC varies among ethnic groups, with increasing incidence rates found in Japanese (5.5/100,000 in men and 4.3/100,000 in women), African American (7.1/100,000 in men and 2.1/100,000 in women), Hispanics (9.8/100,000 in men and 3.5/100,000 in women), and Chinese (16.2/100,000 in men and 5/100,000 in women) populations. Even though the incidence rates are greater in men compared to women, there is a two- to fivefold higher incidence rate among women of various ethnicities compared to non-Hispanic white females. During the last two decades, increasing trends in the incidence of HCC have been noted in Australia, Central Europe, United Kingdom, Japan, and North America (3). In addition, during the same two decades, there has been an increase in mortality due to liver cancer in all countries. In the United States, as the incidence of HCC has increased in recent years, the distribution of patients with HCC has shifted toward younger patients, with the greatest increase in those between 45 and 60 years of age, likely due to the fact that the hepatitis C virus (HCV) epidemic was in the 1960 s and 1970 s and the aging of this cohort (4). The recent review of the Surveillance, Epidemiology and End-Result (SEER) program in the United States, which is a population-based study of cancer epidemiology, has shown that over the last 10 years liver cancer has been the tumor with the highest change in increase compared to other solid tumors.
2.2. Viral Factors The etiological agents leading to HCC have been largely established. In Japan, Europe, and America, about 60% of the patients with HCC are attributed to chronic HCV infection, whereas 20% are attributed to chronic hepatitis B (HBV) infection and about 20%
Viral Hepatitis and Hepatocellular Carcinoma
433
between cryptogenic and alcoholic liver disease. The broad traits of the epidemiology of HCC can be traced to the prevalence of hepatotrophic viral infections. Chronic HBV infection is the most common underlying etiology of HCC in the world (5). In high-prevalence areas such as Eastern Asia, China, and Africa, about 8% of the population is chronically infected as a result of vertical (mother-to-child) or horizontal (child-to-child) transmission. The pattern of transmission is different in areas with lower prevalence of HBV such as North America, Western Europe, and Australia where infection mostly occurs in adulthood through sexual and parenteral routes. The higher prevalence of chronic HBV, as well as the longer period of exposure to infection, largely explains the higher HBV-related HCC risk in endemic areas. Chronic HCV infection is found in a variable proportion of HCC cases in different populations, accounting for 75–90% of cases in Japan, 31–47% in the United States, 44–76% in Italy, and 60–75% of HCC cases in Spain (6). HCC is the cancer with the highest increase in incidence over the last 10 years in the United States and this increase is mostly due to chronic hepatitis C (HCV) (7). Most of the cases of HBV- and HCV-related HCC occur in the setting of cirrhosis as shown in Table 1(6). The risk of HCC in persons with chronic HBV is from 2.2 to 4.3 per 100 person-years in compensated cirrhotics, while it is less than 1 per 100 person-years in non-cirrhotic patients. About 20% of patients with HBV-related HCC present without evidence of cirrhosis, indicating that other factors are important in hepatocarcinogenesis. The risk of HCC among patients with chronic HCV infection also occurs in the setting of patients with cirrhosis as shown in Table 1 (6). In Japanese studies, the summary HCC incidence rate for patients with chronic hepatitis was 1.8 per 100 person-years and 7.1 per 100 person-years in those with compensated cirrhosis. In the United States and Europe, the summary incidence rate was 3.7 per 100 person-years, which is lower than that in Japan (8–11). The natural history of cirrhosis in patients with chronic HCV infection was assessed in 136 patients and followed for a mean of 6.8 years (12). The 5-year cumulative risk for HCC was 10%, the mean interval between diagnosis of cirrhosis and HCC development was 5 years (range, 0.5–10 years), and the median age for diagnosis of HCC was 63 (range, 50–74). Interestingly, more than half of the patients that developed HCC did not experience hepatic decompensation at the time of HCC diagnosis, indicating that HCC arising in cirrhosis can be clinically silent. In addition to the presence of cirrhosis, host viral factors are important in hepatocarcinogenesis. Important host factors are male gender
434
Marrero Table 1 Incidence Rates of Hepatocellular Carcinoma in Prospective Studies in Patients with Hepatitis B and Hepatitis C Infection
Setting
Geography
Hepatitis B Carrier America China Chronic Europe hepatitis Taiwan Japan Cirrhosis Europe Taiwan Japan
No. of Studies
2 4 6 2 2 6 3 2
No. of Patients
Mean Follow-up HCC (yrs) Incidence∗
1804 18,869 471 461 737 401 278 306
16 8 5.9 4 5.1 5.8 4.3 5.8
0.1 0.7 0.1 1.0 0.8 2.2 3.2 4.3
239 1451 553 1284 626
4.2 6.2 9.2 4.5 5.8
0.1 0.8 0.3 3.7 7.1
Hepatitis C Chronic hepatitis
Europe 1 Japan 6 Taiwan 1 Cirrhosis Europe/USA 13 Japan 7 ∗
Incidence is per 100 person-years.
and age >50 years of age, which increase the risk for HCC significantly in both HCV- and HBV-related HCC (13, 14). With regard to HBV-derived HCC, evidence of viral replication measured by e antigen status and high serum HBV DNA levels (>105 copies/mL) (15, 16), and HBV genotypes, specifically B, increases the risk of HCC (17). Therefore, host and hepatitis B viral factors play an important part in the development of HCC. To the contrary, viral factors do not appear to increase the risk of HCC in HCV-related HCC. The burden of HCV-related HCC in the United States is expected to continue to increase during the next decades. A recent study using molecular evolutionary analysis based on the coalescent theory (molecular clock) investigated the time origin of HCV infection in Japan and the United States (18). The authors showed an earlier onset of the HCV epidemic in Japan and, therefore, a longer duration of infection in affected individuals, which increases the likelihood for HCC
Viral Hepatitis and Hepatocellular Carcinoma
435
development compared to the United States. The authors postulate that the incidence of HCC in the United States will continue to increase over the next two to three decades. It has been estimated that the number of cases of HCC will continue to increase by 81% (from a baseline of 13,000/year) by the year 2020, primarily due to the hepatitis C (HCV) epidemic (19). Because of the poor overall survival, the projected increase in the number of patients with HCC may lead to a significant health-care burden in North America.
2.3. Non-Viral Factors Other important risk factors in the development of HCC in patients with chronic viral hepatitis are alcohol and tobacco. Synergism between alcohol and viral hepatitis has been found to increase the risk of HCC (20). Obesity is another important risk factor that increases the risk of HCC (21). Aflatoxin B1 (AFB1 ) is a mycotoxin that grows on food stored in humid conditions and is a carcinogen predisposing to human HCC. AFB1 ingestion has been associated with mutations in the coding regions of p53 tumor suppressor gene (22). Diabetes has also been shown in prospective studies to increase the risk of HCC (23). A recent study showed that there is synergy between alcohol exposure >60 g of ethanol a day, >20 pack years of tobacco smoking, and obesity (BMI >30) in a predominant population of patients with HCV infection (24). Therefore, multiple risk factors are important in the process of carcinogenesis in individuals with viral hepatitis.
3. DIAGNOSTIC EVALUATION 3.1. Surveillance The decision to screen an at-risk population for cancer is based on well-established criteria (25). The objective of screening is the use of a relatively simple, inexpensive test in a large number of individuals to determine whether they are likely or unlikely to have the cancer for which they are being screened. Screening is the one-time application of a test that allows detection of a disease at a stage where curative intervention may improve the goal of reducing morbidity and mortality. Surveillance is the continuous monitoring of disease occurrence (using the screening test) within a population to achieve the same goals of screening. HCC meets these criteria for performing surveillance (26). Despite advances in medical technology, the 1-year survival of patients with HCC improved minimally from 2 to 5% between 1977 and 1996 (27). This may be largely due to diagnosis at late stages of the disease. According to US vital statistics, the age-adjusted mortality rates
436
Marrero
of primary liver cancer increased from 2.8/100,000 persons in 1997 to 4.7/100,000 persons in 2001. In the report to the nation on cancer, the change in mortality rates for liver cancer was the highest among all solid tumors from 1996 to 2005 (www.seer.gov). Surveillance of the high-risk group, i.e., patients with cirrhosis, may improve overall outcomes for patients with HCC. Since the goal of surveillance is to reduce mortality by detecting patients with occult disease prior to developing symptoms, the performance characteristics of a test utilized for diagnosis and/or staging (e.g., CT or MRI) cannot be assumed to be the same when utilized in a surveillance/screening situation. The most commonly used screening test for HCC is ␣-fetoprotein (AFP). It has been shown that the optimal balance of sensitivity and specificity is achieved by a cutoff level of 20 ng/mL (28). However, this cutoff leads to sensitivities between 41 and 60% and specificities between 80 and 94% (29, 30). The other surveillance test that is commonly used is ultrasonography of the liver (US). The sensitivity and specificity of ultrasound (US) have been shown to be between 58 and 78% and 93 and 98%, respectively (31–32). However, the performance characteristics of US as a surveillance test for HCC have been extrapolated mostly from studies that evaluated US as a diagnostic test; therefore, its performance as a surveillance test has not been properly identified. A recent randomized controlled study of screening for HCC has been performed in China (33). This study compared US and AFP vs. no screening and achieved a compliance rate of <60%. It showed that screening led to a reduction of 37% in mortality compared to no screening. One problem with this study is that it enrolled patients with exposure to HBV, without mention of the degree of hepatic fibrosis or viral replication; therefore, not all patients were at the same risk level for developing HCC. This is the first evidence that the strategy of surveillance for HCC with AFP and US improves mortality in a population of HBV carriers. Surveillance is recommended in patients with cirrhosis with US and AFP at a frequency of 6–12 months (29). Screening is also recommended in noncirrhotic HBV patients that are older, >20 years of age, born in Africa, have family history of HCC, and evidence of significant inflammation and fibrosis with viral replication (29). New biomarkers are needed to improve the efficacy of the current surveillance tests.
3.2. Diagnosis Once an abnormal screening test is obtained in a cirrhotic patient, there is a need for a recall test to perform a diagnostic evaluation to assess for the presence of HCC. For the diagnosis of HCC, radiological
Viral Hepatitis and Hepatocellular Carcinoma
437
Table 2 Studies That Compared CT Scan and MRI for the Diagnosis of Hepatocellular Carcinoma Author
De Ledinhen Rode Burrel Libbrecht
Gold Standard
Explanted liver Explanted liver Explanted liver Explanted liver
No. of No. of HCC CT Scan Patients Nodules (n)
34 43 50 49
88 69 127 136
54 13 76 77
MRI
Sens Sp Sens
Sp
51 53 61 50
93 58 75 82
84 92 66 79
61 77 76 70
Sens, sensitivity (%); Sp, specificity (%)
imaging such as a triple-phase spiral CT or a dynamic MRI and biopsy are the diagnostic tests of choice. There have been several studies that have compared CT scan to MRI for the diagnosis of HCC as shown in Table 2 (34–37). It appears that MRI is superior to CT scan for the diagnosis of HCC. However, recent studies suggest that not only arterial enhancement of a hepatic nodule but also “washout” of contrast in the delayed phases of enhancement (38) are important findings in making this diagnosis. “Washout” is defined as hypointensity of a nodule in delayed phases of CT or MRI examination compared to surrounding
A
B
Fig. 1. An MRI showing a hepatocellular carcinoma. (A) shows the arterial phase indicating an enhancing mass in the right lobe (white arrow). (B) shows the same lesion in the delayed venous phase (3 min after contrast injection) showing hypointensity compared to the rest of the liver parenchyma indicating washout (black arrow).
438
Marrero
liver parenchyma. It is likely due to arterial neovascularization that is greater in HCC nodules than it is in the surrounding non-neoplastic hepatic parenchyma, while in the delayed phases there is early venous drainage. Figure 1 shows an example of washout in a patient with an arterially enhancing mass in the presence of cirrhosis. The diagnostic work-up of a patient with abnormal surveillance tests for HCC is shown in Fig. 2. In the case of using AFP, a level above 20 ng/mL is the trigger to obtain a CT scan or an MRI for the diagnosis of HCC.
Fig. 2. Recommendations on the evaluation of an abnormal ultrasound performed during surveillance for hepatocellular carcinoma (Ref. (29), obtained by permission).
4. TREATMENT 4.1. Staging The degree of tumor burden, performance status, and liver dysfunction have repeatedly been shown to be independent factors of prognosis (29). At least seven staging systems for HCC have been proposed over the years. The system that provides the most prognostic information is the Barcelona Clinic Liver Cancer (BCLC) and it is the only staging system that has been validated in various countries (39). As shown in Fig. 3, it is the only staging/prognostic system that combines tumor
Viral Hepatitis and Hepatocellular Carcinoma
439
Fig. 3. The Barcelona Clinic staging system for HCC in patients with cirrhosis (Ref. (29), obtained by permission). PST, performance status; CLT, cadaveric liver transplant; LDLT, liver donor liver transplant; PEI, percutaneous ethanol injection; RF, radiofrequency ablation.
burden, hepatic function, and performance status linked to an evidencebased treatment algorithm. It is divided into very early, early, intermediate, advanced, and terminal stages.
4.2. Treatment 4.2.1. V ERY E ARLY S TAGE This stage include single tumors <2 cm with excellent hepatic synthetic function and no portal hypertension, which should be the goal of a surveillance program. For patients at this stage, it is important to determine if there is underlying cirrhosis or not. For those without cirrhosis, surgical resection is the treatment of choice. However, this represents a minority of patients with HCC in North America and Europe. In patients with underlying cirrhosis, the risks and benefits of resection must be carefully weighed against the available alternatives. For patients with cirrhosis at this stage with normal bilirubin, no portal hypertension (portal pressure <10 mm Hg, no varices, and no ascites), and at least 40% of the liver volume remaining after resection, resection leads to 5-year survivals of about 75% (40–42). The efficacy of resection is related to tumor diameter with better outcomes in those with tumors <3 cm. Another treatment alternative for these patients is radiofrequency ablation (RFA). A randomized trial compared
440
Marrero
surgical resection vs. RFA for patients with HCC <3 cm without portal hypertension and normal liver function (43). There was no difference in 5-year survivals among the two groups and the group treated with RFA, but the latter had less morbidity. The main limitation of resection and RFA is the significant recurrence rates: more than 50% at 5 years (29). The choice between resection and RFA should be determined by tumor location, hepatic function, degree of portal hypertension, and local expertise. 4.2.2. E ARLY S TAGE HCC This stage includes a single tumor between 2 and 5 cm in size in diameter or three tumors each ≤3 cm in size, without gross vascular invasion or metastatic disease. These criteria are termed the “Milan” criteria (44). Liver transplantation is considered the best treatment for patients at this stage because it removes not only the malignancy but also the diseased liver, thus preventing complications of end-stage liver disease as well as de novo hepatocarcinogenesis in the future. When these criteria are applied, the 5-year survival after transplantation is approximately 70% (45), which approaches the survival of patients transplanted for non-malignant liver disease. The main limitation of transplant is the overall organ shortage. In areas of the country with the most severe organ shortage, patient dropout while waiting for a transplant can approach 50% (46). This has led some centers to perform neoadjuvant ablation or chemoembolization as a bridge to transplantation, especially in patients with larger tumors. While there is no evidence that this is beneficial, there is also no evidence of a lack of benefit. Higher quality trials are needed. Another option to address the high dropout rates while awaiting deceased donor liver transplantation (DDLT) is living donor liver transplantation (LDLT). Recently, the enthusiasm for LDLT has been dampened by evidence of increased HCC recurrence after transplantation when compared with DDLT (47). Furthermore, the risk to the donors raises a number of ethical concerns (48). LDLT should be performed only at experienced centers, ideally in the setting of a clinical trial. Patients with HCC exceeding Milan criteria may still benefit from transplantation, but transplanting these patients has been controversial because of the shortage of organs. A recent study showed that transplanting such patients increases the risk of another patient dying on the waiting list by 44%, with the risk being the highest among those without HCC and MELD scores >20 (49). Percutaneous ablation is the best treatment option for patients with early stage HCC who are not suitable candidates for resection or OLT.
Viral Hepatitis and Hepatocellular Carcinoma
441
In three randomized trials comparing percutaneous ethanol injection (PEI) with radiofrequency ablation (RFA), patients treated with RFA required fewer treatment sessions, higher rates of complete tumor ablation, had fewer recurrences, equal rates of complications, and better overall survival (50, 51, 52). The 5-year survival rate of RFA has been about 50% in these randomized trials and in large case series (53). Therefore, RFA is the method of choice for local ablation for tumors within this tumor range.
4.3. Intermediate Stage The tumors at this stage exceed Milan criteria and may be either single tumors >5 cm or multinodular tumors. Unlike the liver parenchyma which derives most of its blood supply from portal venous flow, HCC is almost entirely supplied by branches of the hepatic artery. Chemoembolization takes advantage of this vascular anatomy, combining particle embolization with local delivery of a chemotherapeutic agent. A meta-analysis of 14 randomized controlled trials showed that transarterial chemoembolization (TACE) increases survival from 27% to 41% at 2 years compared to best supportive care in patients with unresectable HCC (54). No significant benefit was seen in patients receiving embolization without chemotherapy (TAE), though the chemotherapeutic agent chosen does not seem to matter. It is important to note that the majority of patients in the clinical trials of chemoembolization had Child A cirrhosis, only half had multinodular tumors, and the median tumor size have been between 5 and 7 cm. Intraarterial radioembolization with Ytrium-90 is another form of intraarterial therapy that has been performed delivering higher doses of radiation locally in the liver, thereby potentially allowing the treatment of diffuse multifocal therapy. A recent single-center study showed some efficacy in patients with tumors at this stage but was no different than TACE (55). Further trials are needed to assess the efficacy of this therapy and its place in the treatment armamentarium.
4.4. Advanced Stage Despite surveillance efforts for early detection of HCC, more than 70% of patients are currently diagnosed at late stages of the disease and are thus ineligible for potential curative therapies discussed above. The main characteristic that separates intermediate from advanced tumors is the presence of portal vein invasion (29). Patients with HCC and vascular invasion have median survivals between 6 and 8 months (56). Systemic chemotherapy and hormonal therapy have been shown to be ineffective. Sorafenib has been studied in a large placebo-controlled
442
Marrero
randomized trial. Sorafenib is a multikinase inhibitor that has antiproliferative and antiangiogenic properties. In this randomized study of 602 patients, median overall survival was 7.9 months in the patients receiving placebo and 10.7 months in the patients receiving sorafenib (hazard ratio 0.69; 95% confidence interval, 0.55–0.87; P<0.001) (57). Importantly, it delayed the time to progression from 2.8 months to 5.5 months (p<0.001). The medication was very well tolerated. This is the first large study that showed that systemic therapy does improve survival in advanced HCC. It should be the first-line therapy for patients with advanced HCC.
4.5. Terminal Stage This stage include patients that have poor liver function and significant tumor burden and that are not transplant candidates. The median survival is 3 months for these patients. Supportive care should be recommended to these patients.
5. PREVENTION 5.1. Hepatitis B Regardless of the mechanisms for the occurrence of hepatocarcinogenesis in patients with chronic HBV infection, eliminating the virus is of utmost importance in decreasing the risk of HCC. HBV vaccine is the first vaccine shown to prevent cancer. A study of Taiwanese children found that the average annual incidence of liver cancer decreased from 0.70/100,000 between 1981 and 1986 to 0.57/100,000 between 1986 and 1990 and to 0.36/100,000 between 1990 and 1994 (p < 0.0001) (58). It is anticipated that the implementation of global vaccination of all newborns will ultimately lead to a worldwide reduction in the incidence of HBV-related HCC, although it may take a few decades for the impact to be observed among adults. For the 350 million persons estimated to have chronic HBV infection worldwide, HBV vaccination would not be effective in preventing HCC. The best strategy for prevention is eliminating modifiable risk factors such as alcohol and tobacco and to treat with agents aimed at eliminating viral replication. A meta-analysis of seven studies that evaluated the use of interferon-␣ showed that treatment had reduction in the risk of HCC of 6.4% (59). With the recent development of newer antivirals such as lamivudine, adefovir, and entecavir, the potential of antiviral therapy to prevent HCC may be further enhanced. There has been one randomized controlled trial that aimed to determine whether treatment with lamivudine can prevent HCC (60). The
Viral Hepatitis and Hepatocellular Carcinoma
443
authors randomly assigned 651 patients who were HBe antigen-positive and/or had detectable HBV DNA (98% Asian and 85% male) to receive lamivudine or placebo. HCC occurred in 3.9% (n = 17) of those in the lamivudine group and 7.4% (n = 17) of those in the placebo group (hazard ratio, 0.49; p= 0.047). Even though this trial was very well done and provided some insights, there are still questions remaining about the appropriate length of treatment, target HBV DNA level, endpoints of therapy, and management of viral resistance. The development of newer and more powerful antivirals raises the possibility for an improved prevention rate for HCC among those with chronic HBV infection.
5.2. Hepatitis C Cirrhosis is by far the single most important risk factor for the development of HCC. It is also known that male gender, older age, coinfection with HBV, alcohol, tobacco, obesity, and diabetes are important risk factors for HCC. As with HBV, only alcohol and tobacco are modifiable. There are three randomized controlled trials that focused on prevention of HCC as an outcome (61–63). The largest trial from Japan randomized 90 patients to treatment or no treatment. HCC developed in 33 of the untreated patients and in only 12 of the treated patients after a follow-up of 8.2 years (p<0.001). The other studies suffer from lack of an adequate sample size, long-term follow-up and also the fact that the overall effect was small. The largest trial to date for secondary prevention of HCC is a multicenter trial in the United States that randomized non-responders with advanced fibrosis to chronic pegylated interferon␣ for 3 years vs. no treatment (64, 65). The results showed that chronic interferon therapy did not reduce the risk of HCC or hepatic decompensation when compared to best supportive care.
REFERENCES 1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2: 533–43. 2. El-Serag HB. Global epidemiology of hepatocellular carcinoma. Clin Liver Dis 2001;5:87–107. 3. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127:S5–S16. 4. H.B. El-Serag. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004;127:S7–S34. 5. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet 1981;2:1129–33.
444
Marrero
6. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35–S50. 7. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139:117–23. 8. Hassan MM, Frome A, Patt YZ, El-Serag HB. Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States, J Clin Gastroenterol 2002;35:266–9. 9. Kulkarni K, Barcak E, El-Serag HB, Goodgame R. The impact of immigration on the increasing incidence of hepatocellular carcinoma. Aliment Pharmacol Ther 2004;20:445–502. 10. El Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230. 11. Davila J, Morgan R, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the rising incidence of hepatocellular carcinoma: a population-based study, Gastroenterology 2004;127:1372–80. 12. Niederau C, Lange C, Heintges T, Erhardt A, Buschkamp M, Hurter D, et al. Prognosis of hepatitis C: results of a large, prospective cohort study, Hepatology 1998;28:1687–95. 13. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis C: a retrospective follow-up study of 384. Gastroenterology 1997;112:463–72. 14. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B. Hepatology 1995;21:77–82. 15. Yang HI, Lu SN, Liaw YF, et al.; Taiwan Community-Based Cancer Screening Project Group: Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168–74. 16. Chen CJ, Yang HI, Su J, et al., REVEAL-HBV Study Group: Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006, 295:65–73. 17. Chan HL, Tse CH, Mo F, et al.: High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 2008; 26:177–82. 18. Tanaka Y, Hanada K, Mizokami M, Yeo AE, Shih JW, Gojobori T, Alter HJ. Inaugural Article: A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci USA 2002;99:15584–9. 19. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 2008 May;134:1752–63. 20. Donato F, Tagger A, Gelatti U, Parrinello G, Bofetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and viral hepatitis infection in men and women. Am J Epidemiol 2002;155:323–31. 21. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38. 22. Wang LY, Hatch M, Chen CJ, Levin B, You SL, Lu SN, et al. Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan. Int J Cancer 1996;67:620–5.
Viral Hepatitis and Hepatocellular Carcinoma
445
23. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–8. 24. Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, Tobacco and Obesity Are Synergistic Risk Factors for Hepatocellular Carcinoma. J Hepatology 2005;42:218–24. 25. Cole P, Morrison AS. Basic issues in population screening for cancer. J Natl Cancer Inst 1980;64:1263–72. 26. Singal A, Marrero JA. Screening for Hepatocellular Carcinoma. Gastroenterol and Hepatol 2008;4:201–8. 27. El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology 2001;33: 62–5. 28. Trevisani F, D Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, Domenicali M, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and antiHCV status. J Hepatol 2001;34:570–5. 29. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. 30. Marrero JA. Screening tests for Hepatocellular Carcinoma. Clin Liver Dis. 2005 May;9:235–51. 31. Chen TH, Chen CJ, Yen MF, Lu SN, Sun CA, Huang GT, et al. Ultrasound screening and risk factors for death from hepatocellular carcinoma in a high risk group in Taiwan. Int J Cancer 2002;98:257–61. 32. Larcos G, Sorokopud H, Berry G, Farrell GC. Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation. AJR Am J Roentgenol 1998;171:433–5. 33. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–22. 34. Burrel M, Llovet JM, Ayuso C, Iglesias C, Sala M, Miquel R, et al. MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: An explant correlation. Hepatology 2003;38:1034–42. 35. Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, et al. Small nodule detection in cirrhotic livers: evaluation with US, spiral CT and MRI and correlation with Pathologic examination of explanted liver. J Comput Assist Tomogr 2001;25:327–336. 36. de Ledinghen V, Laharie D, Lecesne R, et al. Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients. Eur J Gastroenterol Hepatol 2002 Feb;14(2):159–65. 37. Libbrecht L, Bielen D, Verslype C, Vanbeckevoort D, Pirenne J, Nevens F, Desmet V, Roskams T. Focal lesions in cirrhotic explant livers: pathological evaluation and accuracy of pretransplantation imaging examinations. Liver Transpl. 2002 Sep;8(9):749–61. 38. Marrero JA, Hussain HK, Nghiem HV, et al. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl. 2005 Mar;11(3):281–9. 39. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41: 707–16.
446
Marrero
40. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: A retrospective and nationwide survey in Japan. Hepatology. 2000;32: 1224–9. 41. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–40. 42. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229:790–9. 43. Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243: 321–8. 44. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693–9. 45. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200. 46. Freeman RB Jr, Steffick DE, Guidinger MK, Farmer DG, Berg CL, Merion RM. Liver and intestine transplantation in the United States, 1997–2006. Am J Transplant. 2008;8:958–76. 47. Berg CL, Gillespie BW, Merion RM, Brown RS Jr, Abecassis MM, Trotter JF, et al. Improvement in survival associated with adult-to-adult living donor liver transplantation. Gastroenterology. 2007 Dec;133:1806–13. 48. Volk ML, Marrero JA, Lok AS, Ubel PA. Who decides? Living donor liver transplantation for advanced hepatocellular carcinoma. Transplantation. 2006 Nov 15;82:1136–9. 49. Volk ML, Vijan S, Marrero JA. A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria. Am J Transplant. 2008 Apr;8:839–46. 50. Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–40. 51. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma
Viral Hepatitis and Hepatocellular Carcinoma
447
55. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47:71–81. 56. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, Br´u C, Rod´es J, Bruix J. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29:62–7. 57. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. 58. Chang CJ, Chen MS, Lai HM, Hsu TC, Wu MS, Kong DC, Liang WY, Shau DS,. Chen and Taiwan Childhood Hepatoma Study Group, Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855–9. 59. Camma A, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis An evidence-based approach. J Hepatol 2001;34:593–602. 60. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J, Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31. 61. Nishiguchi S, Shiomi S, Nakatani T, Takeda K, Fukuda A, Tamori D, et al. Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis. Lancet 2001;357:196–7. 62. Valla D, Chevallier M, Marcellin P, Payen JL, Trepo C, Fonck M, et al. Treatment of hepatitis C virus related cirrhosis a randomized controlled trial of interferon alfa 2b versus no treatment. Hepatology 1999;29:1870–5. 63. Bernardinello E, Cavalletto L, Chemello L, Mezzocolli C, Donada C, Benvegnu L, et al. Long-term clinical outcome after beta-interferon therapy in cirrhotic patients with chronic hepatitis C, Hepatogastroenterology 1999;46:3216–22. 64. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al. Prolonged therapy of Advanced Chronic Hepatitis C with low dose peginterferon: The Hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) Trial. N England J Med 2008; 359(23):2429–41. 65. Lok AS, Seeff LB, Morgan TR, Di Bisceglie AM, HALT-C Trial Group. The incidence of HCC and associated risk factors in hepatitis C related advanced liver disease. Gastroenterology 2009;136(1):138–48.
Hepatitis B Vaccines Oren Shibolet, MD and Daniel Shouval, MD CONTENTS I NTRODUCTION S TRUCTURE AND G ENOMIC O RGANIZATION OF T HE H EPATITIS B V IRUS E NVELOPE P ROTEINS R ELEVANT TO VACCINE D EVELOPMENT ROLE OF T HE I MMUNE R ESPONSE AGAINST HBV E NVELOPE P ROTEINS IN L ONG -T ERM P ROTECTION AGAINST HBV T RANSMISSION OF HBV I NFECTION H ISTORY OF HBV VACCINATION I MMUNOGENICITY AND E FFICACY OF H EPATITIS B VACCINES H EPATITIS B V IRUS M UTANTS F OLLOWING I MMUNIZATION AGAINST HBV M ODE OF A DMINISTRATION I NTERCHANGEABILITY OF VACCINES S TRATEGIES OF I MMUNIZATION AND W ORLDWIDE I MPACT S AFETY AND T OLERABILITY OF HBV VACCINES
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 18, C Humana Press, a part of Springer Science+Business Media, LLC 2009
449
450
Shibolet and Shouval
R ATIONALE FOR I MMUNIZATION OF S PECIAL P OPULATIONS AT R ISK N ON -R ESPONDERS TO C ONVENTIONAL VACCINATION R ECIPIENTS OF B ONE M ARROW AND P ERIPHERAL S TEM -C ELL T RANSPLANTATION C ONTRAINDICATIONS T HE F UTURE OF HBV VACCINES S UMMARY R EFERENCES
Key Principles
• Initial immunization strategies against hepatitis B virus (HBV) infection concentrated on high-risk groups. This strategy, which was successful in individual situations, failed to reduce the incidence and prevalence of HBV in the general population. • As a result, in 1991 the World Health Organization (WHO) has recommended that HBV universal immunization should be integrated into national immunization programs in all countries with an HBsAg prevalence of >8%. • The results of this impressive global effort have already been translated into a reduction in the incidence of HBV infection, and its complications including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) in individual countries who were among the pioneers of universal infant immunization. • Yeast (and plasma)-derived HBV vaccines are highly efficacious in preventing HBV infection, and in reducing the incidence of persistent infection as well as of hepatocellular carcinoma. • Hepatitis B vaccines have had an excellent safety profile, and are generally well tolerated. Adverse reactions which are usually mild and resolve quickly tend to decrease with successive doses of the vaccine. • Despite the excellent efficacy of HBV vaccines, immunization failure may occur, and can sometimes be explained by variables such as improper storage or administration, advanced age, obesity, renal failure, chronic liver disease, and especially immunosuppression. • Another important factor that may affect non-responsiveness to HBsAg immunization seems to be genetically determined resistance.
Hepatitis B Vaccines
451
• Bypass of non-response to conventional vaccination has recently been achieved using Pre-S1 /Pre-S2 /S third-generation HBV vaccines. • Contraindications for HBV vaccines include hypersensitivity to yeast or any component of the vaccine. Patients who develop hypersensitivity after vaccination should not receive further injections of the vaccine. • Actively pursued research avenues intended to stimulate TH1 immune responses, include the development of more potent adjuvants as compared to the currently used aluminum hydroxide as well as development of DNA vaccines.
1. INTRODUCTION Persistent hepatitis B virus (HBV) infection is a common public health problem, worldwide (1). Following acute HBV infection, between 30 and 90% of babies born to HBV-carrier mothers and 5–10% of infected adults will become chronic HBV carriers, positive for HBV surface antigen (HBsAg). Such HBsAg+ individuals are at increased risk for developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (2). The global burden of HBV infection, as determined by prevalence of HBsAg positivity, can be divided into three major areas of high (>8%), intermediate (>2–<8%) and low (<2%) endemicity. According to the World Health Organization (WHO) estimates, at least 2 billion people of the world population have been infected by HBV during their lifetime of whom about 380 million (∼6% of the world population) are still HBV carriers with persistent infection. Annually, approximately 4.5 million patients develop acute HBV infection worldwide and about 600,000 die of complications of chronic HBV infection including cirrhosis and HCC (3). Efficacious and safe hepatitis B vaccines are now available for more than 25 years. This chapter will review the history of development, the immunogenicity, safety and impact of this technological marvel on the global epidemiology of HBV infection.
2. STRUCTURE AND GENOMIC ORGANIZATION OF THE HEPATITIS B VIRUS ENVELOPE PROTEINS RELEVANT TO VACCINE DEVELOPMENT HBV is a 3,200 base pair (bp) DNA virus. It has a genome of relaxed, circular, partially double-stranded configuration (see Chapter 1 for a detailed discussion of HBV structure). The genome has four reading
452
Shibolet and Shouval
frames encoding several overlapping viral proteins including Pre-S1 , S2 , S, core, HBe, X, and the polymerase proteins. The virus requires an RNA intermediate for replication and undergoes reverse transcription lacking proof reading that leads to a high mutation rate. To date, eight genotypes have been identified with an 8% divergence in the complete nucleotide sequence(4–8). All available HBV vaccines contain one or more of the hepatitis B envelope proteins or surface antigens HBsAg. The HBsAg is composed of three related envelope proteins, synthesized by an alternate use of three translational start codons and a common stop codon. The HBsAg proteins include a major polypeptide of 226 amino acids (aa) designated small HBs (SHBs) in a non-glycosylated (p24) and glycosylated (gp27) forms. The middle-sized protein (MHBs), which shares the 226 aa of the p24 region at the C-terminus and has an additional 55 aa residue at the N-terminus, is termed Pre-S2 corresponding to p33 and gp36. The large HBs protein (LHBs) contains, in addition to the S and Pre-S2 domains, the Pre-S1 domain of 119 aa (p39, gp42). In the native HBV envelope, all proteins SHBs, MHBs, and LHBs are covalently linked by intermolecular disulfide bonds between the S domains, and partially embedded in membrane lipids (9).
3. ROLE OF THE IMMUNE RESPONSE AGAINST HBV ENVELOPE PROTEINS IN LONG-TERM PROTECTION AGAINST HBV Induction of immune memory against HBsAg and generation of antiHBs antibodies are essential for long-term protection against HBV. In addition, Pre-S antigen(s) induce neutralizing antibodies, which block attachment, endocytosis, and possibly membrane penetration of HBV into the hepatocyte (10). In patients with acute HBV infection who clear HBV from their blood, detection of protective anti-HBs antibodies in serum may be delayed for weeks up to 6 months. In contrast, Pre-S1 and Pre-S2 antigens, which have a role in inducing T-cell help for anti-HBs production, induce generation of anti-Pre-S antibodies which appear and disappear early after acute infection, sometimes in a biphasic pattern. T-cell recognition of HBV proteins requires presentation to T cells of HBV antigenic determinants, which must be processed by antigen presenting cells prior to expression on the surface of T cells in association with HLA antigens (11–14) . Milich and coworkers have characterized the T-cell-mediated immune response to Pre-S antigens and have shown
Hepatitis B Vaccines
453
that immunity to HBsAg can be enhanced using Pre-S antigens in nonresponder mice resistant to SHBs antigen (15, 16). Antibody responses to HBV envelope proteins after exposure to wildtype HBV or after immunization are well characterized. Anti-HBs antibodies can be either subtype-specific or common to all genotypes of HBsAg, for example, against the “a” determinant, which is an epitope present in all HBV vaccines in use (14). By convention, seroconversion to anti-HBs is defined as detection of anti-HBs in an immunological assay at ≥2.1 standard deviations from the reading of the negative control, which is usually 1 mIU/ml (2.1–9 mIU/ml). Seroprotection against infection is present when anti-HBs levels are ≥10 mIU/ml. Numerous studies have shown that most children and young adults will develop hundreds to several thousand mIU/ml of anti-HBs following three doses of a conventional HBV vaccine (17,18). Vaccinees that develop an antiHBs level between 10 and 100 mIU/ml after three doses are referred to as low responders. In the United Kingdom, seroprotection against HBV infection was re-defined at anti-HBs levels ≥100 mIU/ml (19). This approach has public health implications and may require redefinition of non-responsiveness to routine immunization. Anti-HBs levels tend to fall with time, but primed immune memory will usually respond to challenge with wild-type virus as well as to booster inoculation with HBsAg by an anamnestic anti-HBs response. Currently, there is no reason to offer booster doses to vaccinees who developed anti-HBs titers >100 mIU/ml following immunization with three vaccine doses (20–23).
4. TRANSMISSION OF HBV INFECTION The virus is transmitted from patients with acute or chronic infection to HBV naive persons via parenteral or mucosal exposure to body fluids. Infective virions are present in all body fluids with a decreasing concentration in blood, serous fluids, saliva, semen, breast milk, tears, sweat, urine, stool, and respiratory secretions, respectively (24). Vertical and perinatal transmission of HBV from HBsAg-positive mothers with a high viral load to their babies, as well as sexual contact of HBV patients are the most common routes of transmission in Africa and Asia. In the western hemisphere, the most important routes of infection include sexual contact (both heterosexual and Men who have sex with Men – MSM), via sharing of needles in I.V drug abusers, and occupational exposure among health-care workers (25). Other less common routes include tattooing, body piercing, acupuncture, eye splashes, and other forms of direct contact between infected material and mucosal surfaces (26).
454
Shibolet and Shouval
5. HISTORY OF HBV VACCINATION Following the detection of the hepatitis B surface antigen in 1967 by Dr. Baruch Blumberg, Dr. Saul Krugman has made the first, at that time controversial, attempt to develop a hepatitis B vaccine. He used crude, heat-inactivated serum obtained from children with HBV as an immunogen for protection of individuals at risk (27). The first HBV vaccines were developed simultaneously between 1976 and 1980 in France and in the United States using plasma obtained from HBsAg carriers (28, 29). These first-generation plasma-derived vaccines contained mainly HBsAg, subjected to various combinations of urea, pepsin, formaldehyde, and heat, which led to partial disruption of the HBV envelope proteins. Similar vaccines were then produced in Korea and China. Plasma-derived vaccines had an excellent record of safety and immunogenicity. Yet, the advance in recombinant DNA technology and concerns regarding the safety of the plasma used for purification of HBsAg, led in 1986 to the development of the second-generation recombinant yeast-derived vaccines which are currently used in the majority of countries worldwide (30, 31). These new HBV vaccines were the first genetically engineered vaccines produced from yeasts (i.e., Saccharomyces cerevisiae and later also Hansenula polymorpha) transfected with HBV–DNA sequences coding for the small HBV envelope protein. All second-generation hepatitis B vaccines contain purified nonglycosylated HBsAg (small HBs) absorbed to aluminum hydroxide as an adjuvant for stimulation of anti-HBs producing B cells. Currently, there are several available yeast-derived vaccines with variable amounts of the envelope protein, but with comparable immunogenicity (Table 1). In the past decade, several bivalent and pentavalent combination vaccines were developed in an attempt to reduce the number of vaccine injections, especially in young babies. These vaccines, mainly available in the western hemisphere, include DTP, HBV, Hemophilus influenza, polio, and hepatitis A antigens in various combinations, which in general do not significantly reduce the immunogenicity of the individual components (32–34). A “third-generation” mammalian cell-derived vaccine was first developed in the early 1980s at the Pasteur Institute in transfected Chinese hamster ovary (CHO) cells, expressing S and Pre-S2 antigens (35). Subsequently, two mammalian cell-derived vaccines containing three HBV envelope proteins, namely Pre-S1 , Pre-S2 and small S, were developed in mouse and CHO cell lines in Germany and Israel, respectively (36, 37). Such vaccines were shown to induce a rapid and augmented anti-HBs response with anti-HBs seroconversion appearing earlier as
*
7.5 mcg of HIB and 125 mcg meningococcal protein conjugate with 0.5 mcg of HBsAg 0.5 ml
720 IU/ml inactivated HAV and 20 mcg/m HBsAg–1 ml
20 mcg/0.5 ml–0.5 ml
10–20 mcg/0.5–1.0 ml
1. Pediatric/adolescent formulation – 10 mcg/ml-0.5 ml 2. Adult formulation – 10 mcg/ml-1 ml 3. Dialysis formulation – 40 mcg/ml-1 ml
1. Pediatric formulation – 20 mcg/ml–0.5 ml 2. Adult formulation – 20 mcg/ml–1 ml
Dose
Diphtheria and tetanus toxoids and acellular pertussis, hepatitis B recombinant yeast, and inactivated poliovirus
Hemophilus b conjugate (HIB) and hepatitis B recombinant yeast
Hepatitis A inactivated and HBsAg (recombinant yeast)
HBsAg (recombinant, yeast)
HBsAg (incl. recombinant S, Pre-S1 , and Pre-S2 in CHO cells)
HBsAg (recombinant yeast)
HBsAg (recombinant yeast)
Components
Examples of licensed vaccines. Not all vaccines are available globally
R Pediarix
R Comvax
R Twinrix
R Fendrix
∗
R Sci B Vac∗ Previously called R , or Bio-Hep-B∗ HepimmuneTM
R Recombivax-HB
R Engerix-B
Name of Vaccine
0.5 ml × 3 at 6–8-week intervals (preferably 8 weeks), starting at 2 months of age (may be given starting at 6 weeks of age)
0.5 ml × 3 (0, 1, 12–15 months of age) should not be given before 6 weeks of age
Adults 1 ml × 3 (0, 1, 6 months) or 1 ml × 4 (0, 7, 21–30 days, followed by booster at month 12)
Predialysis and dialysis patients age 15 years and older 20 mcg/0.5 ml × 4 (0, 1, 2, 6 months)
Infants and children 5 mcg x 3 (0,1, 6 months) Adults 10micg × 3 (0,1,6 months) Non-responders (adults) to yeast-derived vaccines 20 mcg × 2 (0 and 2–3 month)
Infants/children/adolescents (0–19 years) 5 mcg × 3 (0, 1, 6 months). Adolescent (11–15 years of age) 5 mcg × 3 or 10 mcg × 2 (0 and 4–6 months later). Adults 10 mcg × 3 (0, 1, 6 months) Predialysis/dialysis 40 mcg × 3 (0, 1, 6 months)
Infants/children/adolescents (0–19 years) 10 mcg/0.5 ml × 3 (0, 1, 6 months) Adults 20 mcg/1 ml (0, 1, 6 months) Adults dialysis 40 mcg/2 ml (0, 1, 2, 6 months)
Vaccine Schedule and Route of Administration
Table 1 ——Commercially Available Second- and Third-Generation HBV Vaccines∗
456
Shibolet and Shouval
compared to yeast-derived vaccines and with higher anti-HBs titers (38, 39). Furthermore, these vaccines were also more immunogenic in immune suppressed patients, in patients on hemodialysis and in nonresponders to conventional SHBs-containing vaccines as compared to yeast-derived vaccines (36, 40, 41).
6. IMMUNOGENICITY AND EFFICACY OF HEPATITIS B VACCINES Following the successful clinical trial by Szmuness et al. reported in 1980 on efficacy of a plasma-derived HBV vaccine in MSM (29), and the development of yeast-derived vaccines, hundreds of million doses were administered worldwide with excellent immunogenicity. After administration of three HBV vaccine doses, usually given at 0, 1, and 6 months, seroprotection rates, as measured by anti-HBs serum levels >10 mIU/ml, reach almost 100% in children and ∼95% in young healthy adults (17, 41, 42, 43). HBV vaccines are also highly immunogenic when started at birth. Risk factors associated with a suboptimal response to immunization include overweight, age, heavy smoking, immune suppression, hemodialysis, systemic diseases, and genetically determined non-response (see later). Anti-HBs levels following the third yeast-derived vaccine dose usually reach several hundreds to thousands mIU/ml, dropping rapidly within 12–24 months after complete immunization. Frequently, anti-HBs antibodies become undetectable within several years. However, immune memory providing protection against challenge with HBV remains intact for at least two decades in the majority of healthy vaccinees (43–45). The recently developed third-generation Pre-S/S HBV vaccines containing Pre-S/S envelope proteins have been shown to induce a higher and faster anti-HBs response as compared to yeast-derived vaccines (36, 38–40, 46). A mathematical model has been designed to assess the changes, through time after vaccination, in circulating vaccine antigen, immune memory, and antibody titer. The model parameters were estimated from a database of 10,815 post-vaccination antibody titers obtained from 1923 adult individuals from hepatitis B vaccine trials in Belgium, Cuba, Israel, Italy, Sweden, and the United States (47). Results of this assessment suggest that a Pre-S/S vaccine induced an immune memory against HBsAg, already after the first vaccine dose and a faster and higher anti-HBs response as compared to yeast-derived vaccines. Furthermore, the models predicted that such third-generation HBV vaccines may induce a long-lasting immune memory for protection against HBV even after two instead of the three conventional vaccine doses.
Hepatitis B Vaccines
457
7. HEPATITIS B VIRUS MUTANTS FOLLOWING IMMUNIZATION AGAINST HBV HBV envelope protein escape mutants have been described in Italy, Singapore, Gambia, and the United States, in recipients of plasmaderived, as well as recombinant, HBV vaccines (8, 48–50). Such mutants have emerged in children born to HBsAg-carrier mothers who were immunized against HBV receiving active (plasma or recombinant vaccines) as well as passive immunization with hepatitis B immune globulin (HBIG). Breakthrough infection occurred in these children despite an adequate anti-HBs response to active immunization. Similar mutants have also been described in liver transplant patients receiving polyclonal or monoclonal HBIG for protection against reinfection with HBV (48–52). The common reason for generation of such mutants is a single point mutation in one of the amino acids coding for the determinant of HBsAg, often as a result of amino acid substitution from glycine to arginine at position 145 (G145R). Yet, despite the fact that such mutants were shown to be infective in chimpanzees, a conventional yeast-derived vaccine was able to protect these animals against an HBV envelope mutant (53). At present, emergence of such mutants is a relatively rare event, and does not seem to pose a serious threat to public health.
8. MODE OF ADMINISTRATION All commercially available HBV vaccines should be administered intramuscularly preferably in the deltoid region or the lateral aspect of the thigh. Infants and neonates have a low muscle mass in the deltoid and in this population it may be preferable to inject in the thigh. Injections in the gluteal region are not recommended as it was shown that they are frequently given into fatty tissue instead of muscle and result in lower seroconversion rates. For patients with a risk of hemorrhage following intramuscular injection, HBV vaccines can be given subcutaneously. However, the effect of this route of administration on seroconversion efficacy is unknown (54).
9. INTERCHANGEABILITY OF VACCINES Yeast-derived HBV vaccines containing aluminum hydroxide are usually interchangeable regardless of manufacturer (55). Furthermore, R the HBsAg used in combination vaccines such as in Pediarix and
458
Shibolet and Shouval
R R Twinrix is the same as that used in Engerix-B and is, therefore, interchangeable. For example, a yeast-derived monovalent HBV vaccine may be given within 48 h after birth followed by combination pentavalent vaccine containing among others also HBsAg given 2–6 or 12 months later.
10. STRATEGIES OF IMMUNIZATION AND WORLDWIDE IMPACT Following licensure of HBV vaccines in the early 1980s, immunization strategies concentrated on high-risk groups including newborns to HBsAg-positive mothers (with simultaneous HBIG administration), health-care workers (HCW), family members and partners with close contact to an HBV carrier, illicit drug users, MSM, and patients at sexually transmitted disease clinics (STD).This strategy, which was successful in individual situations, failed to reduce the incidence and prevalence of the general population. As a result, in 1991 the World Health Organization (WHO) has recommended that HBV universal immunization should be integrated into national immunization programs in all countries with an HBsAg prevalence of >8% by 1995 (56). This recommendation was extended to countries with an HBsAg prevalence between 2 and 8% in 1997. In countries with high and intermediate prevalence, it was recommended to start immunization within 48 h of birth (preferably within 24 h) followed by booster doses at the age of 1 and 6 months (54). In countries with low HBV endemicity, starting immunization may be postponed to the second month of life or even later, provided that pregnant women are screened for HBsAg (57). Catch-up vaccination against HBV has been introduced in many European countries as well. By 2005, 168 countries (85% of the world) introduced routine immunization (usually universal) with an estimated three-dose coverage over 60% (Fig. 1). Cost–benefit analyses have strongly supported the introduction of universal immunization against HBV to newborns in countries with high and intermediate endemicity of HBV infection (58–63). The results of this impressive global effort has already been translated into a reduction in the incidence of HBV infection, and its complications including chronic hepatitis, cirrhosis, and hepaticellular carcirouna (HCC) in individual countries who were among the pioneers of universal infant immunization. In Taiwan, which was the first country to introduce universal vaccination in newborns in 1984, the prevalence of HBsAg in children up to the age of 15 years, decreased from 9.8% in 1984 to 0.7% in 1999
Hepatitis B Vaccines
459
Fig. 1. Number of countries that introduced hepatitis B vaccine and global infant three-dose hepatitis B vaccine coverage, 1989–2004 (adopted from http://www.who.int/immunization˙monitoring/diseases/hepatitis/en/index.html and Hot Topics in Viral Hepatitis in 5/2007, Zanetti AR et al.) (for color version see http://www.springer.com/series/7672)
(51, 64). Furthermore, the average annual incidence of HCC in children 6–14 years of age measured between 1981 and 1986 dropped by 50% (measured between 1990 and 1994) (65). In Gambia, childhood prevalence of HBsAg dropped from 10.0 to 0.6% in an immunized population of children followed since 1984 (66). A similar and gradual drop in incidence of HBV is now being observed in several regions and countries worldwide which were the pioneers of massive vaccination efforts, including Alaska, Italy, and Hawaii (67–69).
460
Shibolet and Shouval
11. SAFETY AND TOLERABILITY OF HBV VACCINES During the past 25 years, hepatitis B vaccines have had an excellent safety profile, and are generally well tolerated. Adverse reactions which are usually mild and resolve quickly tend to decrease with successive doses of the vaccine. The most common reactions for the two most frequently used HBV R R vaccines, namely Engerix-B and Recombivax-HB , include injection site soreness (17–22%) and fatigue (13–15%). Other reactions included local reaction at the injection site such as swelling, induration, and erythema (1–10%). Systemic adverse events following immunization include fatigue, fever, headache, tingling, sweating, nausea, abdominal pain, vomiting, and weakness may occur (≤1%). Rarely serious adverse reactions were reported, including anaphylaxis, serum sickness-like syndrome, erythema multiforme, Steven-Johnson syndrome, GuillainBarre syndrome, transverse myelitis, and optic neuritis. In 1998, French investigators reported a putative association between immunization against HBV, and relapse or induction of multiple sclerosis (MS) (70). In 2004, Hern`an and coworkers suggested, in a prospective study, a possible relation between hepatitis B vaccination and an increased risk of MS (71). However, the WHO Global Advisory Committee on Vaccine Safety concluded that the evidence reported in this study was insufficient to support such a link (72). Yet, in patients with MS the benefit of immunization should be weighed against the putative risk of exacerbation of the disease. Hepatitis B vaccination has been anecdotally linked to rheumatoid arthritis, lupus erythematosus, diabetes mellitus, acute lymphoblastic leukemia, chronic fatigue syndrome, and even hair loss. Reviews of these studies by WHO experts do not support such a link (72–74). Despite the absence of controlled trials, individual experience suggests that vaccination against hepatitis B is not contraindicated in pregnant or lactating women (75). The only absolute contraindications are known hypersensitivity to any component of the vaccine or a history of anaphylaxis to a previous dose.
12. RATIONALE FOR IMMUNIZATION OF SPECIAL POPULATIONS AT RISK Heterosexuals with multiple sex partners. Sexual transmission of HBV is the most common route of HBV transmission in North America, accounting for approximately 40% of all new HBV cases in the United States. Sexual transmission among homosexuals accounts for another 25%.
Hepatitis B Vaccines
461
Intravenous drug users (IVDU). These account for approximately 15% of all new HBV infections. The risk for HBV transmission is associated with frequency of injection and sharing of drug paraphernalia. Household contacts of chronic HBV infected persons. The risk of acquiring HBV infection is high in household contacts of persons with chronic HBV infection, and high viral load and can reach 60%. Populations at highest risk include sex partner, where seroprevalence ranges from 25 to 60%, and in children. Occupational exposure to HBV. Occupational exposure was previously considered a significant risk for contracting HBV (25). Following implementation of vaccination programs, the incidence of HBV infection among health-care workers in the western hemisphere is dropping rapidly. The prevalence of HBV infection among public service workers with exposure to blood (police and correctional facilities officers and fire fighters) is similar to the general population. Hemodialysis patients. Following implementation of HBV vaccination and infection control programs in dialysis patients, the rates of new infection considerably declined. HIV-positive persons. Because of similar routes of transmission, the prevalence of HIV/HBV coinfection is relatively high ranging from 6 to 75% in certain groups. Optimal response to immunization against HBV is achieved when HIV is controlled and in remission. Persons in long-term care and correctional facilities. The rates of new HBV infections in these facilities have been declining since the implementation of vaccination programs. However, because of a higher prevalence of chronic HBV-infected patients in these facilities; unvaccinated persons are at an increased risk for acquiring HBV infection. Patients with chronic non-HBV liver disease. Such patients should be immunized against hepatitis B (and A). Persons traveling to endemic regions with HBV. These persons are not necessarily at a higher risk for acquiring HBV infection. However, immunization against HBV is advised especially for those individuals who intend to stay in such areas for a prolonged time. Acceleration of vaccine administration (i.e., at 0, 1, 2, and then 6 or 12 months) may be considered in individuals requiring rapid protection.
13. NON-RESPONDERS TO CONVENTIONAL VACCINATION Yeast (and plasma)-derived HBV vaccines are highly efficacious in preventing HBV infection, and in reducing the incidence of persistent infection as well as of hepatocellular carcinoma. In 2001, a review of 181 clinical studies evaluating 24,277 individuals who were immunized
462
Shibolet and Shouval
R R with Engerix-B and 8627 with Recombivax HB provided evidence for the extraordinary immunogenicity of yeast-derived HBV vaccines (42). The recommended pediatric dose per injection was 10 and 5 g for both vaccines, and the adult dose was 20 and 10 g, respectively. Seroprotection (>10 mIU/ml) was achieved in 95.8 and 94.3%, respectively, using the three-dose schedule at 0, 1, and 6 months. Children and adolescents (1–19 years) achieved the highest seroprotection rates, namely 98.6 and 98.8%, respectively. Thus, the degree of non-response in children and young adults is low. Yet, despite the excellent efficacy of second-generation HBV vaccines, immunization failure may occur, and can sometimes be explained by variables such as improper storage or administration, advanced age, obesity, renal failure, chronic liver disease, and especially immunosuppression. Another important factor that may affect non-responsiveness to SHBs immunization seems to be genetically determined resistance (76, 77). The ability to produce antibodies in response to immunization with HBsAg is controlled by autosomal dominantly expressed HLA class II molecules (76–79). Hohler and coworkers have reported enhanced expression of DRB 1∗ 3, DRB 1∗ 7, and DRB 1∗ 14 in non-responders to an HBV vaccine (78). In contrast, response to vaccination is related to DRB 1∗ 13, which seems to have a promoting effect on anti-HBs seroconversion. Milich and others have shown that non-responsiveness to SHBs immunization in mice can be circumvented through immunization with Pre-S proteins (79). Furthermore, immunization with synthetic MHBs (Pre-S2 or PreS2 /S) peptides, as well as with yeast and mammalian CHO cell-derived Pre-S2 /S vaccines, may induce neutralizing antibodies and protect chimpanzees against HBV (80). A major determinant of immunological response to vaccination is age. Response rates decrease by about 15 and 25% in persons aged 40 and 60, respectively, compared to younger persons. Other determinants that cause decreased response to vaccination include smoking, obesity, and immunosuppression. Although the HBV vaccines are highly immunogenic, 5–15% of vaccinated persons do not respond to the primary vaccine series (i.e., anti-HBs <10 IU/ml). These persons should complete a second three-dose vaccine series, and be evaluated for HBV-carrier status. Following the second vaccine series, there is a 30–50% chance of developing a protective anti-HBs titer. A person who does not develop protective antibodies (and is not an HBsAg carrier) is considered a HBV “vaccine non-responder”. Nonresponders belonging to risk groups for contracting HBV infection are susceptible to HBV infection, and should be protected with HBIG after exposure as soon as possible, preferably within 24 h and no later than 1 week post exposure.
Hepatitis B Vaccines
463
Bypass of non-response to conventional vaccination has recently been achieved using Pre-S1 /Pre-S2 /S third-generation HBV vaccines (41). In one such study, the primary study population of 330 HBV vaccine non-responders after ≥4 previous injections was randomized 2:1 R to receive one or two injections of HepimmuneTM (Bio-Hep-B , Sci R R B Vac ) 20 mcg/dose or Engerix-B , 20 mcg/dose given at 1-month interval. An intention to treat analysis revealed that 81.7% of the PreS/S CHO-derived vaccine recipients compared to 49.1% recipients of the SHBs yeast-derived vaccine developed anti-HBs titers >10 mIU/ml at 1 month after the first or second dose (P<0.001) . Similar results were obtained with another mammalian Pre-S/S HBV vaccine (36). Finally, in a preliminary study performed in Hong Kong in a small cohort of 20 HBV liver transplant recipients, ∼50% of stable patients after transplantation seroconverted to anti-HBs+ following immunization with a Pre-S/S HBV vaccine (81). Thus, non-response to conventional HBV vaccination can be partially resolved using Pre-S/S HBV vaccines.
14. RECIPIENTS OF BONE MARROW AND PERIPHERAL STEM-CELL TRANSPLANTATION Bone marrow transplantation (BMT) recipients are immunosuppressed, respond poorly to conventional vaccination post-BMT, and are at risk of acquiring severe infections including HBV. Non-response to HBV immunization in such patients may be partially overcome through immunization of bone marrow and peripheral stem-cell donors against HBV. Such a maneuver may induce anti-HBs seroconversion in >50% of BMT recipients through adoptive transfer of immunity from the healthy immune-competent donor to the BMT recipient (82, 83).
15. CONTRAINDICATIONS Contraindications for HBV vaccines include hypersensitivity to yeast or any component of the vaccine. Patients who develop hypersensitivity after vaccination should not receive further injections of the vaccine. Patients who develop serious hypersensitivity after receiving a multivalent vaccine should not receive further vaccination with the same vaccine or any of its components.
16. THE FUTURE OF HBV VACCINES Despite the excellent efficacy and safety of currently used HBV vaccines, attempts are still being made to improve vaccine efficacy in special non-responder risk groups. Actively pursued research
464
Shibolet and Shouval
avenues intended to stimulate TH1 immune responses, include the development of more potent adjuvants as compared to the currently used aluminum hydroxide as well as development of DNA vaccines. New adjuvants include MPL (3-deacylated monophosphoryl lipid A) (84), MF59 (85), and synthetic oligodeoxynucleotides containing immunostimulatory CpG motifs that specifically target Tolllike receptor 9 with a corresponding innate immune response (86). All three adjuvants have been shown to induce excellent anti-HBs seroconversion rates and titers when administered to non-responders of conventional HBV vaccines or immunosuppressed patients. An MPLcontaining HBV vaccine intended for patients in renal failure or on R dialysis (Fendrix ) is already licensed in several countries (87). In the past decade, several immune modulatory and immunotherapeutic modalities intended to augment an anti-HBV response have been tested. These include among others, development of experimental T cell (88) and DNA vaccines for protection against HBV infection as well as intervention in persistent HBV infection (89); stimulation of the innate immune responses through administration of cytokines and granulocyte-macrophage colony-stimulating factors (90, 91); and injecR tion of HBV vaccines intradermally (92). So far, except for Fendix , none of these compounds has reached clinical application.
17. SUMMARY HBV is a major human pathogen causing morbidity and mortality. HBV-associated disease can be almost totally prevented by universal vaccination with the highly effective HBV vaccine. Already there have been major therapeutic benefits from HBV vaccination, including a reduction in the rates of HCC and cirrhosis. Now, efforts are being directed at further improving response rates, shortening dosing regimens and targeting non-responsive, or hard to vaccinate populations.
REFERENCES 1. Ganem, D., and A. M. Prince. 2004. Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 350:1118. 2. Fattovich, G., F. Bortolotti, and F. Donato. 2008. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 48:335. 3. http://www.who.int/immunization˙monitoring/diseases/hepatitis/en/index.html 4. Block, T. M., H. Guo, and J. T. Guo. 2007. Molecular virology of hepatitis B virus for clinicians. Clin Liver Dis 11:685. 5. Lau, J. Y., and T. L. Wright. 1993. Molecular virology and pathogenesis of hepatitis B. Lancet 342:1335.
Hepatitis B Vaccines
465
6. Kidd-Ljunggren, K., Y. Miyakawa, and A. H. Kidd. 2002. Genetic variability in hepatitis B viruses. J Gen Virol 83:1267. 7. Norder, H., A. M. Courouce, P. Coursaget, J. M. Echevarria, S. D. Lee, I. K. Mushahwar, B. H. Robertson, S. Locarnini, and L. O. Magnius. 2004. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 47:289. 8. Schaefer, S. 2005. Hepatitis B virus: significance of genotypes. J Viral Hepat 12:111. 9. Howard, C. R. 1995. The structure of hepatitis B envelope and molecular variants of hepatitis B virus. J Viral Hepat 2:165. 10. Neurath, A. R., S. B. Kent, K. Parker, A. M. Prince, N. Strick, B. Brotman, and P. Sproul. 1986. Antibodies to a synthetic peptide from the PreS 120–145 region of the hepatitis B virus envelope are virus neutralizing. Vaccine 4:35. 11. Gerlich, W. H., R. Deepen, K. H. Heermann, B. Krone, X. Y. Lu, M. Seifer, and R. Thomssen. 1990. Protective potential of hepatitis B virus antigens other than the S gene protein. Vaccine 8 Suppl:S63. 12. Heermann, K. H., U. Goldmann, W. Schwartz, T. Seyffarth, H. Baumgarten, and W. H. Gerlich. 1984. Large surface proteins of hepatitis B virus containing the Pre-S sequence. J Virol 52:396. 13. Klinkert, M. Q., L. Theilmann, E. Pfaff, and H. Schaller. 1986. Pre-S1 antigens and antibodies early in the course of acute hepatitis B virus infection. J Virol 58:522. 14. Neurath, A. R., S. B. Kent, N. Strick, P. Taylor, and C. E. Stevens. 1985. Hepatitis B virus contains Pre-S gene-encoded domains. Nature 315:154. 15. Milich, D. R., A. McLachlan, F. V. Chisari, S. B. Kent, and G. B. Thorton. 1986. Immune response to the Pre-S1 region of the hepatitis B surface antigen (HBsAg): a Pre-S1 -specific T cell response can bypass nonresponsiveness to the Pre-S2 and S regions of HBsAg. J Immunol 137:315. 16. Milich, D. R., G. B. Thornton, A. R. Neurath, S. B. Kent, M. L. Michel, P. Tiollais, and F. V. Chisari. 1985. Enhanced immunogenicity of the Pre-S region of hepatitis B surface antigen. Science 228:1195. 17. Petersen, K. M., L. R. Bulkow, B. J. McMahon, C. Zanis, M. Getty, H. Peters, and A. J. Parkinson. 2004. Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth. Pediatr Infect Dis J 23:650. 18. Wu, J. S., L. Y. Hwang, K. J. Goodman, and R. P. Beasley. 1999. Hepatitis B vaccination in high-risk infants: 10-year follow-up. J Infect Dis 179:1319. 19. Shouval, D. 2003. Hepatitis B vaccines. J Hepatol 39 Suppl 1:S70. 20. Are booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on Hepatitis B Immunity. 2000. Lancet 355:561. 21. Banatvala, J. E., and P. Van Damme. 2003. Hepatitis B vaccine – do we need boosters? J Viral Hepat 10:1. 22. Kao, J. H., and D. S. Chen. 2005. Hepatitis B vaccination: to boost or not to boost? Lancet 366:1337. 23. West, D. J., and G. B. Calandra. 1996. Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine 14:1019. 24. Lee, W. M. 1997. Hepatitis B virus infection. N Engl J Med 337:1733. 25. Gunson RN∗ , Shouval D∗ , Roggendorf M, Zaaijer H, Nicholas H, Holzmann H, de Schryver A. et al. 2003. Hepatitis B virus (HBV) and Hepatitis C virus (HCV)
466
26. 27. 28. 29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
39.
Shibolet and Shouval infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients. J Clin Virol 27:213–230. Reed, E., M. R. Daya, J. Jui, K. Grellman, L. Gerber, M. O. Loveless. 1993. Occupational infectious disease exposures in EMS personnel. J Emerg Med 11:9. Giles, J. P., R. W. McCollum, L. W. Berndtson, Jr., S. Krugman. 1969. Relation of Australia-SH antigen to the Willowbrook MS-2 strain. N Engl J Med 281:119. Maupas P, Goudeau A, Coursaget P, Drucker J, Bagros P. 1976. Immunization against hepatits B in Man. Lancet 1:1367–70. Szmuness, W., C. E. Stevens, E. J. Harley, E. A. Zang, W. R. Oleszko, D. C. William, R. Sadovsky, J. M. Morrison, and A. Kellner. 1980. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 303:833. Emini EA, Ellis RW, Miller WJ, McAleer WJ, Scolnick EM, Gerety RJ. 1986. Production and immunological analysis of recombinant hepatitis B vaccine. J Infect 13 Suppl: 3–9. Zahradnik, J. M., R. B. Couch, and J. L. Gerin. 1987. Safety and immunogenicity of a purified hepatitis B virus vaccine prepared by using recombinant DNA technology. J Infect Dis 155:903. Flehmig, B., U. Heinricy, and M. Pfisterer. 1990. Simultaneous vaccination for hepatitis A and B. J Infect Dis 161:865. West, D. J., T. M. Hesley, L. C. Jonas, L. K. Feeley, S. R. Bird, P. Burke, and J. C. Sadoff. 1997. Safety and immunogenicity of a bivalent Haemophilus influenzae type b/hepatitis B vaccine in healthy infants. Hib-HB Vaccine Study Group. Pediatr Infect Dis J 16:593. Aristegui, J., R. Dal-Re, E. Garrote, A. Gonzalez, J. P. Arrate, and A. Perez. 1998. Assessment of the immunogenicity and reactogenicity of a quadrivalent diphtheria, tetanus, acellular pertussis and hepatitis B (DTPa-HBV) vaccine administered in a single injection with Haemophilus influenzae type b conjugate vaccine, to infants at 2, 4 and 6 months of age. Vaccine 16:1976. Michel, M. L., P. Pontisso, E. Sobczak, Y. Malpiece, R. E. Streeck, and P. Tiollais. 1984. Synthesis in animal cells of hepatitis B surface antigen particles carrying a receptor for polymerized human serum albumin. Proc Natl Acad Sci USA 81:7708. Zuckerman, J. N., A. J. Zuckerman, I. Symington, W. Du, A. Williams, B. Dickson, and M. D. Young. 2001. Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines. Hepatology 34:798–802. Hourvitz, A., R. Mosseri, A. Solomon, Y. Yehezkelli, J. Atsmon, Y. L. Danon, R. Koren, and D. Shouval. 1996. Reactogenicity and immunogenicity of a new recombinant hepatitis B vaccine containing Pre S antigens: a preliminary report. J Viral Hepat 3:37. Shouval, D., Y. Ilan, R. Adler, R. Deepen, A. Panet, Z. Even-Chen, M. Gorecki, and W. H. Gerlich. 1994. Improved immunogenicity in mice of a mammalian cellderived recombinant hepatitis B vaccine containing Pre-S1 and Pre-S2 antigens as compared with conventional yeast-derived vaccines. Vaccine 12:1453. Yap, I., R. Guan, and S. H. Chan. 1995. Study on the comparative immunogenicity of a recombinant DNA hepatitis B vaccine containing Pre-S components of the HBV coat protein with non Pre-S containing vaccines. J Gastroenterol Hepatol 10:51.
Hepatitis B Vaccines
467
40. Young, M. D., W. M. Gooch, 3rd, A. J. Zuckerman, W. Du, B. Dickson, and W. C. Maddrey. 2001. Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination. J Med Virol 64:290. 41. Rendi-Wagner, P., D. Shouval, B. Genton, Y. Lurie, H. Rumke, G. Boland, A. Cerny, M. Heim, D. Bach, M. Schroeder, and H. Kollaritsch. 2006. Comparative immunogenicity of a PreS/S hepatitis B vaccine in non- and low responders to conventional vaccine. Vaccine 24:2781. 42. Coates, T., R. Wilson, G. Patrick, F. Andre, and V. Watson. 2001. Hepatitis B vaccines: assessment of the seroprotective efficacy of two recombinant DNA vaccines. Clin Ther 23:392. 43. Just, M., R. Berger, and N. Scheiermann. 1988. Persistence of antibodies following vaccination with a yeast-derived recombinant hepatitis B vaccine. Vaccine 6:401. 44. Jilg W, Schmidt M, Deinhardt F, Zachoval R. 1984. Hepatitis B vaccination: how long does protection last? Lancet 2: 458. 45. Jilg, W., M. Schmidt, and F. Deinhardt. 1988. Persistence of specific antibodies after hepatitis B vaccination. J Hepatol 6:201. 46. Goldstein, S. T., F. Zhou, S. C. Hadler, B. P. Bell, E. E. Mast, and H. S. Margolis. 2005. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol 34:1329. 47. Wilson, J. N., D. J. Nokes, G. F. Medley, and D. Shouval. 2007. Mathematical model of the antibody response to hepatitis B vaccines: implications for reduced schedules. Vaccine 25:3705. 48. Carman, W. F., A. R. Zanetti, P. Karayiannis, J. Waters, G. Manzillo, E. Tanzi, A. J. Zuckerman, and H. C. Thomas. 1990. Vaccine-induced escape mutant of hepatitis B virus. Lancet 336:325. 49. Mele A, Tancredi F, Romano L, Giuseppone A, Colucci M, Sangiuolo A, Lecce R, Adamo B, Tosti ME, Taliani G, Zanetti AR. 2001. Effectiveness of hepatitis B vaccination in babies born to hepatitis B surface antigen-positive mothers in Italy. J Infect Dis184: 905–8. 50. Francois, G., M. Kew, P. Van Damme, M. J. Mphahlele, and A. Meheus. 2001. Mutant hepatitis B viruses: a matter of academic interest only or a problem with far-reaching implications? Vaccine 19:3799. 51. Hsu, H. Y., M. H. Chang, Y. H. Ni, and H. L. Chen. 2004. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination program in Taiwan. Gut 53:1499. 52. Zuckerman, A. J. 2000. Effect of hepatitis B virus mutants on efficacy of vaccination. Lancet 355:1382. 53. Ogata, N., P. J. Cote, A. R. Zanetti, R. H. Miller, M. Shapiro, J. Gerin, and R. H. Purcell. 1999. Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus. Hepatology 30:779. 54. Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L et. al. 2006. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the US. MMWR 55:1–25. 55. Feldman S. 2001. Interchangeability of vaccines. Pediatr Infect Dis J 20 Suppl: S23–9. 56. World Health Organization, 1992. WHO expanded program on immunization. Global Advisory Group. Weekly Epidemiol Rec:11.
468
Shibolet and Shouval
57. Organization, W. H. 2004. Hepatitis B vaccines. WHO position paper Weekly Epidemiol Rec 255. 58. Arevalo, J. A., and A. E. Washington. 1988. Cost-effectiveness of prenatal screening and immunization for hepatitis B virus. Jama 259:365. 59. Banatvala, J., P. Van Damme, and N. Emiroglu. 2006. Hepatitis B immunization in Britain: time to change? Bmj 332:804. 60. Ginsberg, G. M., and D. Shouval. 1992. Cost-benefit analysis of a nationwide neonatal inoculation programme against hepatitis B in an area of intermediate endemicity. J Epidemiol Community Health 46:587. 61. Kane, M. A. 1996. Global status of hepatitis B immunisation. Lancet 348:696. 62. Kretzschmar, M., and A. de Wit. 2008. Universal hepatitis B vaccination. Lancet Infect Dis 8:85. 63. Zanetti, A. R., E. Tanzi, L. Romano, and I. Grappasonni. 1993. Vaccination against hepatitis B: the Italian strategy. Vaccine 11:521. 64. Chan, C. Y., S. D. Lee, and K. J. Lo. 2004. Legend of hepatitis B vaccination: the Taiwan experience. J Gastroenterol Hepatol 19:121. 65. Chang, M. H., C. J. Chen, M. S. Lai, H. M. Hsu, T. C. Wu, M. S. Kong, D. C. Liang, W. Y. Shau, and D. S. Chen. 1997. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336:1855. 66. Viviani, S., A. Jack, A. J. Hall, N. Maine, M. Mendy, R. Montesano, and H. C. Whittle. 1999. Hepatitis B vaccination in infancy in The Gambia: protection against carriage at 9 years of age. Vaccine 17:2946. 67. Perz, J. F., J. L. Elm, Jr., A. E. Fiore, J. I. Huggler, W. L. Kuhnert, and P. V. Effler. 2006. Near elimination of hepatitis B virus infections among Hawaii elementary school children after universal infant hepatitis B vaccination. Pediatrics 118:1403. 68. Wainwright, R. B., L. R. Bulkow, A. J. Parkinson, C. Zanis, and B. J. McMahon. 1997. Protection provided by hepatitis B vaccine in a Yupik Eskimo population– results of a 10-year study. J Infect Dis 175:674. 69. Zanetti, A. R., A. Mariano, L. Romano, R. D Amelio, M. Chironna, R. C. Coppola, M. Cuccia, R. Mangione, F. Marrone, F. S. Negrone, A. Parlato, E. Zamparo, C. Zotti, T. Stroffolini, and A. Mele. 2005. Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study. Lancet 366:1379. 70. Touze, E., A. Fourrier, C. Rue-Fenouche, V. Ronde-Oustau, I. Jeantaud, B. Begaud, and A. Alperovitch. 2002. Hepatitis B vaccination and first central nervous system demyelinating event: a case-control study. Neuroepidemiology 21:180. 71. Hernan, M. A., S. S. Jick, M. J. Olek, and H. Jick. 2004. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 63:838. 72. Safety, W. H. O. G. A. C. o. V. Response to the paper by MA Hern´an and others in Neurology 14th September 2004 issue entitled. Recombinant Hepatitis B Vaccine and the Risk of Multiple Sclerosis. 73. Duclos, P. 2003. Safety of immunization and adverse events following vaccination against hepatitis B. J Hepatol 39 Suppl 1:S83. 74. Naismith, R. T., and A. H. Cross. 2004. Does the hepatitis B vaccine cause multiple sclerosis? Neurology 63:772.
Hepatitis B Vaccines
469
75. Ingardia, C. J., L. Kelley, J. D. Steinfeld, and J. R. Wax. 1999. Hepatitis B vaccination in pregnancy: factors influencing efficacy. Obstet Gynecol 93:983. 76. Alper, C. A., M. S. Kruskall, D. Marcus-Bagley, D. E. Craven, A. J. Katz, S. J. Brink, J. L. Dienstag, Z. Awdeh, and E. J. Yunis. 1989. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl J Med 321:708. 77. Craven, D. E., Z. L. Awdeh, L. M. Kunches, E. J. Yunis, J. L. Dienstag, B. G. Werner, B. F. Polk, D. R. Syndman, R. Platt, C. S. Crumpacker, and et al. 1986. Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings. Ann Intern Med 105:356. 78. Hohler, T., C. U. Meyer, A. Notghi, B. Stradmann-Bellinghausen, P. M. Schneider, R. Starke, F. Zepp, R. Sanger, R. Clemens, K. H. Meyer zum Buschenfelde, and C. Rittner. 1998. The influence of major histocompatibility complex class II genes and T-cell Vbeta repertoire on response to immunization with HBsAg. Hum Immunol 59:212. 79. Milich, D. R. 1988. T- and B-cell recognition of hepatitis B viral antigens. Immunol Today 9:380. 80. Itoh, Y., E. Takai, H. Ohnuma, K. Kitajima, F. Tsuda, A. Machida, S. Mishiro, T. Nakamura, Y. Miyakawa, and M. Mayumi. 1986. A synthetic peptide vaccine involving the product of the Pre-S2 region of hepatitis B virus DNA: protective efficacy in chimpanzees. Proc Natl Acad Sci USA 83:9174. 81. Lo, C. M., G. K. Lau, S. C. Chan, S. T. Fan, and J. Wong. 2007. Efficacy of a Pre-S containing vaccine in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. Am J Transplant 7:434. 82. Ilan, Y., A. Nagler, R. Adler, E. Naparstek, R. Or, S. Slavin, C. Brautbar, and D. Shouval. 1993. Adoptive transfer of immunity to hepatitis B virus after Tall depleted allogeneic bone marrow transplantation. Hepatology 18:246. 83. Shouval, D., and Y. Ilan. 1995. Transplantation of hepatitis B immune lymphocytes as means for adoptive transfer of immunity to hepatitis B virus. J Hepatol 23:98. 84. Bienzle, U., M. Gunther, R. Neuhaus, P. Vandepapeliere, J. Vollmar, A. Lun, and P. Neuhaus. 2003. Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease. Hepatology 38:811. 85. Heineman, T. C., M. L. Clements-Mann, G. A. Poland, R. M. Jacobson, A. E. Izu, D. Sakamoto, J. Eiden, G. A. Van Nest, and H. H. Hsu. 1999. A randomized, controlled study in adults of the immunogenicity of a novel hepatitis B vaccine containing MF59 adjuvant. Vaccine 17:2769. 86. Cooper, C. L., H. L. Davis, M. L. Morris, S. M. Efler, M. A. Adhami, A. M. Krieg, D. W. Cameron, and J. Heathcote. 2004. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 24:693. 87. Tong, N. K., J. Beran, S. A. Kee, J. L. Miguel, C. Sanchez, J. M. Bayas, A. Vilella, J. R. de Juanes, P. Arrazola, F. Calbo-Torrecillas, E. L. de Novales, V. Hamtiaux, M. Lievens, and M. Stoffel. 2005. Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int 68:2298. 88. Milich, D. R., J. L. Hughes, A. McLachlan, G. B. Thornton, and A. Moriarty. 1988. Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope. Proc Natl Acad Sci USA 85:1610.
470
Shibolet and Shouval
89. Reyes-Sandoval, A., and H. C. Ertl. 2001. DNA vaccines. Curr Mol Med 1:217. 90. Hess, G., F. Kreiter, W. Kosters, and K. Deusch. 1996. The effect of granulocytemacrophage colony-stimulating factor (GM-CSF) on hepatitis B vaccination in haemodialysis patients. J Viral Hepat 3:149. 91. Scheerlinck, J. P., G. Casey, P. McWaters, J. Kelly, D. Woollard, M. W. Lightowlers, J. M. Tennent, and P. J. Chaplin. 2001. The immune response to a DNA vaccine can be modulated by co-delivery of cytokine genes using a DNA prime-protein boost strategy. Vaccine 19:4053. 92. Fabrizi, F., V. Dixit, M. Magnini, A. Elli, and P. Martin. 2006. Meta-analysis: intradermal vs. intramuscular vaccination against hepatitis B virus in patients with chronic kidney disease. Aliment Pharmacol Ther 24:497.
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C Richard C. Duke, PhD, Alex Franzusoff, PhD and David Apelian, MD, PhD CONTENTS I NTRODUCTION T-C ELL -M EDIATED I MMUNE R ESPONSES T O HCV I NFECTION G ENERAL OVERVIEW OF T-C ELL -M EDIATED I MMUNITY I MMUNOTHERAPEUTIC VACCINES AND C ONCEPTS G OALS AND E VALUATION OF I MMUNOTHERAPY IN C HRONIC HCV I NFECTION S UMMARY R EFERENCES
Key Principles
• Numerous reports suggest that viral replication, the level of viremia, and progression to the chronic state in hepatitis
From: Clinical Gastroenterology: Chronic Viral Hepatitis, Edited by: K. Shetty and G. Y. Wu, DOI 10.1007/978-1-59745-565-7 19, C Humana Press, a part of Springer Science+Business Media, LLC 2009
471
472
• •
•
• •
Duke et al.
C-infected individuals are influenced directly and indirectly by HCV-specific cellular immunity mediated by CD4+ helper (Th) and CD8+ cytotoxic T lymphocytes (CTLs). A method to increase the ability of dendritic cells to adequately present antigens should lead to an improved T-cell-mediated cellular response. More recently, it has been recognized that in addition to the immunoregulation afforded by differences in the balance between Th1 vs. Th2 cells, some T cells can also exhibit distinct inhibitory properties and directly prevent the activation, proliferation, and function of helper and cytotoxic effector T cells. As described above, successful control of HCV is associated with strong and broadly directed HCV-specific CD4+ and CD8+ T-cell responses, while chronic HCV infection is characterized by attenuated and functionally impaired T-cells. Therefore, an immunotherapeutic approach that stimulates potent cellular immunity against one or more HCV antigens could be beneficial in chronic HCV disease. In addition to being able to interact directly with dendritic cells, yeast have a variety of other characteristics that make them an ideal platform for immunotherapy. The proposed action of an immunotherapy, for example, a yeastbased Tarmogen engineered to induce adaptive cellular immune responses to multiple HCV antigens (GI-5005) (61) would favor hepatic clearance (the rate-limiting portion of the viral dynamics profile) and should complement the direct antiviral effects of IFNbased therapy.
1. INTRODUCTION Hepatitis C virus (HCV) is a major causative agent of acute and chronic hepatitis worldwide. HCV infection affects more than 200 million people worldwide and represents a significant health problem in many countries (1, 2). Approximately 20–40% of individuals infected with HCV clear the virus during the acute phase, whereas the remaining 60–80% develop chronic disease which may result in hepatic failure and liver cancer (3–5). There is at present no preventative vaccine, and therapeutic options are limited to interferon/ribavirin therapy which is often poorly tolerated, is contraindicated in many subjects, and is expensive. In addition, the efficacy of the current standard treatment with interferon and ribavirin is limited, especially in genotype 1, the most prevalent genotype in the United States and most industrialized countries
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
473
(6). Thus, only a proportion of HCV-infected persons can be successfully treated at this time and alternative treatment modalities, including immunotherapies and prophylactic vaccines, are clearly needed.
2. T-CELL-MEDIATED IMMUNE RESPONSES TO HCV INFECTION HCV is a non-cytopathic virus that induces both acute and chronic hepatitis and interacts in a highly complex manner with the immune system (7). Likewise, the immune system has a unique role in the pathogenesis of HCV infection as it contributes both to control of viral infection and liver repair, and also to the development of chronic infection and liver cirrhosis. T-cell-mediated immune responses in acute and chronic HCV infection will now be discussed in brief; however, it should be appreciated that humoral (antibody)-mediated immune responses as well as cells and effectors of innate immunity (e.g., natural killer (NK) cells, macrophages, and type 1 interferons) also impact the outcome of HCV infection, and the reader is referred to excellent reviews that discuss these responses in greater detail (8–12). It is equally important to understand that T-cell responses both influence and are influenced by innate and humoral immunity. Numerous reports suggest that viral replication, the level of viremia, and progression to the chronic state in hepatitis C-infected individuals are influenced directly and indirectly by HCV-specific cellular immunity mediated by CD4+ helper (Th) and CD8+ cytotoxic T lymphocytes (CTLs) (13–17). Studies of humans and chimpanzees have revealed that HCV can replicate for weeks before the onset of CD4+ and CD8+ T-cell responses can be detected in the liver and in the blood. Moreover, there may be a delay in the acquisition of function by CD8+ (and perhaps CD4+ ) T cells even after their expansion in blood (17). The appearance of functional CD8+ T cells is kinetically associated with control of viremia and, at least in some cases, with an elevation in serum aminotransferases, suggesting that liver damage during acute hepatitis C is immunopathological. At highest risk of persistent HCV infection are those individuals who fail to generate a detectable virus-specific T lymphocyte response in the blood, liver, or both. Perhaps most importantly, generation of a cellular immune response does not necessarily ensure that the infection will be permanently controlled. CD4+ and CD8+ Tcell responses must be sustained for weeks or months beyond the point of apparent control of virus replication to prevent relapse and establishment of a persistent infection. CD4+ T cells play an essential role in anti-HCV immunity by providing help for activating and sustaining CD8+ T-cell responses. Protective
474
Duke et al.
CD4+ T cells appear to predominantly recognize epitopes in Core, NS3, NS4, and NS5 proteins although responses against the other HCV gene products have also been reported (1, 18). In addition to the help that CD4+ T cells provide to CD8+ T cells, it also appears critical that they produce gamma interferon and other lymphokines that are pro-inflammatory/pro-cell-mediated immunity, as opposed to pro-humoral immunity (Th1- vs. Th2-type lymphokines as described below). Equally important for control of chronic infection is the establishment of HCV-specific memory CD4+ T cells (18, 19). The finding that CD4+ and CD8+ T-cell responses are common to self-limited HCV infections suggests that they cooperate to bring about control of viremia. Memory CD4+ and CD8+ T cells primed during acute resolving hepatitis C infection provide long-term protection from virus persistence in chimpanzees and probably humans. Through antibody-mediated depletion of each memory T-cell subset, the chimpanzee model has provided direct proof of the importance of CD8+ T cells in the control of acute hepatitis C and their dependence on CD4+ T-cell help (20). In contrast to CD4+ T cells, both acute and memory CD8+ T cells appear to recognize all of the HCV proteins equally and, as with CD4+ T cells, it may be critical that they be capable of producing pro-inflammatory cytokines including gamma interferon (17). The transition from acute to chronic HCV infection is associated with substantial loss of HCV-specific CD4+ T cells that do not appear to recover during the life of the host. CD8+ T-cell activity is also impaired, as it is insufficient for resolution of infection. The conclusion from the clinical observations is that control and clearance of HCV requires both CD4+ and CD8+ T cells and that the lack and/or loss of adequate cellular immunity is associated with development of chronic infection. It is appealing, therefore, to hypothesize that stimulation of existing, but insufficient HCV-specific CD4+ and CD8+ T cells in chronically HCVinfected individuals may have a therapeutic benefit.
3. GENERAL OVERVIEW OF T-CELL-MEDIATED IMMUNITY It is the aim of this chapter to provide the reader with an understanding of T-cell-mediated immune responses in HCV infection, and how immunotherapy can be approached and utilized in the chronic setting. In this regard, a general overview of T-cell-mediated immune responses is warranted. In brief, the immune system consists of a collection of bone marrow-derived cells and several plasma proteins that work together to fight threats to an organism’s integrity including organ and tissue damage, infection, and cancer. The immune system uses a variety of
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
475
receptor-based recognition mechanisms to discriminate between “self” (i.e., the body’s own constituents) and “non-self” (i.e., any foreign material including toxins, bacteria, viruses, and parasites that penetrates the body’s external surfaces). The immune system has two major mechanisms that allow the body to combat microbial diseases: innate and adaptive immunity. Innate immunity is evolutionally conserved and refers to the first line of defense to protect against invading organisms and consists of the preexisting defense mechanisms of skin, macrophages, neutrophils, stomach acid, and anti-microbial proteins in the bloodstream. It also refers to the innate response of cells upon viral infection and would, therefore, include type 1 interferons. Adaptive immunity, which is present in vertebrates and is comprised of humoral and cellular immunity, relies on receptors expressed on T and B lymphocytes which allow these cells to specifically recognize “antigens.” An antigen is any substance, but most typically a protein, that can be bound by antigen receptors present on T and B cells. Humoral immunity results from production of antibodies by B cells that, in regard to viral infections, bind specifically to viruses that have entered the body, but not yet infected cells, while cellular immunity induces death of cells that have already been infected. Understanding how these types of immunity are controlled is essential to the design of effective vaccines and immunotherapy.
3.1. Cells of the Immune System All of the cells of the immune system arise from precursors in the bone marrow. They circulate freely throughout the bloodstream, are able to leave the vasculature, and enter tissues. They recirculate into the blood via the lymphatics. Cells of the immune system congregate in lymph nodes and in the spleen. In these “peripheral” lymphoid organs, the necessary interactions between antigen-presenting cells and antigen-specific T and B cells can occur leading to a productive immune response. The first cells that respond during an immune response are dendritic cells and macrophages which play a central role in both innate and adaptive immunity. These cells are actively recruited to the site of tissue damage, and are intimately involved in repair processes. Until recently, innate immunity was considered as being a largely nonspecific response mediated by neutrophils and macrophages that engulf and digest microbial pathogens. However, it is now clear that both cell types, and especially macrophages and the related dendritic cells, recognize “not-self” to some degree in that they preferentially phagocytose damaged proteins and cells as well as bacteria, yeast, and other
476
Duke et al.
substances that enter the body. Macrophages and dendritic cells do so because they express receptors that are collectively referred to as pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). PAMPs represent organism-specific differences in glycosylation patterns, lipoproteins, and nucleic acid composition. Hence, APCs have receptors for microbial mannoproteins, peptidoglycans, glucans, lipoproteins, double-stranded RNA, and CpG island-containing DNA (21–23). Engagement of these receptors results in what has been termed a “danger” signal leading to dendritic cell maturation, activation, enhanced phagocytosis, and efficient presentation of antigens that were associated with the engaging material (24). Examples of PRRs include Toll-like receptors (TLRs) that will be described in detail later (25). Dendritic cell and macrophage activation is further amplified by pro-inflammatory lymphokines, soluble stimulatory factors secreted by T cells during an immune response, and by cytokines secreted by cells at the site of tissue damage. Activated macrophages and dendritic cells play a central role in induction of inflammation and fever due to the release of arachidonic acid metabolites (e.g., prostaglandins) and endogenous pyrogen (also called interleukin-1; IL-1). Inflammation is beneficial in the sense that it recruits additional white blood cells to the tissue or organ where an immune response may be needed. Dendritic cells and macrophages are intimately involved in the activation of T lymphocytes by acting as “professional antigen-presenting cells” (APC). Macrophages are also capable of killing and causing damage to normal, infected, or tumor cells by releasing toxic substances such as tumor necrosis factor (TNF) and nitric oxide (NO). While macrophages and dendritic cells are absolutely critical in initiating immune responses, T cells, or T lymphocytes, are the central control cells of the adaptive immune system. T lymphocytes do not respond to foreign materials directly but, rather, recognize peptide fragments of foreign proteins that are presented in association with major histocompatibility (MHC) molecules (see Figs. 1 and 2). Each T cell has an antigen receptor (TCR) of only one specificity. It has been estimated that at least 100 million different receptors can be made. This diversity allows the immune system to react against any foreign substance, natural or man-made. T cells come in two functional types: helper/inducer and cytotoxic/killer T cells. Helper T cells (Th) express the CD4 cell surface molecule and respond to antigens presented in the context of MHC class II molecules. CD4+ helper T cells produce and secrete soluble factors (lymphokines) that activate macrophages (to induce inflammation), cytotoxic T cells (to kill virally infected or tumor cells), and B cells (to secrete antibody).
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C Exogenous antigens
Lymphokines
CD4
Helper T Cell
Endosome (digestion) MHC-II
TCR CD3
Peptides
Dendritic cell
477
CD80/86 or CD40
Cell activation
CD28 or CD40L
Fig. 1. Dendritic cell presentation of exogenous antigens via MHC class II to CD4+ helper T cells. Effector functions
Endogenous antigens Proteasome (digestion)
Cytotoxic T Cell
CD8
MHC-I
TCR CD3
Peptides
Cell activation
CD28 or CD40L
Any cell
Fig. 2. Recognition of endogenous antigens by CD8+ cytotoxic T cells via MHC class I.
Cytotoxic T cells (CTL) express the CD8 cell surface molecule and recognize antigens in the context of MHC class I molecules. (Note: MHC class I molecules are expressed by all cell types in the body whereas MHC class II expression is limited, for the sake of this discussion, to professional antigen-presenting cells including macrophages, dendritic cells, and B cells.) CTL are effective at killing cells infected with viruses, as well as intracellular bacteria and parasites (e.g., mycobacterium tuberculosis, toxoplasma, and leishmania). They hold promise for tumor immunotherapy as well because of their ability to recognize cells making mutant proteins. Finally, B lymphocytes use antibody molecules as their antigen receptors and, in contrast to T cells, recognize foreign materials like
478
Duke et al.
bacteria, viruses, and toxins directly. Each B cell expresses antibody of only one specificity and, as for T cells, at least 100 million antibody specificities are possible.
3.2. Humoral Immunity in Response to Exogenous (Extracellular) Antigens Immune responses are initiated when dendritic cells and macrophages endocytose foreign particles (e.g., bacteria and viruses), protein antigens (e.g., toxins and allergens), or cellular debris (e.g., from cells killed by viruses) that are present in extracellular fluids. Foreign proteins are digested into polypeptides (10–20 amino acids long) which are bound to MHC class II molecules in specialized vesicles, endosomes, dendritic cells, and macrophages. The peptide and MHC class II complex is then expressed on the surface of the dendritic cell or macrophage (Fig. 1). An antigen-specific CD4+ helper T cell binds to the combination of MHC class II and peptide, becomes activated and produces lymphokines, including IL-2, IL-4, and IL-5 (not all produced by the same helper T cell – see below). Type 2 helper T cells (Th2), which produce IL-4 and IL-5, but not IL-2, seem to dominate over type 1 helper T cells (Th1) cells in responses to exogenous antigens and typically lead to an antibody-mediated (humoral) immune response. CTL are not normally activated in response to exogenously introduced antigens. Antibody is effective in coating bacteria and making them more likely to be phagocytosed by macrophages and granulocytes (IgG subclass). Antibody can “neutralize” viruses and prevent them from getting into the body (IgA) or infecting cells (IgG) and, with the help of complement factors, can directly kill certain bacteria (IgM and IgG). However, it is important to understand that antibody generated in an individual, as opposed to therapeutic monoclonal antibodies, generally has little direct effect on cells expressing foreign antigens, including tumor or viral antigens expressed on the surface of a cell.
3.3. Cellular Immunity in Response to Endogenous (Intracellular) Antigens In contrast to extracellular antigens, foreign or mutant proteins being synthesized by, or merely present in the cytoplasm of infected cells, are digested into polypeptides (8–10 amino acids long) in the ER/Golgi/proteasome complex. The polypeptides are bound to MHC class I and expressed on the surface of the infected or tumor cell (Fig. 2). CD8+ T cells respond to the combination of MHC class I and peptide,
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
479
and produce lymphokines which, in general, lead to a cell-mediated immune response. They can also kill infected cells directly. CTL appear to require IL-2 and IL-12 in order to be effectively activated. While CTL can produce some IL-2, it is generally accepted that CD4+ Th1 cells are the major source of IL-2, and dendritic cells are the major source of IL12 for CTL-mediated responses. In addition, it is also clear that in order to obtain maximal CTL activation, presentation of antigens by dendritic cells is required. Thus, as for CD4+ Th1 cells, CTL require interaction with an APC in order to become maximally activated and then respond to virally infected cells. It was initially unclear how antigens being synthesized by a virally infected cell could find their way into the MHC class I pathway in dendritic cells, unless the dendritic cell itself became infected. However, recent data indicates that dendritic cells can recognize infected cells that become apoptotic as a result of infection and that “cross-priming” (delivery of exogenous antigens into the endogenous antigen presentation pathway) can occur such that some of the proteins associated with cells/particles engulfed by dendritic cells and macrophages find their way into the MHC class I pathway (26). In addition, certain “danger” signals mediated by PRRs including TLRs (described below) can enhance this process (27). As with presentation to CTL, it was also unclear how virus-specific CD4+ Th1 cells would become activated in response to endogenously synthesized antigens (particularly in cells which do not express MHC class II); however, it is possible that cells that die as a result of the initial infection are ingested by dendritic cells or macrophages leading to helper T-cell activation, production, and secretion of the appropriate lymphokines to initiate cellular immunity.
3.4. Th1 vs. Th2 Cells: Cell-Mediated vs. Antibody-Mediated Immunity As discussed above, there are two potential positive outcomes in response to antigens: cell-mediated and antibody-mediated immunity. In the past, it was thought that both occurred with any antigen. However, today it is recognized that these arise by diametrically opposed mechanisms, and in fact one or the other type of response may dominate against many antigens. Understanding how these types of immunity and dominance are controlled is essential to the design of effective vaccines and immunotherapy. At the present time, it can be shown that Th1 cells are preferentially involved in cell-mediated responses. These cells lead to the activation of CTL and macrophages by producing IL-2, and the pro-inflammatory
480
Duke et al.
cytokines gamma interferon (IFN-␥), granulocyte/macrophage colonystimulating factor (GM-CSF), and lymphotoxin (TNF-). IL-12 produced by activated dendritic cells and macrophages is also necessary for development of cell-mediated immunity, and in combination with IL-2 may act to suppress Th2 cells and, hence, antibody-mediated responses. Th2 cells produce IL-4 and IL-5 that act on B cells to stimulate antibody production. IL-10 produced by Th2 cells is also necessary for development of antibody-mediated immunity, and in combination with IL-4 appears to suppress Th1 cells and, hence, cell-mediated responses. In brief, the body usually initiates a cellular response against infectious agents first, and then works its way toward a humoral response. As noted above, immune responses are initiated by dendritic cells and macrophages that take up foreign material from extracellular fluids. A method to increase the ability of these cells to adequately present antigens should lead to an improved T-cell-mediated cellular response. Exogenous antigens are preferentially expressed via MHC class II leading to activation of CD4+ T cells that initially differentiate into predominantly Th1 cells and stimulate cell-mediated immunity including activation of CTL and pro-inflammatory macrophages. Over time, the immune response matures and CD4+ T cells increasingly differentiate into Th2 cells. The lymphokines produced by Th2 activate B cells to make antibody while at the same time suppressing Th1 cells. This shift from Th1 to Th2 allows production of protective antibody that prevents reinfection, but unfortunately may not lead to eradication of cells that are already infected with viruses or other intracellular pathogens. In addition, if the body should become reintroduced to that antigen, it will generally respond with a much stronger secondary humoral response than cellular response.
3.5. Regulatory T Cells More recently, it has been recognized that in addition to the immunoregulation afforded by differences in the balance between Th1 vs. Th2 cells, some T cells can also exhibit distinct inhibitory properties and directly prevent the activation, proliferation, and function of helper and cytotoxic effector T cells (28–32). These regulatory T cells (Tregs) most typically express the forkhead P3 transcriptional factor that is involved in T-cell differentiation, the CD4 molecule and the CD25 IL-2 receptor, and are thus referred to as Foxp3+ /CD4+ /CD25+ Tregs. An increased frequency of T cells with regulatory phenotypes and functions have been described by numerous groups in HCV-infected humans and non-human primates. In humans, it has been reported that Tregs are expanded during acute HCV infection, maintained during the
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
481
chronic stage, and lowered to the frequency of control individuals upon immune-mediated clearance (33, 34). Collectively, these findings suggest an important role for Tregs in the pathogenesis of HCV infection, but also imply that a certain balance between the frequency and the function of Tregs is necessary to achieve an immune response that provides a reasonable chance for HCV clearance. It is not clear how Tregs mediate their suppressive activity, but likely involves both cell-to-cell contact and induction of inhibitory cytokines. Cell surface molecules that appear to be involved include CTLA-4, GITR, and PD-1; whereas IL-10 and TGF- have been implicated as soluble suppressor molecules (35–38). It remains largely unknown how Tregs are induced, how they function, and how they contribute to acute and chronic HCV infection.
4. IMMUNOTHERAPEUTIC VACCINES AND CONCEPTS As described above, successful control of HCV is associated with strong and broadly directed HCV-specific CD4+ and CD8+ T-cell responses, while chronic HCV infection is characterized by attenuated and functionally impaired T-cells (6, 7). Therefore, an immunotherapeutic approach that stimulates potent cellular immunity against one or more HCV antigens could be beneficial in chronic HCV disease. Prophylactic vaccines (i.e., vaccines that protect an individual against subsequent infections) have had a major impact worldwide in reducing both morbidity and mortality for a variety of bacterial and viral diseases. The majority of these are pediatric vaccines, and they are effective because the pathogens and toxins they target are readily inactivated by “neutralizing” antibody. These vaccines typically lead to strong humoral immune responses at the expense of cellular immunity because they tend to induce Th2 rather than Th1 cells. Thus, it is clear that approaches that stimulate cellular immunity may be needed for many unmet targets including HCV. Prophylactic vaccines consist of three main types: purified, pathogen-derived antigenic proteins (subunit vaccines); heat- or chemically killed viruses; and live attenuated viruses. The following is a description of these conventional vaccine approaches and some of their shortcomings.
4.1. Conventional Vaccine Approaches Purified, pathogen-derived, antigenic proteins or killed pathogens (e.g., tetanus, diphtheria, Salk polio, hepatitis B subunit, whole and a cellular pertussis, rabies, yellow fever, influenza) are injected along with acceptable adjuvants (cofactors that stimulate the immune
482
Duke et al.
response; e.g., aluminum salts). Antigenic proteins can be difficult to produce and/or purify and viruses can be costly to make and production can be unpredictable. The adjuvants that are currently approved for use in humans do not induce a significant inflammatory response, meaning that the vaccines typically induce weak humoral, but not cellular immune responses and require multiple “booster” administrations. Conventional vaccine approaches to neutralize HCV by inducing antibodies that target the surface glycoproteins E1 and E2 have so far shown only limited success. In chimpanzees, immunization with recombinant E1 and E2 glycoproteins was able to prevent experimental infection after challenge with homologous virus, but not heterologous virus (39). A study evaluating a recombinant E1 protein as a therapeutic HCV vaccine clearly showed that this strategy was not sufficient to achieve virus clearance. A small phase 1 study of truncated recombinant HCV E1 protein intramuscularly showed good tolerability in chronic hepatitis C patients, a limited increase in E1-specific CD4+ T-cell responses and E1 antibody levels, but failed to decrease viral RNA titers. (40). Overall, approaches using vaccines delivering HCV surface glycoproteins seem to be of limited promise, especially as immunotherapy for chronic disease. In the setting of chronic infection, where HCVharboring cells need to be eliminated, immunotherapeutic approaches inducing a cellular immune response are a logical approach to improved control of HCV. In addition, if sterilizing antibody-mediated immunity cannot be achieved for HCV, as is indicated by many studies, agents inducing CD4+ and CD8+ T-cell responses specific for HCV might also be the best option for prophylactic vaccines, as they might help to prevent the establishment of chronic infection. Live attenuated vaccines (weakened versions of pathogenic viruses or bacteria that closely resemble the actual disease; e.g., smallpox, Sabin polio, measles, mumps, rubella, chicken pox, and BCG tuberculosis) are injected or ingested and cause a mild form of the natural infection. The tissue damage that occurs as a result of the initial infection causes inflammation and leads to potent cellular and humoral immunity. This class of vaccine has been extremely useful for some diseases, but the potential to revert to a more pathogenic form and the difficulty of generating attenuated versions of many pathogenic viruses and bacteria limit its potential use for unmet indications. For example, it has not proven possible to make clinically useful, attenuated vaccine versions of HIV, RSV, HCV, HBV, herpes, salmonella, shigella, etc. To overcome the shortcomings of existing vaccine technologies, a variety of new technologies are under development in academic laboratories and industrial settings. In general, these approaches tend to take advantage of recombinant DNA technology to create vaccines that do
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
483
not require purification of an antigenic protein or the pathogen itself. A brief description of these approaches follows.
4.2. Recombinant DNA and Virus-based Vaccine Approaches Live, attenuated recombinant viruses and bacteria that express pathogen-derived, antigen-encoding genes (e.g., recombinant vaccinia (smallpox), canary pox, Venezuelan equine encephalitis virus, adenovirus, and salmonella) that are injected and cause a mild form of the natural infection are being developed. These types of vaccines can induce potent cellular and humoral immunity. However, as with live, attenuated naturally occurring organisms, the potential pathogenicity of the recombinant vaccine vectors themselves may limit application (none are currently approved) and they are costly and difficult to make. In addition, recombinant viruses are subject to neutralization which limits their usefulness in immunotherapy settings where repeated immunization may be required. DNA vaccines encoding pathogen-derived antigen genes employ naked DNA that is injected directly into muscle tissue where it is taken up by cells that then produce the pathogen-derived antigens encoded by the DNA “vaccine”. DNA vaccines are easy to prepare and are relatively inexpensive. However, long-lived protection may require booster shots composed of “subunit” proteins and/or recombinant viruses. In addition, it has proven difficult to predict the degree of immunity that results with new applications and individuals. Despite the shortcomings described above, promising results with both recombinant viral vectors and DNA vaccine approaches as well as with dendritic cell-based vaccines in the setting of HCV prophylaxis have been reported (41–46). Nonetheless, the considerations described above suggest that the ideal HCV immunotherapy might consist of a non-pathogenic vector that can deliver multiple HCV antigens into the MHC class I and class II antigen presentation pathways to stimulate potent CD4+ and CD8+ T-cell responses. If possible, this vector would also be capable of repeated administration similar to that for therapeutic drugs.
4.3. Vaccine Approaches that Target Pattern Recognition Receptors As discusssed above, the role of pattern recognition receptors (PRRs), including Toll-like receptors (TLR), in the activation of innate and adaptive immunity has recently been elucidated (Table 1) (21–24, 47, 48). Recognition of the importance of PRRs has led to the testing of agents that target specific TLRs. These agents include isatoribine
484
Duke et al. Table 1 Pattern Recognition Receptors, Their Ligands, and Cellular Expression Patterns
Receptor TLR-1 TLR-2
TLR-3 TLR-4 TLR-5 TLR-6 TLR-7/8
TLR-9 CD14 Dectin-1/2 Mannose receptors
Ligand Triacyl lipopeptides Glycolipids, lipopeptides, lipoproteins, lipoteichoic acid, peptidoglycans, zymosan, Hsp70 Double-stranded RNA Lipopolysaccharide, heat shock proteins, fibrinogen Flagellin Diacyl lipopeptides Single-stranded RNA, imidazoquinolone, loxoribine, bropirimine CpG-containing DNA Lipopolysaccharide Beta-glucan Mannans
Pathogen
Expression
Bacteria Cell surface Bacteria, fungi, Cell surface tissue damage
Viruses Bacteria, tissue damage Bacteria Mycoplasma Viruses
Intracellular Cell surface Cell surface Cell surface Intracellular
Bacteria Bacteria Fungi Fungi
Intracellular Cell surface Cell surface Cell surface
and imiquimod that target TLR-7 and CpG containing double-stranded DNA that targets TLR-9 (49–54). Additional agents are in preclinical development that target TLR-2, TLR-4, and TLR-5. In practice, these agents act as adjuvants to stimulate innate immunity in infected individuals, and will hopefully induce a productive adaptive immune response. Another approach that is currently being employed in human phase II clinical trials and that also targets PRRs involves the use of recombinant, non-pathogenic Saccharomyces cerevisiae (Baker’s yeast), termed TarmogensTM , as a vaccine and immunotherapy vector. Yeast cell wall components appear to interact with more pattern recognition receptors than perhaps any other microbe and are especially effective at stimulating antigen presentation. These receptors include TLR-2, TLR-4, TLR-6, CD14, Dectin-1, Dectin-2, DEC-205, and the mannose receptor
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
485
family (21, 47). Uptake of zymosan, a crude S. cerevisiae yeast cell wall preparation, results in upregulation of a multitude of pro-inflammatory genes (47, 50–57). Data indicate that uptake of whole yeast by mouse and human dendritic cells and macrophages results in upregulation of a variety of cell surface molecules including adhesion molecules (ICAM1, CD54), co-stimulatory molecules (B7-1, B7-2, CD80, CD86), and MHC class I and class II molecules, as well as promoting the secretion of pro-inflammatory cytokines including IL-12 (58). Yeast-associated proteins are efficiently presented via MHC class I and class II and Tarmogens have been shown to induce antigen-specific, protective, and therapeutic immune responses in preclinical studies (58–63). In addition to being able to interact directly with dendritic cells, yeast have a variety of other characteristics that make them an ideal platform for immunotherapy. First, multiple antigens may be engineered for expression within a single yeast strain, and these formulations share many advantages with DNA vaccines, including ease of construction and the ability to target multiple antigens. Unlike DNA vaccines, yeastbased immunotherapeutic formulations do not require extensive purification to remove potentially toxic contaminants. Finally, and perhaps most surprising and important, yeast can be administered multiple times without apparent neutralization of their ability to boost antigen-specific T-cell responses (61) making them an ideal candidate for immunotherapy which may require repeated administration.
5. GOALS AND EVALUATION OF IMMUNOTHERAPY IN CHRONIC HCV INFECTION The behavior of the serum HCV RNA levels in chronic HCV has been predicted in various settings using a three compartment model of viral kinetics which includes uninfected liver cells, infected liver cells, and free virus in the serum. Viral levels in the peripheral blood early during the course of interferon (IFN) therapy have served as an early predictor of response to therapy due to the fact that they can be measured easily, and have been correlated to other more meaningful endpoints in the setting of long-term IFN treatment such as sustained virologic response (SVR, defined as negative peripheral viral levels for at least 6 months after the completion of IFN-based therapy). Viral clearance in the setting of interferon therapy is biphasic; a rapid early phase of peripheral viral load reduction which occurs in the first week(s) (phase 1), followed by the rate limiting, gradual second phase of peripheral viral load reduction which occurs over many months (phase 2, see Fig. 3) (64, 65). While phase 1 kinetics reflect the efficiency of inhibition of viral replication (driven by rapid peripheral
486
Duke et al.
Fig. 3. Kinetics of plasma (phase 1) and hepatic (phase 2) viral clearance with IFN plus ribavirin (solid line) vs. putative improved phase 2 clearance induced by immunotherapy (dashed line) (adapted from Layden-Almer, JE, et al., J Viral Hepatitis 2006; 13: 499–504).
viral clearance), phase 2 kinetics represent direct clearance of infected liver cells. Clearance of infected hepatocytes is the rate-limiting step in achieving complete eradication of hepatic infection and SVR. The use of an agent that stimulates an adaptive cellular immune response would be predicted to have a favorable impact on second phase viral clearance and, therefore, improve virologic endpoints and ultimately improve SVR rates. The proposed action of an immunotherapy, for example, a yeastbased Tarmogen engineered to induce adaptive cellular immune responses to multiple HCV antigens (GI-5005) (61), would favor hepatic clearance (the rate-limiting portion of the viral dynamics profile) and should complement the direct antiviral effects of IFN-based therapy. The potential of this combination of immune and antiviral effects to substantially improve response rates in chronic genotype 1 HCV infection support development of GI-5005 and analogous agents in combination with IFN-based standard of care (pegylated IFN plus ribavirin). Furthermore, type 1 interferons have been associated with other immune effects that are potentially synergistic with cell-mediated immunity, including upregulation of major histocompatibility genes in antigen-presenting cells and target cells, as well as upregulation of dendritic cells, natural killer cells, and CD8+ cytotoxic T lymphocytes (66).
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
487
6. SUMMARY There is an unmet medical need for treatment of chronic HCV infection that is either more effective, better tolerated, or both. Combination of an immunotherapeutic vaccine which elicits adaptive cellular immunity with the standard of care (PegIFN/ribavirin) should be studied to evaluate the complementarity of the two approaches with a goal to improve remission rates in the form of sustained virologic responses for patients with chronic genotype 1 HCV infection. Long-term development goals should also include interferon and/or ribavirin sparing approaches to mitigate the safety and tolerability issues inherent in interferon-based therapies.
REFERENCES 1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345: 41–52. 2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5:558–567. 3. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999; 29:908–914. 4. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36:S35–S46. 5. Cox AL, Netski DM, Mosbruger T, et al. Prospective evaluation of communityacquired acute-phase hepatitis C virus infection. Clin Infect Dis 2005; 40: 951–958. 6. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006; 130: 231–264. 7. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5:215–229. 8. Ahmad A, Alvarez F. Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis. J Leukocyte Biol 2004; 76:743–759. 9. Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transplantation 2006; 12:363–362. 10. Boyton RJ, Altmann DM. Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. Clin Exp Immunol 2007; 149:1–8. 11. Rosen HR. Hepatitis C pathogenesis: mechanisms of viral clearance and liver injury. Liver Transplantation 2003; 9:S35–S43. 12. Kanto T, Hayashi N. Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med 2006; 45:183–191. 13. Cooper S, Erickson E, Adams J, et al. Analysis of a successful immune response against hepatitis C virus. Immunity 1999; 10:439–449.
488
Duke et al.
14. Gerlac JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4+ T-cell response in acute hepatitis C. Gastroenterology 1999; 117:933–941. 15. Lechner F, Wong DK, Dunbar PR. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191:1499–1512. 16. Thimme R, Oldach D, Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406. 17. Shoukry NH, Cawthon AG, Walker CM. Cell-mediated immunity and the outcome of hepatitis C virus Infection. Annual Rev Microbiol 2004; 58:391–424. 18. Day CL, Lauer GM, Robbins GK, et al. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol 2002; 76:12584–12595. 19. Grakoui A, Shoukry NH, Woollard DJ, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003; 302:659–662. 20. Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003; 197: 1645–1655. 21. Underhill DM. Toll-like receptors: networking for success. Eur J Immunol 2003; 33:1767–1775. 22. Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 2000; 97:13766–13771. 23. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2:675–680. 24. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298–300. 25. Kawai T, Akira S. TLR signaling. Cell Death Differ 2006; 13:816–825. 26. Yewdell JW, Norbury CC, Bennink JR. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv Immunol 1999; 73:1–77. 27. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296: 301–305. 28. Cabrera R, Tu Z, Xu Y, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004; 40: 1062–1071. 29. Boettler T, Spangenberg HC, Neumann-Haefelin C, et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 2005; 79: 7860–7867. 30. Rushbrook SM, Ward SM, Unitt E, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79:7852–7859. 31. Chang KM. Regulatory T cells in hepatitis C virus infection. Hepatol Res 2007; 37:S327–S330. 32. Manigold T, Shin EC, Mizukoshi E, et al. Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 2006; 107:4424–4432.
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C
489
33. Billerbeck E, Bottler T, Thimme R. Regulatory T cells in viral hepatitis. World J Gastroenterol 2007; 13:4858–4864. 34. Dolganiuc A, Szabo G. T cells with regulatory activity in hepatitis C virus infection: what we know and what we don’t. J Leukocyte Biol 2008. Sep; 84(3):614–22. 35. Tang Q, Boden EK, Henriksen KJ, et al. Distinct roles of CTLA-4 and TGF-b in CD4+CD25+ regulatory T cell function. Eur J Immunol 2004; 34:2996–3005. 36. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16:311–323. 37. Radziewicz H, Ibegbu CC, Fernandez ML, et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007; 81: 2545–2553. 38. Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80:11398–11403. 39. Choo Q, Kuo G, Ralston R, et al. Vaccination of chimpanzees against infection by the hepatitis C virus. Proc Natl Acad Sci USA 1994; 91:1294–1298. 40. Nevens F, Roskams T, Van Vlierberghe H, et al. A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C. Hepatol 2003; 38:1289–1296 41. Capone S, Meola A, Ercole BB, et al. A novel adenovirus type 6 (Ad6)-based hepatitis C virus vector that overcomes preexisting anti-ad5 immunity and induces potent and broad cellular immune responses in rhesus macaques. J Virol 2006; 80:1688–1699. 42. Fattori E, Zampaglione I, Arcuri M, et al. Efficient immunization of rhesus macaques with an HCV candidate vaccine by heterologous priming-boosting with novel adenoviral vectors based on different serotypes. Gene Ther 2006; 13: 1088–1096. 43. Capone S, Zampaglione I, Vitelli A, et al. Modulation of the immune response induced by gene electrotransfer of a hepatitis C virus DNA vaccine in nonhuman primates. J Immunol 2006; 177:7462–7471. 44. Zabaleta A, Llopiz A, Arribillaga L, et al. Vaccination against hepatitis C virus with dendritic cells transduced with an adenovirus encoding NS3 protein. Mol Ther 2008; 16:210–217. 45. Tian Y, Zhang HH, Wei L, et al. The functional evaluation of dendritic cell vaccines based on different hepatitis C virus nonstructural genes. Viral Immunol 2007; 20:553–561. 46. Martin P, Simon B, Lone YC, et al. A vector-based minigene vaccine approach results in strong induction of T-cell responses specific of hepatitis C virus. Vaccine 2008; 26:2471–2481. 47. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197:1107–1117. 48. Underhill DM, Gantner B. Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect 2004; 6:1368–1373. 49. Horsmans Y, Berg T, Desager JP, et al. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 2005; 42:724–731.
490
Duke et al.
50. Lee J, Wu CC, Lee KJ, et al. Activation of anti-hepatitis C virus responses via Toll-like receptor 7. Proc Natl Acad Sci USA 2006; 103:1828–1833. 51. Pockros PJ, Guyader D, Patton H, et al. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J Hepatol 2007; 47:174–182. 52. Thomas A, Laxton C, Rodman J, et al. Investigating Toll-like receptor agonists for potential to treat hepatitis C virus infection. Antimicrob Agents Chemother 2007; 51:2969–2967. 53. McHutchison JG, Bacon BR, Gordon SC, et al. Phase 1B, randomized, doubleblind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus. Hepatology 2007; 46:1341–1349. 54. Cooper CL, Ahluiwalia NK, Efler SM, et al. Immunostimulatory effects of three classes of CpG oligodeoxynucleotides on PBMC from HCV chronic carriers. J Immune Based Ther Vaccines 2008; 6:in press. 55. Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001; 294:870–875. 56. Ikeda Y, Adachi Y, Ishibashi K, Miura N, Ohno N. Activation of toll-like receptormediated NF-kappa beta by zymosan-derived water-soluble fraction: possible contribution of endotoxin-like substances. Immunopharmacol Immunotoxicol 2005; 27:285–298. 57. Tada H, Nemoto E, Shimauchi H, et al. Saccharomyces cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD14- and Toll-like receptor 4-dependent manner. Microbiol Immunol 2002; 46:503–512. 58. Stubbs AC, Martin KS, Coeshott C, et al. Whole recombinant yeast vaccine activates dendritic cells and elicits protective cell-mediated immunity. Nature Med 2001; 7:625–629. 59. Lu Y, Bellgrau D, Dwyer-Nield LD, et al. Mutation-selective tumor remission with Ras-targeted, whole yeast-based immunotherapy. Cancer Res 2004; 64: 5084–5088. 60. Franzsusoff A, Duke RC, King TH, Lu Y, Rodell TC. Yeasts encoding tumor antigens in cancer immunotherapy. Expert Opin Biol Ther 2005; 5:565–575. 61. Haller AA, Lauer GM, King TH, et al. Whole recombinant yeast-based immunotherapy induces potent T cell responses targeting HCV NS3 and Core proteins. Vaccine 2007; 25:1452–1463. 62. Bernstein MB, Chakraborty M, Wansley EK, et al. Recombinant Saccharomyces cerevisiae (yeast-CEA) as a potent activator of murine dendritic cells. Vaccine 2008; 26:509–521. 63. Wansley EK, Chakraborty M, Hance KW, et al. Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clin Cancer Res 2008; 14:4316–4325. 64. Layden-Almer JE, Cotler SJ, Layden TJ. Viral kinetics in the treatment of chronic hepatitis C. J Viral Hep 2006; 13:499–504. 65. Herrmann E, Zeuzem S. The kinetics of hepatitis C virus. Eur J Gastroenterol Hepatol 2006; 18:339–342. 66. Caruntu A, Benea L. Acute hepatitis C virus infection: Diagnosis, pathogenesis, treatment. J Gastrointestin Liver Dis 2006; 15:249–256.
Index AAP, see American Academy of Pediatrics AASLD, see American Association for the Study of Liver Diseases Acetaminophen hepatotoxicity, NAC in, 298 ACIP, see Advisory Committee on Immunization Practices ACTG 5071 study, in chronic co-infected patients, 107 Activator protein-1, 23 Acupuncture, in viral heptatitis treatment, 298 See also Viral hepatitis Acute hepatitis C, treatment, 109 Acyclic phosphonates, in chronic HBV infection, 278–279 Adaptive immunity, defined, 475 See also Hepatitis C virus (HCV) Adefovir dipivoxil, 264, 278, 409, 415 in CHB treatment, 347 for chronic hepatitis B treatment, 250–251 in HBV infection, 265, 381 Adenosine monophosphate, 10 ADV, see Adefovir dipivoxil Advisory Committee on Immunization Practices, 361 Aflatoxin B1 (AFB1 ), 435 AFP, see Alpha-fetoprotein Africa, HBV infection patterns in, 187–189 African Americans population, HCV prevalence, 112–115 Alanine aminotransferase, 9, 297 histology in patients with normal level, 220–222 levels and disease progression, 219 ribavirin role in, 83 Albumin interferon, in HCV treatment, 167 Alcoholic liver disease, 298 ALD, see Alcoholic liver disease Alfa 2-a and b drug, in HBV infection, 264–265 Alpha-fetoprotein, 114, 406, 436 ALT, see Alanine aminotransferase Alternative medicine, complementary, 291 Alternative reading frame protein, 21 American Academy of Pediatrics, 418
491
American Association for the Study of Liver Diseases, 263, 379 AMP, see Adenosine monophosphate AMP-dependent protein kinase, 25 Anemia, in CHC treatment, 339–340 See also Chronic hepatitis C Anthracyclines, in HBV reactivation, 314 See also Hepatitis B reactivation Antibody to hepatitis B core antigen, 245 Antigen-presenting cells, 476 Anti-HBc, see Antibody to hepatitis B core antigen Anti-HBs, see Anti-hepatitis B surface antigen Anti-HCV immunity CD4+ T cells in, 473–474 CD8+ T cells in, 474 See also Hepatitis C virus (HCV) Anti-HCV nucleic acids, in chronic hepatitis C treatment, 172–173 Anti-hepatitis B core, 188 usage, 394–395 See also Liver transplantation (LT) Anti-hepatitis B surface antigen, 309 Antiphospholipid syndrome and hepatitis C, 145 Antiretroviral therapy, 100, 101 Anti-TNF, see Antitumor necrosis factor Antitumor necrosis factor, 310 Antiviral drugs, 76 modification of doses, 80–81 Anti-viral resistance in chronic hepatitis B, 274–275 clinical consequences of, 279–280 drug resistance in, 275–277 drugs used in, 277–279 management of, 280–283 prevention of, 284 detection, 276–277 drugs, nomenclature of, 275–277 See also Chronic hepatitis B Anti-viral therapy, for chronic hepatitis C treatment, 338–339 and side effects dermatologic, 345 endocrine, 344–345
492 general side effects, 345–346 hematologic, 339–342 ophthalmologic, 343 psychiatric, 342 pulmonary, 343–344 See also Chronic hepatitis C Antiviral therapy non-responders, management, 88–89 Antiviral treatment for chronic hepatitis C, monitoring, 78–79 goals of, 247 in hepatitis B reactivation, 321–324 See also Hepatitis B reactivation AP-1, see Activator protein-1 APC, see Antigen-presenting cells APRICOT trial, in chronic co-infected patients, 103, 105, 107 ARFP, see Alternative reading frame protein ART, see Antiretroviral therapy Arthralgia and chronic HCV association, 144 Aspartate aminotransaminase, 358 AST, see Aspartate aminotransaminase Astragalus membranaceous, 296 See also Herbal medicine 861, in viral hepatitis treatment Barcelona Clinic Liver Cancer, 438 BCLC, see Barcelona Clinic Liver Cancer Biochemical breakthrough, defined, 276 See also Chronic hepatitis B Blood and tissue donations, hepatitis B virus transmission by, 198–199 Blood transfusions, in HCV transmission, 41 See also Hepatitis C virus (HCV) BMT, see Bone marrow transplantation Boceprevir, in HCV treatment, 170 Body mass index (BMI), 117, 416 Bone marrow transplantation, 463 Breastfeeding and HBV, 361–362 in HCV transmission, 45 See also Hepatitis C virus (HCV); Viral hepatitis CAM, see Complementary alternative medicine CDC, see Centers for Disease Control CD4+ T cells, in anti-HCV immunity, 473–474 See also Hepatitis C virus (HCV) CD8+ T cells, in anti-HCV immunity, 474 See also Hepatitis C virus (HCV)
Index Centers for Disease Control, 35 Centers for Medicare and Medicaid Services, 46 CHB, see Chronic hepatitis B CHB treatment, adefovir dipivoxil in, 347 CHC, see Chronic hepatitis C CH-100 drug, in viral hepatitis treatment, 297 See also Viral hepatitis Chemotherapy, in hepatitis B reactivation, 310–311, 318–319 Children HBV in, 406–407 history of, 407–408 immunomodulatory therapy, 410–416 recommendations in, 416 screening and prevention of, 408–409 treatment of, 409–410 HCV in, 416–417 history of, 417–418 screening and prevention of, 418–419 treatment of, 419–425 immunomodulatory therapy in adefovir, 415 combination therapy of IFN and LAM, 414–415 interferons in, 410–413 LAM, 413–414 newer therapy, 416 oral antiviral agents, 413 China Chronic HBV infection in, 433, 434, 436 HBV infection patterns in, 193–194, 204, 217, 220 and HBV vaccination, 454 Chinese hamster ovary (CHO) cells, and mammalian cell-derived vaccine, 452 Chronic hepatitis B, 244–245, 291, 309 anti-viral resistance in, 274–275 clinical consequences of, 279–280 drug resistance in, 275–277 drugs used in, 277–279 management of, 280–283 prevention of, 284 approved drugs for treatment entecavir and telbivudine, 251–252 lamivudine and adefovir dipivoxil, 250–251 peginterferon alfa-2a, 249–250 tenofovir, 252 combination therapy for, 252–253 in HIV coinfected patients, natural history, 224–226 indication for treatment, 247–248
Index infection and HCC, 433 infection, phases of, 246 natural history of, 245–247 pegIFN monotherapy for, 111 roadmap concept, for on-treatment management, 253–254 treatment adefovir dipivoxil, 347 entecavir, 348 interferon alpha-2b/2a, 346–347 lamivudine, 347 telbivudine, 348 tenofovir, 348–349 See also Hepatitis B virus (HBV); Hepatocellular carcinoma Chronic hepatitis C epidemiology, 160–161 factors influencing progression, 59 global prevalence, 72 host cell, drugs for, 173–174 infection, immunotherapy, 485–486 and liver-related death host-related factors, 54–57 study design, 50–54 virus-related factors, 57–59 See also Hepatitis C virus (HCV) natural history of, 48–49 nonspecific immunomodulators in, 174 progression to cirrhosis, hepatocellular carcinoma, and death, 49–59 host-related factors responsible for, 54–57 prospective studies, with acute hepatitis patients, 51–52 retrospective analysis of patients, 50–51 retrospective–prospective studies for, 52–54 virus-related factors responsible for, 57–59 rationale treatment management decisions in treatment of, 77 recombinant interferon in treatment of, 72–74 specifically targeted antiviral therapies for HCV anti-HCV nucleic acids, 172–173 polymerase inhibitors, 171–172 protease inhibitors, 166–170 specific treatment for in African-Americans, 86 extrahepatic manifestations, 87–88 fibrosis and cirrhosis, bridging of, 85 HIV–HCV coinfection, 86
493 obesity and hepatic steatosis, 87 post-transplantation and viral non-responders, 88–89 steatosis in, 116–117 therapeutics agent in development, 89–90 therapies for, 163–164 interferons usage, 73 patient selection, drug administration, and therapy monitoring, 75–82 Ribavirin usage, 74 treatment regimens, optimization, 75 treatment response assessment, 83–84 therapy refinement alternatives to ribavirin, 165–166 novel interferon, 164–165 treatment and side effects, 338–339 dermatologic, 345 endocrine, 344–345 general side effects, 345–346 hematologic, 339–342 ophthalmologic, 343 psychiatric, 342 pulmonary, 343–344 vaccination for, 174–175 valopicitabine in treatment, 170 See also Hepatitis C virus (HCV) Chronic kidney diseases (CKD), HCV in, 118–120 Chronic viral hepatitis, herbal supplements in, 299 CIFN, see Consensus interferon Cirrhosis and chronic HBV infections, 216–217 and HCC development, 443 host-related factors, 54–57 study design, 50–54 virus-related factors, 57–59 See also Hepatitis C virus (HCV); Hepatocellular carcinoma Clevudine, 277 CMS, see Centers for Medicare and Medicaid Services Complementary alternative medicine, 291 Consensus interferon, 164–165 Core protein, in hepatocarcinogenesis, 26 Corticosteroids, in HBV reactivation, 314 See also Hepatitis B reactivation Covalently closed circular (ccc) DNA, 5–6 Cryoglobulinemia treatment, 139 Cryoglobulins, in HCV patients, 138–139, 146 See also Extrahepatic manifestations
494 CTL, see Cytotoxic T lymphocyte CT scan, for HCC diagnosis, 437 Cytotoxic T lymphocyte, 12, 473 DC-SIGN, see Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin DDLT, see Deceased donor liver transplantation DEBIO-025 (Debiopharm) inhibitor, 173 Deceased donor liver transplantation, 440 Delta hepatitis, 364–365 See also Hepatitis D virus (HDV) Dendritic cell, of exogenous antigens, 476–477 Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, 19 Department of Health and Human Services, 263 Dermatological manifestations and HCV, 142–143 See also Extrahepatic manifestations DHHS, see Department of Health and Human Services Diabetes development, in CHC treatment, 344–345 See also Chronic hepatitis C Diabetes prevalence, in HCV, 115–118 See also Chronic hepatitis C DNA vaccinations, usage, 175 Double-stranded linear DNA, 8 dslDNA, see Double-stranded linear DNA EACS, see European AIDS Clinical Society Early virologic response (EVR), 71, 83, 117 EHM, see Extrahepatic manifestations Emtricitabine drug, 264, 277, 382 Endocrine manifestations and HCV, 143–144 See also Extrahepatic manifestations End of treatment response (ETR), 422 End-stage liver disease, 53, 100 R Engerix-B vaccine, in HBV treatment, 460, 463 Entecavir, 265, 279 in CHB treatment, 348 for chronic hepatitis B treatment, 251 in HBV infection, 265–266 in HBV polymerase inhibition, 381 in HBV treatment, 416 See also Chronic hepatitis B Epoetin alfa, in ribavirin-induced anemia management, 340
Index See also Chronic hepatitis C Epsilon, role, 8 ESLD, see End-stage liver disease European AIDS Clinical Society, 264 Europe, HBV infection prevalence in, 196 EVR, see Early virological response Extrahepatic manifestations (EHM), of chronic HCV infection, 136–138 cardiac, 148 clinical signs and symptoms prevalence, 138 dermatological manifestations, 141–143 endocrine, 143–144 evaluation by MULTIVIRC group, 141 HCV-related MPGN and treatment, 140–141 lymphoproliferative disorders, 139–140 mechanism for CNS manifestations, role of cytokines, 147 neurological manifestations, 146–147 pulmonary manifestations, 147 renal manifestations, 140–141 rheumatoid factor, 144–146 vascular manifestations, 138–139 Famciclovir-associated polymerase gene mutations, 15 FCH, see Fibrosing cholestatic hepatitis FHF, see Fulminant hepatic failure Fibrosing cholestatic hepatitis, 378 First line therapy, for lichen planus, 143 Food and Drug Administration (FDA), 348 Fulminant hepatic failure, 359 Gambian Hepatitis Intervention Study, role of, 204 GAVI, see Global Alliance on Vaccines and Immunization G-CSF, see Granulocyte colony-stimulating factor Genotypic resistance, definition of, 276 See also Chronic hepatitis B ␥-glutamyl transpeptidase, 293 GGTP, see ␥-glutamyl transpeptidase Global Advisory Group of Expanded program on Immunization, for hepatitis B vaccine, 202 Global Alliance on Vaccines and Immunization, 202–203 Glomerulonephritis (GN) and chronic hepatitis C, 87–88 Glycocorticoid response (GRE), 7
Index Glycyrrhiza glabra, 294 Glycyrrhizin, in viral hepatitis treatment, 294 See also Viral hepatitis GM-CSF, see Granulocyte/macrophage colony stimulating factor Granulocyte colony-stimulating factor, 341 Granulocyte/macrophage colony stimulating factor, 480 GRE, see Glycocorticoid response HAART, see Highly active anti-retroviral therapy Hashimoto’s thyroiditis or Graves’ disease, 143 HBc, see Anti-hepatitis B core HBcAb, see Hepatitis B core antibody HBeAb, see Hepatitis Be antibody HBeAg, see Hepatitis Be antigen HBeAg/anti-HBe marker, usage, 201 HBeAg-negative CHB patients, treatment of, 248 HBIG, see Hepatitis B immune globulin; Hepatitis B immunoglobulin HBsAg, see Hepatitis B surface antigen HBsAg epitopes, role, 2 HBV, see Hepatitis B virus HBV cccDNA genome, role, 6–7 HBV RNA, transcription, 7–8 HBV X protein (HBxAg), 7 HBx protein, 218 HCC, see Hepatocellular carcinoma HCIG, see Hepatitis C immunoglobulin HCT, see Hematopoietic cell transplantation HCV, see Hepatitis C virus HCV-associated arthritis, treatment, 144 HCV gene, structure, 21–22 HCV/HIV co-infected patients See also Hepatitis C virus HCV replicon systems, development, 162 HCV RNA measurement, importance, 83 HCV RNA transfection, in human hepatoma cell line, 162 Health care injections, in HCV transmission, 47–48 See also Hepatitis C virus (HCV) Health-care workers and hepatitis B virus transmission, 200–202 Health-care workers (HCW), 458 Heat-shock protein, 8 HELLP, see Hemolysis, elevated liver enzymes, and low platelets Helper T cells (Th), 476 Hematopoietic cell transplantation, 314
495 Hemodialysis, in HCV transmission, 45–46 See also Hepatitis C virus (HCV) Hemolysis, elevated liver enzymes, and low platelets, 354 HENCORE, see Hepatitis C European Network for Cooperative Research Hepadnavirus family, 2 Hepatic steatosis and chronic hepatitis C, treatment for, 87 Hepatic venous pressure gradient, 393 Hepatitis A virus (HAV), 354, 356–358 See also Viral hepatitis Hepatitis B core antibody, 110, 362 Hepatitis Be antibody, 346 Hepatitis B e antigen, 295 Hepatitis B immune globulin, 361, 457 Hepatitis B immunoglobulin, 382–386 Hepatitis B reactivation, 309 addendum in, 325–326 antiviral therapy in, 321–324 awareness, 325 clinical presentation, 316–318 history, 309–310 immunization, 319 management, 319–321 pathophysiology, 316 patients screening, 318–319 preemptive therapy, cost-effectiveness, 324–325 prevalence, 310–311 risk factors, 311–315 Hepatitis B surface antigen, 296 influence on host immune response, 11 prevalence in Africa, 187–189 in China, 193–194 global patterns of, 186–187 in Latin America, 191–192 in Middle East and Europe, 196 in Taiwan and India, 194–196 in United States, 189–191 in Western Pacific and Southeast Asia regions, 192–193 See also Hepatitis B virus (HBV) Hepatitis B vaccination impact, primary indicators, 203 Hepatitis B virus, 2–3, 451–452 cccDNA, 5–6 cellular entry, 4–5 in children, 406–407 history of, 407–408 immunomodulatory therapy, 410–416 recommendations, 416
496 screening and prevention, 408–409 treatment, 409–410 epidemiology in Africa, 187–189 in China, 193–194 effect of vaccination, 202–205 global patterns, 186–187 of HBV HCV coinfection, 205–206 in Latin America, 191–192 in Middle East and Europe, 196 molecular epidemiology, 207–210 occult HBV and HBV HIV coinfection, 206–207 in Taiwan and India, 194–196 transmission patterns, 197–202 in United States of America, 189–191 in Western Pacific and Southeast Asia, 192–193 genome replication, mutation frequency, 2 genotypes and geographic prevalence, 208–210 HBV/HCV co-infected patients, epidemiology, 205–206 and hepatitis C virus, co-infection, 110–112 high-risk populations screening, 210–212 HIV co-infection and epidemiology of, 260–261 history in, 261–263 management of, 263–269 immune-escape mutants, 13–15 immune response, and role, 452–453 immune system evasion, 12–13 infection adefovir, 265 alfa 2-a and alfa 2-b drug, 264–265 and chronic HCV, 56 entecavir, 265–266 HAART therapy, 268 and HIV disease, 261 lamivudine, 265 tenofovir, 266 transmission, 453 integration, 8–9 liver transplantation, 377 antiviral therapy, 379–386 post-LT recurrence, 377–379 mechanism for pdsDNA convertion to cccDNA, 5–6 natural history chronic Hepatitis B in HIV coinfected patients, 224–226 HBV and HCV coinfected patients, 222–224
Index horizontal transmission, phases, 216 occult HBV infection, 226–228 predictors of disease progression, 216–222 vertical transmission, phases, 212–216 occurence, 292 and pdsDNA synthesis, 11 polymerase mutants, 15–16 in pregnancy, 360–364 See also Viral hepatitis structure and genomic organization, 451–452 and replication cycle, 3–4 transcription, 6–7 translation, encapsidation and reverse transcription, 7–8 treatment, silymarin in, 293 See also Viral hepatitis vaccination BMT and peripheral stem-cell transplantation, 463 contraindications, 463 future, 463–464 history, 454–456 immunization against, 457 immunogenicity and efficacy, 456 interchangeability, 457–458 mode of administration, 457 non-responders to conventional, 461–463 rationale for immunization, 460–461 safety and tolerability, 460 worldwide impact and immunization strategies, 458–459 vaccine and HCC, 442–443 viral mutation and, 12–13 virion production, 11 X protein and hepatocarcinogenesis, 9–11 See also Hepatitis C virus (HCV) Hepatitis B virus (HBV) HIV co-infection and lamivudine therapy, 265 HIV influence, 261–262 occult infection epidemiology, 206–207 natural history, 226–228 Hepatitis C in chronic kidney diseases (CKD), 118–120 epidemiology genotypes and subtypes, 37–38 global prevalence, and in U.S., 34–36 anti-HCV prevalence, 36–37 insulin resistance and diabetes in HCV, 115–118
Index in Latinos and African Americans, 112–115 in population, co-infected with Hepatitis B, 110–112 in population, co-infected with HIV, 97–110 natural history, 100–102 prevalence and epidemiology, 99–100 treatment, 102–110 in special population, 97 Hepatitis C European Network for Cooperative Research, 40–41 Hepatitis C immunoglobulin, 392 Hepatitis C virus (HCV), 1, 16–17, 118–120, 291, 472–473 CDC recommendations for screening, 40 in children, 415–417 history, 417–418 screening and prevention, 418–419 treatment, 419–425 in chronic kidney diseases, 118–120 and extrahepatic manifestations, 136–138 cardiac, 148 dermatological manifestations, 141–143 endocrine, 143–144 lymphoproliferative disorders, 139–140 neurological manifestations, 146–147 pulmonary manifestations, 147 renal manifestations, 140–141 rheumatoid factor, 144–146 vascular manifestations, 138–139 and hepatitis B, co-infection of, 110–112 and hepatocarcinogenesis core protein role, 25–26 and HIV co-infection patients natural history, 100–102 prevalence and epidemiology, 99–100 treatment, 102–110 immune system evasion, 23–24 immunotherapeutic vaccines, 481–485 immunotherapy, evaluation, 485–486 infection, T-cell-mediated immune responses, 473–474 insulin resistance and diabetes prevalence, 115–118 intracellular antiviral response inhibition, 24–25 intrafamilial transmission of hepatitis C, 42–44 intranasal drug usage, in HCV transmission, 46–47 Latinos and African Americans, variations, 112–115 life cycle and structure, 161–163 liver transplantation, 386–387
497 antiviral therapy, 390–394 post-LT recurrence, 387–390 natural history chronic Hepatitis C, 48–49 cirrhosis, hepatocellular cancer, and liver-related death, 49–59 occurence, 292 in pregnancy, 365–367 See also Viral hepatitis prevalence, 72 proteins and processing, 21–23, 25–26 replication cycle and experimental systems, 17–19 risk factors in transmission, 38–40 blood products, 41 breastfeeding and hemodialysis, 45–46 high-risk sexual activity, 41–42 intrafamilial and monogamous sexual transmission, 42–44 intranasal drug use, 46–47 intravenous drug use, 40–41 mother to infant transmission, 44–45 tattooing and health care setting, 47–48 RNA replication, 26–28 secretion, 28–29 T-cell-mediated immunity, 474–475 cells of, 475–478 endogenous antigens, cellular immunity in response to, 478–479 exogenous antigens, humoral immunity in response to, 478 regulatory T cells, 480–481 Th1 vs. Th2 cells, 479–480 translation, 20–21 treatment, silymarin in, 293 See also Viral hepatitis vaccination, 174–175 viral entry, 19–20 virion assembly, 28–29 Hepatitis D virus (HDV), 354, 364–365 See also Viral hepatitis Hepatitis E virus (HEV), 354, 358–360 See also Viral hepatitis Hepatocellular cancer and chronic HCV infections host-related factors, 54–57 study design, 50–54 virus-related factors, 57–59 See also Hepatitis C virus (HCV) Hepatocellular carcinoma, 9, 72, 119, 274, 376
498 and chronic HBV infection, 217–218 diagnostic evaluation, 435–438 epidemiology, 432–435 prevention, 442–443 treatment, 438–442 See also Hepatitis B virus (HBV); Hepatitis C virus (HCV) HepimmuneTM , in HBV treatment, 463 Hep-Net B/C Co-infection Study Group, trials, 111–112 Herbal/CAM, in HCV and HBV efficacy, 300 See also Viral hepatitis Herbal medicine 861, in viral hepatitis treatment, 296–297 See also Viral hepatitis Heterosexual transmission, of HCV, 99 Highly active anti-retroviral therapy, 86, 261, 395 in HBV/HIV-co-infection, 262–263 in HBV infection, 268 serum ALT levels in, 262–263 See also Hepatitis B virus HIV-1, see Human immunodeficiency virus 1 HIV co-infection and HBV epidemiology, 260–261 history, 261–263 management, 263–269 HIV/HBV co-infected population epidemiology, 99 natural history of, 100–102 treatment of co-infection, 102–110 contraindications to combined HCV therapy, 104 differences, HCV treatment in mono/co-infection, 108 factors associated with SVR in, 103 HIV-HCV coinfected patients, education for, 86 HIV infection and HBV disease, 261–262 See also Hepatitis B virus (HBV) HIV infection, HBV influence, 261 See also Hepatitis B virus (HBV) HOMA, see Homeostatic Model Assessment HOMA-IR scores, application, 117 Homeostatic Model Assessment, 116 Host risk factors, for HBV reactivation, 312–314 See also Hepatitis B reactivation Hsp, see Heat-shock protein Human hepatoma cell line (HepaRg), 3 Human immunodeficiency virus 1, 260 HVPG, see Hepatic venous pressure gradient HVR1, see Hypervariable region-1
Index Hypertrophic and dilated cardiomyopathy, chronic HCV prevalence, 148 Hypervariable region-1, 24 ICER, see Incremental cost-effectiveness ratio Idiopathic pulmonary fibrosis, 147 Idiopathic thrombocytopenia, 146 Immune system evasion and viral mutation, HBV in, 12–13 Immunization, in hepatitis B, 319 See also Hepatitis B reactivation Immunomodulatory therapy, for viral hepatitis in children adefovir, 413 combination therapy of IFN and LAM, 414–415 interferons in, 410–413 LAM, 413–414 newer therapy, 416 oral antiviral agents, 413 Immunosuppressants, role in hepatitis B reactivation, 314–315 See also Hepatitis B reactivation Immunosuppression, in hepatitis B reactivation, 318–319 See also Hepatitis B reactivation Immunotherapeutic vaccines, in HCV treatment, 481–485 See also Hepatitis C virus (HCV) Immunotolerance of HBV antigens, role, 12 Incremental cost-effectiveness ratio, 325 India, HBV infection patterns, 194–196 Innate immunity, definition, 475 See also Hepatitis C virus (HCV) Insulin resistance (IR) prevalence, in HCV, 115–118 See also Chronic hepatitis C Interferon alpha-2b/2a, in CHB treatment, 346–347 See also Chronic hepatitis B Interferon-associated hypothyroidism, treatment, 143–144 Interferon (IFN), 409 in chronic HBV treatment, 410–413 in hepatitis B control, 319 induced retinopathy, in CHC treatment, 343 monotherapy in HCV-associated arthritis treatment, 144 in HCV infected children, 420–421 in HCV infection treatment, 164–165 in skin lesions treatment, 142 for thyroid diseases, 143–144
Index therapy, chronic HCV infection, 485 See also Hepatitis B reactivation Internal ribosome entry site (IRES), 17, 20 Intravenous drug use, 99, 407 IPF, see Idiopathic pulmonary fibrosis IRES, see Internal ribosome entry site ITP, see Idiopathic thrombocytopenia IVDU, see Intravenous drug use LADR, see Low accelerated dose regimen Lamivudine (LAM), 264, 277, 279, 409 in CHB treatment, 347, 380 for chronic hepatitis B treatment, 250 in HBV infection, 265 in hepatitis B reactivation, 322–323 therapy, for hepatitis B reactivation prevention, 319–324 See also Chronic hepatitis B Large HBs protein (LHBs), 452 Latin America, HBV infection patterns, 191–192 Latino population, HCV prevalence, 112–115 LDLT, see Living donor liver transplantation Leukocytoclastic vasculitis, 142 Lichen planus and association of chronic HCV, 143 first line therapy for, 143 Lifecycle, HBV, 3–4 Liv 52 drug, in viral hepatitis treatment, 297 See also Viral hepatitis Liver fibrosis and HIV infection, progression, 100–101 Liver function, effect of pregnancy on, 355 Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin, 19 Liver-related death and chronic HCV infections host-related factors, 54–57 study design, 50–54 virus-related factors, 57–59 See also Hepatitis C virus (HCV) Liver transplantation (LT), 376 in early stage HCC, 440–441 for end-stage liver disease, 269 in HBV, 377 antiviral therapy in, 379–386 post-LT recurrence in, 377–379 in HCV, 386–387 antiviral therapy in, 390–394 post-LT recurrence in, 387–390 in HIV coinfected individuals, 395 management of hepatitis B in, 382–386
499 virologically compromised organs in, 394–395 See also Hepatitis B virus (HBV) Living donor liver transplantation, 440 L-nucleoside, in chronic HBV infection, 277–278 Low accelerated dose regimen, 391 L-SIGN, see Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin Lymphoproliferative disorders and chronic HCV, 139–140 Major histocompatibility, 476 MALT, see Mucosa-associated lymphoid tissue Maternal–fetal transmission, of hepatitis B virus, 197–198 MELD, see Model for end-stage liver disease Membranoproliferative glomerulonephritis, 140 Men who have sex with men, 99 Metabolic syndrome, definition, 56–57 MHBs, see Middle-sized protein MHC, see Major histocompatibility Middle East, HBV infection prevalence, 196 Middle-sized protein, 452 Mixed cryoglobulinemia, in chronic hepatitis C, 87 MMF, see Mycophenolate mofetil Model for end-stage liver disease, 376 Monogamous sexual transmission, of hepatitis C, 42–44 See also Hepatitis C virus (HCV) Mother to infant transmission, of HCV, 44–45 See also Hepatitis C virus (HCV) MPGN, see Membranoproliferative glomerulonephritis MRI, in HCC diagnosis, 437 See also Hepatocellular carcinoma MSM, see Men who have sex with men Mucosa-associated lymphoid tissue, 140 Multiple sclerosis (MS), 460 MULTIVIRC group, 141–142 Mutation frequency, in HBV genome replication, 2 Myalgia and chronic HCV association, 144 Mycophenolate mofetil, 389 NAC, see N-Acetyl cysteine N-Acetyl cysteine, 298 NAFLD, see Nonalcoholic fatty liver disease National Center for Health Statistics, 35
500 National Electronic Telecommunications System for Surveillance, 37 National Health and Nutrition Examination Survey (NHANES III), 113 National Institute of Diabetes, Digestive and Kidney Diseases, 47 National Institutes of Digestive and Kidney Diseases, 44 National Institutes of Health, 51 National Management of Chronic HBV: 2006 workshop, 275 NCR, see 5 -Noncoding region NETSS, see National Electronic Telecommunications System for Surveillance Neurological manifestations and HCV, 146–147 See also Extrahepatic manifestations (EHM), of chronic HCV infection Neutropenia, in CHC treatment, 341–342 See also Chronic hepatitis C NHANES, see National Center for Health Statistics NHL, see Non-Hodgkin lymphoma NIDDK, see National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Digestive and Kidney Diseases NIH, see National Institutes of Health Nitazoxanide (NTZ), in HCV treatment, 173 Nonalcoholic fatty liver disease, 56 5 -Noncoding region, 17 Non-Hispanic population, HCV prevalence in, 113 Non-Hodgkin lymphoma, 139 NRTIs, see Nucleoside reverse transcriptase inhibitors NS5A and NS5B proteins, role of, 23 NS4B protein, role, 23 Nucleoside reverse transcriptase inhibitors, 109 Obesity and chronic hepatitis C, treatment for, 87 Occult HBV, definition of, 315 Occult hepatitis B virus definition of, 315 infection epidemiology of, 206–207 natural history of, 226–228 See also Hepatitis B reactivation Open-reading frames, 6 precore/core translation, 7
Index ORFs, see Open-reading frames Osteosclerosis and hepatitis C, 145 12-O-tetradecanoylphorbol-13-acetate, 10 Palpable purpura, cause of, 138, 139 PAMPs, see Pathogen-associated molecular patterns Partially double-stranded (pdsDNA), viral, 3–5, 8, 9, 11 Pathogen-associated molecular patterns, 476 Pattern recognition receptors, 476 PBMCs, see Peripheral blood mononuclear cells pdsDNA, see Partially double-stranded (pdsDNA), viral pdsDNA genome of HBV, cellular entry of, 4–5 PEG-IFN, see Pegylated interferon; Pegylated interferon-␣ 2␣ PegIFN and RBV, for HCV mono-infection and chronic HBV, 111 pegIFN monotherapy, for chronic HBV, 111 Peginterferon alfa-2a, for chronic hepatitis B treatment, 249–250 Pegylated interferon, 75, 390 in co-infected patients treatment, 105 in HCV treatment, 72–74, 82 monotherapy, in HCV infected children, 422–423 and RBV, for HCV mono-infection, 111 See also Hepatitis B virus (HBV); Hepatitis C virus (HCV) Pegylated interferon-␣ 2␣, 416 PEI, see Percutaneous ethanol injection Percutaneous ethanol injection, 441 Peripheral blood mononuclear cells, 19 Peripheral neuropathy and chronic HCV, 146 Peripheral stem-cell transplantation, in HBV treatment, 463 See also Hepatitis B virus (HBV) Person-to-person horizontal transmission, of HBV, 197 pgRNA, see Pregenomic RNA Phenotypic resistance, definition of, 276 See also Chronic hepatitis B PHH, see Primary human hepatocytes Phyllanthus amarus drug, in viral hepatitis treatment, 294–295 See also Viral hepatitis PKA, see AMP-dependent protein kinase PKR, see Protein kinase Plantago asiatic, in viral hepatitis treatment, 296
Index See also Viral hepatitis Polyarteritis nodosa (PAN), and HCV association, 145 Polymerase gene, translation, 5 Polymerase inhibitors, in chronic hepatitis C treatment, 170–172 Porphyria cutanea tarda (PCT) and association with chronic HCV, 142–143 Post-LT hepatitis B infection, definition of, 386 See also Hepatitis B virus (HBV) Preemptive therapy, in hepatitis B reactivation, 324–325 See also Hepatitis B reactivation Pregenomic RNA, 3, 8 Pregnancy, viral hepatitis during, 355–356 hepatitis A, 356–358 hepatitis B, 360–364 hepatitis C, 365–367 hepatitis D, 364–365 hepatitis E, 358–360 PRESCO trial, in chronic co-infected patients, 108 Primary human hepatocytes, 3 Primary non-response, in chronic hepatitis B, 275–276 See also Chronic hepatitis B Protease inhibitors, in chronic hepatitis C treatment, 166–170 Protein kinase, 24 PRRs, see Pattern recognition receptors Pruritus, and chronic HCV association, 141–142 Quantitative Insulin Sensitivity Check Index (QUICKI), 116 Radio frequency ablation, 439 Rapid viral response, 75, 83 Rationale treatment management decisions, in HCV treatment, 77 Reactive oxygen species (ROS), 297 Recombinant interferon, in chronic HCV treatment, 72–74 R Recombivax-HB vaccine, in HBV treatment, 460 Recurrent hepatitis B factors affecting, 378–379 mechanism, 377 patterns, 378 See also Hepatitis B virus (HBV) Recurrent hepatitis C
501 history, 387 patterns, 387–388 See also Hepatitis C virus (HCV) Regulatory T cells, in HCV infection, 480–481 See also T-cell-mediated immunity, in HCV infection Relaxed circular DNA genomes, conversion, 5 Renal manifestations, and HCV association, 140–141 See also Extrahepatic manifestations Renal replacement therapy and hepatitis B virus transmission, 199–200 Replication cycle HCB, life cycle in, 3–4 HCV, life cycle in, 17–19, 166, 172 Rescue therapy, in HBeAG patients, 283 See also Chronic hepatitis B Reverse transcriptase polymerase chain reaction (RT-PCR), 365 RFA, see Radio frequency ablation Rheumatoid factor, in chronic HCV, 144–146 See also Extrahepatic manifestations RIBAVIC trial, in chronic co-infected patients, 107 Ribavirin (RBV), 339–340, 390 in aminotransferase, 83 combination therapy and PEG-IFN, in HCV infected children, 423–424 in HCV infected children, 421–422 See also Children in HCV treatment, 72–74, 82, 165–166 and PegIFN, for HCV mono-infection, 111 use in HCV, 141 Rituximab, in cryoglobulinemia treatment, 139 Roadmap approach, for on-treatment management of CHB, 253–254 RVR, see Rapid viral response Saccharomyces cerevisiae, 484 S-Adenosylmethionine, 298 Safe Injection Global Network, 48 Salvia miltiorrhiza, 296 See also Herbal medicine 861 SAM, see S-Adenosylmethionine Scavenger receptor class B type I, 19 SEER, see Surveillance, Epidemiology and End-Result Serum biomarkers, 102 Sexual activity, in HCV transmission, 41–42 See also Hepatitis C virus (HCV) Sexually transmitted disease (STD), 458
502 Sho-saiko-to drug, in viral hepatitis treatment, 295–296 See also Viral hepatitis Sicca syndrome and HCV association, 144–145 SIGN, see Safe Injection Global Network Silymarin, 291–293 See also Viral hepatitis siRNA, see Small interfering RNA molecules SLE, see Systemic lupus erythematosus Small HBs (SHBs), 452 Small interfering RNA molecules, 172 SMR, see Standardized mortality ratio SNMC, see Stronger Neo-Minophagen C Sorafenib, in HCC, 442 Spatholobus suberectus, 296 See also Herbal medicine 861 Specifically targeted antiviral therapies for HCV, 89, 161, 176 anti-HCV nucleic acids, 172 polymerase inhibitors, 170–172 protease inhibitors, 166–170 SPLIT, see Study of Pediatric Liver Transplantation SR-BI, see Scavenger receptor class B type I Standardized mortality ratio, 111 STAT-C, see Specifically targeted antiviral therapies for HCV Steatosis, in chronic HCV, 116–117 Steroids, role in hepatitis B reactivation, 314–315 See also Hepatitis B reactivation St. John’s wort, in viral hepatitis treatment, 296 See also Viral hepatitis Stronger Neo-Minophagen C, 294 Study of Pediatric Liver Transplantation, 418 Surveillance, Epidemiology and End-Result, 432 Sustained virological response, 83, 102, 139, 163, 390–391, 420, 422 SVR, see Sustained virological response Symmetrical non-deforming polyarthritis, and HCV association, 144 Symptomatic cryoglobulinemia, symptoms of, 138–139 Systemic lupus erythematosus, 145 TACE, see Transarterial chemoembolization Taiwan, HBV infection patterns in, 194 TarmogensTM vaccine, in HCV treatment, 484 Tattooing, role in HCV transmission, 47–48 See also Hepatitis C virus (HCV)
Index T-cell-mediated immunity, in HCV infection, 474–475 cells of, 475–478 endogenous antigens, cellular immunity in response to, 478–479 exogenous antigens, humoral immunity in response to, 478 regulatory T cells, 480–481 Th1 vs. Th2 cells, 479–480 See also Hepatitis C virus (HCV) TDF, see Tenofovir Telaprevir, in HCV treatment, 166–167 Telbivudine, 264, 277, 363 in CHB treatment, 251–252 in HBV treatment, 381–382 See also Chronic hepatitis B Tenofovir, 264, 278, 363 in CHB treatment, 348–349 for chronic hepatitis B, 252 in co-infected patients treatment, 109 in HBV infection, 266, 382 Thrombocytopenia, in CHC treatment, 340–341 See also Chronic hepatitis C Thyroid diseases, and association with HCV, 143–144 See also Hepatitis C virus (HCV) Thyroid dysfunction development, in CHC treatment, 344 See also Chronic hepatitis C TJ-9 drug, in viral hepatitis treatment, 295–296 See also Viral hepatitis Toll-like receptors (TLRs), 174, 476 TPA, see 12-O-tetradecanoylphorbol-13-acetate Transarterial chemoembolization, 441 Transcription factors (TFs), 7 Transient elastography, role of, 102 Tumor necrosis factor (TNF), 476 Tupaia belangeri (tree shrews), 3 United Network for Organ Sharing, 376 United States of America, HBV infection patterns in, 189–191 UNOS, see United Network for Organ Sharing Unsafe medical practices and hepatitis B virus transmission, 200 5 -Untranslated region, 17 Upper limit of normal (ULN), 409 U.S. Centers for Disease Control and Prevention (CDC), 325 U.S. Preventive Services Task Force, 39
Index USPSTF, see U.S. Preventive Services Task Force UTR, see 5 -Untranslated region Vaccination effects, on chronic hepatitis B epidemiology, 202–205 Valopicitabine, in chronic hepatitis C treatment, 170 Vasculitis, 142 Vertical transmission, as risk factor for HBV infection, 44–45 See also Hepatitis C virus (HCV) VIRAHEP-C study, 115 Viral hepatitis, 289–290 antioxidants and dietary supplements in, 297–298 burden of, 292 economics of medicines in, 291 herbal medicine, 296–297 herbal therapies in, 292–297 in pregnancy, 355–356 hepatitis A, 356–358 hepatitis B, 360–364
503 hepatitis C, 365–367 hepatitis D, 364–365 hepatitis E, 358–360 treatment Liv 52 drug in, 297 Sho-saiko-to drug in, 295–296 Silymarin drug in, 292–293 Viral pgRNA transcript, 3–4 Virological breakthrough, in chronic hepatitis B, 276 See also Chronic hepatitis B Western Pacific and Southeast Asia, HBV infection patterns in, 192–193 World Health Organization (WHO), 31, 34, 362 World Health Report (2002), 200 Xiao-chai-hutang drug, in viral hepatitis treatment, 295–296 See also Viral hepatitis X protein, role, 9–11