Aids: Nursing Perspectives

Jerry D. Durham, Ph.D, R.N., F.A.A.N., is professor and dean of the Barnes College of Nursing at the University of Missouri at St. Louis. Dr. Durham has earned six university degrees, including three in nursing and a doctorate in higher education administration. In addition to his role as an educator, he has held positions as a staff nurse, clinical manager, private practitioner in mental health nursing, and consultant in education and research. He was among the first researchers to investigate the nature of private practice in psychiatric nursing. He has received two fellowships in ethics from the National Endowment for the Humanities. In addition to The Person with HIV/AIDS: Nursing Perspectives, Dr. Durham has coedited Women, Children and HIV/AIDS (1993), as well as The Nurse Psychotherapist in Private Practice (1987). Together, these three books received five American Journal of Nursing Book-of-the-Year Awards. Dr. Durham also served as coeditor of Tuberculosis: A Sourcebook for Nursing Practice, which was selected as a "Best Book of 1995" by Nurse Practitioner. He serves as a reviewer for several nursing journals and is a member of the editorial board of the Journal of Psychosocial Nursing. Dr. Durham chaired the Education Committee of the Association of Nurses in AIDS Care. Felissa R. Lashley, Ph.D, R.N., A.C.R.N., F.A.A.N. (formerly Felissa L. Cohen), is professor and dean of the School of Nursing, Southern Illinois University, Edwardsville. She is also clinical professor of pediatrics at the School of Medicine, Southern Illinois University, Springfield. Dr. Lashley previously served as professor and head of the Department of Medical-Surgical Nursing at the University of Illinois at Chicago (UIC) College of Nursing, clinical chief for Medical-Surgical Nursing at the University of Illinois at Chicago Medical Center, and associate professor, Department of Genetics, School of Medicine, UIC. Dr. Lashley received her doctorate in human genetics with a minor in biochemistry from Illinois State University. She is

certified as a Ph.D. medical geneticist by the American Board of Medical Genetics (the first nurse to be so certified) and is a founding fellow of the American College of Medical Genetics. Dr. Lashley began her practice of genetic evaluation and counseling in 1973. She has authored more than 200 publications including Clinical Genetics in Nursing Practice, which received a Book-of-the-Year Award from the American Journal of Nursing in its first edition, as have two of her other books. She was a coeditor of the Association of Nurses in AIDS Care's Core Curriculum for HIV/AIDS Nursing. Dr. Lashley is a distinguished lecturer for Sigma Theta Tau International and an associate editor of the journal IMAGE: The Journal of Nursing Scholarship, as well as a fellow of the American Academy of Nursing. She was the first nurse to serve on the AIDS Research Review Committee, National Institute of Allergy and Infectious Diseases (NIH), and was a member of the Priority Expert Panel B HIV Infection: Prevention and Care, National Center of Nursing Research. She was a member of the HIV Nursing Clinical Advisory Committee of the National AIDS Education and Training Centers, HRSA Bureau of Health Professions, and was a co-project director and co-investigator of the award for the Midwest AIDS Training and Education Center. She is an active member of the Association of Nurses in AIDS Care and has served as chair of the Nominating Committee. She is presidentelect and a member of the board of directors of the HIV/AIDS Nursing Certifying Board.

The Person with

HIV/AIDS Third Edition

Nursing Perspectives Jerry D. Durham PhD, RN, FAAN

Felissa R. Lashley PhD, RN, ACRN, FAAN Editors

Springer Publishing Company

Copyright © 2000 by Springer Publishing Company, Inc. All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Springer Publishing Company, Inc. Springer Publishing Company, Inc. 536 Broadway New York, NY 10012-3955 Acquisitions Editor: Ruth Chasek Production Editor: Helen Song Cover design by James Scotto-Lavino

Library of Congress Cataloging-in-Publication Data

The person with HIV/AIDS : nursing perspectives /Jerry D. Durham and Felissa R. Lashley, editors.—3rd ed. p. cm. Rev. ed. of: The person with AIDS. 2nd ed. c1991. Includes bibliographical references and index. ISBN 0-8261-1293-5 (hardcover) 1. AIDS (Disease)—Nursing. I. Durham, Jerry D. II. Lashley, Felissa R., 1941- . III. Person with AIDS. [DNLM: 1. Acquired Immunodeficiency Syndrome— nursing. 2. HIV Infections—nursing. WY 153.5 P467 1999] RC607.A26P47 2000 610.73'699—dc21 DNLM/DLC for Library of Congress 99-16258 CIP Printed in the United States of America

To Kathy, whose kindness, love, and understanding have sustained our lives together. Jerry D. Durham To my wonderful and growing family—Pete, Julie, and Benjamin; Neal and Anne; Heather; my mother, Ruth Lashley; and my friend Tony Oliver. Benjamin, may you grow up in a world where HIV disease no longer exists. Felissa R. Lashley

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Contents

List of Tables List of Figures Con tribu tors Preface 1.

ix xii xiii xv

The Etiology, Epidemiology, Transmission, and Natural History of HIV Infection and AIDS Felissa R. Lashley, R.N., Ph.D., A.C.R.N, F.A.A.N.

1

2.

The Pathogenesis of HIV Infection Janice M. Zeller, R.N., Ph.D., F.A.A.N. Barbara Swanson, R.N., D.N.Sc., A.C.R.N.

75

3.

Preventing HIV Infection Barbara Burger, R.N., Ph.D., A.C.R.N. Vida M. Vizgirda, R.N., M.S.

97

4.

Promoting Wellness in Persons with HIV Infection Susan L. Keller, R.N., M.S.

5.

The Clinical Spectrum of HIV Infection and Its Treatment Felissa R. Lashley, R.N., Ph.,D., A.C.R.N., F.A.A.N.

139

167

6.

Symptom Management in HIV/AIDS AnthonyJ. Admolfi, R.N., M.S.N., A.N.P., A.C.R.N.

271

7.

The Medical Treatment of HIV Disease Susan L. Wightman, R.N., B.S.N., A.C.R.N. Michael K. Klebert, R.N., M.S.N., AMP.

311

8.

Principles of Infection Control Barbara Russell, R.N., M.P.H., C.I.C., A.C.R.N.

351

vii

viii

CONTENTS

9. Testing and Counseling Richard S. Ferri, R.N., Ph.D., A.N.P., A.C.R.N., F.A.A.N.

369

10. Principles of HIV/AIDS Case Management Demetrius Porche, R.N., D.N.S., C.S., C.C.R.N.

387

11. HIV Infection in Women Mary Jo Hoyt, R.N., M.S.N., F.N.P. Susan Holman, R.N., M.S., A.N.P.

401

12.

429

HIV Disease in Children Wendy M. Nehring, R.N., Ph.D.

13. Minorities Living with HIV Infection/AIDS: Stories and Practical Strategies Barbara Aranda-Naranjo, R.N., Ph.D. 14. Ethical and Legal Dimensions Jerry D. Durham, R.N., Ph.D., F.A.A.N.

511 523

Appendix I: Considerations in Caring for Persons after Potential Nonoccupational Exposure to HIV When Data Are Inadequate

551

Appendix II: Prophylaxis for First Episode of Opportunistic Disease in HIV-Infected Adults and Adolescents

55 7

Appendix III: Prophylaxis for Recurrence of Opportunistic Disease (After Chemotherapy for Acute Disease) in HIV-Infected Adults and Adolescents

563

Appendix TV: Advising Patients Concerning Prevention of Exposure to Opportunistic Pathogens 567 Appendix V: Selected Sources of Information on the World Wide Web

577

Index

585

List of Tables

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 3.1 4.1 5.1 5.2 5.3 5.4 5.5 5.6 5.7

1992 Revised classification system for HIV infection and expanded AIDS surveillance case definition for adolescents and adults Clinical categories Conditions included in the 1993 AIDS surveillance case definition Selected common epidemiological definitions U.S. AIDS cases by age at diagnosis reported to CDC through December, 1998 Reported AIDS cases worldwide as of June 20, 1998 Adults and children living with HIV/AIDS worldwide, December, 1998 United States adult/adolescent AIDS cases by exposure category as reported to CDC through December, 1998 Pediatric AIDS cases in the United States as reported to CDC through December, 1998 Proper use of condoms to prevent sexual transmission of HIV Living with HIV disease: A summary of research on health promotion Selected opportunistic infections and conditions frequently associated with CD4+ cell count categories Selected HlV-related central nervous system disorders Early symptoms of AIDS dementia complex/HIVassociated dementia Clinical staging of the AIDS dementia complex Selected HIV-related gastrointestinal disorders Major oral disorders manifested in HIV infection Selected cutaneous manifestations seen in HIV infection ix

4 5 6 7 33 39 39 45 46 105

150 170 229 229 231 239 242 245

x

LIST OF TABLES

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 8.1 8.2 8.3 8.4 9.1 10.1 10.2 10.3 10.4 11.1 11.2

12.1 12.2 12.3

Licensed anti-HIV drugs Potential risks and benefits of early initiation of antiretroviral therapy in the asymptomatic HIVinfected patient Guidelines for treatment initiation Strategies for improving adherence to ART At a glance—nucleoside reverse transcriptase inhibitors (NRTIs) At a glance—nonnucleoside reverse transcriptase inhibitors (NNRTIs) At a glance—protease inhibitors (Pis) At a glance—protease inhibitor drug interactions requiring dose modifications At a glance—drug interactions between protease inhibitors and nonnucleoside reverse transcriptase inhibitors Initial antiretroviral 1997 triple-therapy options Health care workers with documented occupationally acquired AIDS/HIV infection, by occupation through December 1998 Components of an effective infection control program Handling of medical devices/equipment for reuse Examples of transmission-based precautions Getting tested Case management process Potential HIV disease case management problems Essential components of prevention case management Basic needs that interfere with prevention interventions Treatment for vaginitis and related conditions Clinical scenarios and recommendations for the use of antiretroviral drugs to reduce perinatal HIV transmission 1994 Revised HIV pediatric classification system: clinical categories 1994 Revised HIV pediatric classification system Prophylaxis for first episode of opportunistic disease in HIV-infected infants and children

312 316 317 322 323 325 335 339 340 343

354 361 362 363 375 390 391 395 395 408

416 434 441 445

LIST OF TABLES

12.4

12.5

12.6 12.7

12.8

12.9 14.1

Recommended antiretroviral regimens for initial therapy for human immunodeficiency virus (HIV) infection in children Indications for initiation of an antiretroviral therapy in children with human immunodeficiency virus (HIV) infection Available pediatric antiretroviral drugs Considerations for changing antiretroviral therapy for human immunodeficiency virus (HIV)-infected children Prophylaxis for recurrence of opportunistic disease (after chemotherapy for acute disease) in HFVinfected infants and children Immunization schedule for HIV-infected children List of Selected Resources on the World Wide Web: Ethics, Law, Research, and Public Policy

xi

455

457 458

466

469 480 539

List of Figures

1.1 Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure: step 1 1.2 Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure: steps 2 and 3 2.1 HIVVirion 13.1 STAC Care Coordination/Case Management Model

xii

27 28 77 514

Contributors

Anthony J. Adinolfi, R.N., M.S.N., A.N.P, A.C.R.N., is assistant clinical professor of nursing and an adult nurse practitioner at the AIDS Research and Treatment Center at Duke University, Durham, North Carolina. Barbara Aranda-Naranjo, R.N., Ph.D., holds the Brigadier General Dunlap Professorial Chair at the University of the Incarnate Word, San Antonio, Texas. Barbara Berger, R.N., Ph.D., A.C.R.N., is clinical assistant professor of medical-surgical nursing at the University of Illinois Chicago, Illinois. Richard S. Ferri, R.N., Ph.D., A.N.P., A.C.R.N., F.A.A.N., is an adult nurse practitioner in private practice in Provincetown, Massachusetts. Susan Holman, R.N., M.S., A.N.P., is director of the Women's Interagency Study Project at the State University of New York at Brooklyn and a consultant to the AIDS Institute, New York State Department of Health. Mary Jo Hoyt, R.N., M.S.N., F.N.P., is manager of the HIV Clinical Trials Unit at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey. Susan L. Keller, R.N., M.S., is Lifecare Program Coordinator at Clarian Health in Indianapolis and an adjunct faculty member at Indiana University School of Nursing, Indianapolis, Indiana. Michael K. Klebert, R.N., M.S.N., A.N.P., is study coordinator of the AIDS Clinical Trials Unit at Washington University, St. Louis, Missouri. xiii

xiv

CONTRIBUTORS

Wendy Nehring, R.N., Ph.D., is associate professor of nursing at Southern Illinois University, Edwardsville, Illinois. Demetrius Porche, R.N., D.N.S., C.S., C.C.R.N., is associate professor of adult nursing at Louisiana State University Medical Center, New Orleans, Louisiana. Barbara Russell, R.N., M.P.H., C.I.C, A.C.R.N., is an infection control practitioner at Baptist Hospital of Miami, Florida. Barbara Swanson, R.N., D.N.Sc., A.C.R.N., is assistant professor of adult health nursing at Rush University, Chicago, Illinois. Vida M. Vizgirda, R.N., M.S., is a doctoral candidate in nursing at the University of Illinois, Chicago, Illinois. Susan Wightman, R.N., B.S.N., A.C.R.N., is co-director of the Midwest AIDS Training and Education Center at Washington University, St. Louis, Missouri. Janice M. Zeller, R.N., Ph.D., F.A.A.N., is professor of adult health nursing and associate professor of immunology-microbiology at Rush University, Chicago, Illinois.

Preface

Since the second edition of this book was published in 1991, people throughout the world have witnessed dramatic changes in the HIV/ AIDS pandemic. In the United States, about a dozen drugs approved for treating HIV infection have extended and improved the lives of many thousands of HlV-infected persons. These drugs, and new ones under development, may eventually not only reduce HIV to undetectable levels but also clear the body of the virus. Other drugs have proven effective in treating or preventing the emergence of opportunistic infections. Although these drugs provide a source of hope for HlV-infected persons, many struggle with the burdensome costs of treatment. Indeed, some Americans, and most other infected persons throughout the world, will never receive the benefits of these expensive drugs. While no vaccine has yet proven effective in preventing HIV infection, several are in the clinical trial phase of development. Many persons living with HIV/AIDS are experiencing better and longer lives, forcing them to reconstruct their lives after expecting an early death (the so-called Lazarus Syndrome), even though their futures remain uncertain. This uncertainty, accompanied by survivor guilt in some persons with HIV/AIDS, has caused significant emotional stress and the need to find new ways of coping. An ever-widening gap between the rich and the poor of the world poses almost insurmountable challenges in controlling the HIV pandemic. Speaking at the 12th World AIDS Conference in the summer of 1998, Brian Boyle summarized the significance of this gap: While developed countries continue to bask in the glow of highly active antiretroviral therapy and other quantum leaps in HIV/AIDS treatment, HIV continues to ravage most of the developing world. Currently, approximately 30.6 million individuals are infected with HFV worldwide, and over two-thirds live in Sub-Saharan Africa, where few, and in most cases no, resources are xv

xvi

PREFACE

available for HIV care or prevention. All told, 89% of HIV-infected people live in countries that, taken as a group, account for less than 10% of the global gross national product.

It is a cruel irony that poor people of developing nations have served as subjects in the testing of drugs used to treat HIV infection, since they often find approved drug treatments beyond their reach. Another HlV-related challenge to the people of developing nations is that of balancing the risk of HIV transmission via breastfeeding (which accounts for a high percentage of mother-to-infant transmission in areas where HIV is endemic) with the need to provide nutrition to their infants. In the United States, the number of persons dying from AIDS declined in 1996 and 1997, even though the United States has one of the highest HIV/AIDS-related mortality rates among industrialized nations. The reduction in the number of Americans dying from AIDS can be largely attributed to early treatment with increasingly effective drug therapies, especially highly active antiretroviral therapy (HAART). While HIV infection and AIDS are increasingly treatable conditions, a cure continues to elude scientists. An emerging view of HIV infection as a chronic condition carries the risk that individuals and communities will lessen activities aimed at preventing infection, thereby leading to increasing numbers of new infections. Viewing HIV infection as a chronic condition remains dangerous because thousands of Americans continue to die of AIDS as a result of late, inadequate, or ineffective treatment. In spite of advances in the treatment of HIV infection, many thousands of Americans continue to be infected each year, even though ample evidence exists that most know those behaviors that place them at risk of infection. In the United States, the epidemiological features of the epidemic have changed, with African-Americans and Hispanics disproportionately affected, a shift that poses significant prevention and treatment challenges to these ethnic communities. Rural America has recently been termed a "new frontier for AIDS," aggravated by social taboos, remoteness and isolation, poverty, and lack of education. Although women now comprise a larger percentage of those with HIV infection and AIDS, better medical treatment during pregnancy has led to fewer infants being infected perinatally; however, detecting and treating HIV infection in pregnant women have spawned significant ethical controversies.

PREFACE

xvii

While injection drug use (IDU) is the second most frequently reported risk for AIDS in the United States, IDU has evolved as the main pathway of infection in women, infants, ethnic minority populations, and others. Unfortunately, public health experts and political leaders disagree on how to address the dual epidemics of HIV/AIDS and drug use in this country. (There are an estimated 1.5 million injection drug users in the United States.) This lack of consensus reflects not only the complexity of preventing and treating drug use but also the concerns of political leaders, many of whom view drug use largely as a legal, rather than a public health, issue. Even though sound evidence exists, for example, that carefully managed needle exchange programs can reduce HIV infection among IDUs, most political leaders have failed to endorse such programs, fearing a backlash from their constituents. Influenced by voters' fears of AIDS, legislators have increasingly passed laws aimed at protecting the public from AIDS. Many of these laws have chipped away at individual civil liberty protections and raise constitutional concerns in such areas as the right to privacy. Ethicist Lawrence Gostin interprets the recent legal shift as a move from a period when the civil rights and civil liberties of HFV-infected persons were protected to a "compulsory and punitive approach." This shift has also been seen as a departure from what has been termed "exceptionalism" for HIV/AIDS, that is, a move away from a time when HIV/AIDS was perceived to affect only gay men who, earlier in the epidemic, voiced well-founded concerns of discrimination. Because the epidemic now affects a broader spectrum of society, laws that protect the public, mandate testing for specific populations, and require reporting of names of HIV-positive persons may supersede laws protecting individual civil liberties. Nurses have played key roles in responding to the HIV/AIDS epidemic. They have conducted important survey and clinical research in efforts to better understand the epidemic and provide excellent care. They have crafted position statements aimed at protecting the rights of infected persons. They have formed a national organization, the Association of Nurses in AIDS Care, that has advanced the knowledge that nurses need to provide expert, compassionate care to HIV-infected persons. They have incorporated HIV/ AIDS content into their curricula and established graduate programs in HIV/AIDS nursing. And, finally, they have provided care for all

xviii

PREFACE

HIV-infected persons wherever they live and whenever possible. While the epidemic has significantly changed, nurses remain a constant source of hope for people struggling throughout the world with HIV/AIDS. JERRY D. DURHAM FELISSA R. LASHLEY

1

The Etiology, Epidemiology, Transmission, and

Natural History of HIV Infection and AIDS Felissa R. Lashley

Imost two decades ago the first observations of a strange immunodeficiency, rare opportunistic infections, and JCaposi's sarcoma (KS) were first made in previously healthy young homosexual men. These observations heralded the beginning of one of the most medically, emotionally, and politically troubling epidemics of this century (Centers for Disease Control, 1981a, 1981b). Yet we have learned more about human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) in a short time than perhaps any organism and disease in history, and some of what we have learned has been applied to other diseases such as cancer. Over the years, emphasis has shifted to the identification of behaviors that place an individual at risk of acquiring HIV infection rather than merely belonging to a certain population

A

l

2

THE PERSON WITH HIV/AIDS

group. Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), emphasized this shift when he stated that "the risk for becoming infected with the AIDS virus is really a behavior. The risk for AIDS is having sex with someone who is infected or being exposed to blood that is infected. The risk is not being a homosexual man or being a member of any group" (Barnes, 1986, p. 1589). Emphasis has also shifted to new approaches to the treatment of HIV, including possible prevention by postexposure prophylaxis, and vaccination based on information from virologic and immunologic studies of HIV and its pathogenesis in the body. DEFINITIONS AIDS is defined generally as a specific group of diseases or conditions that are indicative of severe immunosuppression related to infection with HIV (Centers for Disease Control and Prevention, 1998b). This immunosuppression is reflected in a decrease in CD4+ T lymphocytes (T-helper lymphocytes) below 500/mm3 as well as other abnormalities. In 1982, for surveillance and reporting purposes, the Centers for Disease Control (CDC) first developed case definitions for AIDS in children (see chapter 12) and adults (Centers for Disease Control, 1982d). Also in 1982 CDC defined, for national surveillance purposes, a case of AIDS as a disease at least moderately predictive of a defect in cell-mediated immunity occurring in a person with no known cause for diminished resistance to that disease (Selik, Haverkos, & Curran, 1984). Such diseases included Kaposi's sarcoma (in patients under 60 years of age), lymphoma limited to the brain, Pneumocystis carinii pneumonia, and serious opportunistic infections. At the time of the original surveillance definitions, the etiologic agent of AIDS was unknown. It was necessary, however, to have standardization for national reporting and the interpretation of disease trends. Minor revisions were made between 1982 and 1985. On June 28, 1985, the CDC published a major revision of the original case definition for immediate adoption, largely prompted by the discovery of HIV as the etiologic agent of AIDS (Centers for Disease Control, 1985c). As knowledge further expanded, major revisions of the surveillance definition occurred in 1987 (Centers for Disease

THE ETIOLOGY, EPIDEMIOLOGY, AND TRANSMISSION OF HIV

3

Control, 1987b) and 1993. The 1993 revision, which is the one in current use, had an impact on case reporting, resulting in an artificially high peak for a period after its implementation. A major change in that definition was that a CD4+ cell count below 200 mm3 in a person who was HIV-infected, even without the presence of other symptoms, was defined as AIDS. Three conditions were also added to the AIDS case definition—pulmonary tuberculosis (TB), invasive cervical cancer, and two occurrences within a year of bacterial pneumonia (Centers for Disease Control and Prevention, 1992). HIVinfected persons are now classified on the basis of CD4+ T-cell count or percent in three ranges and three clinical categories resulting in a matrix of nine mutually exclusive categories. These are shown in Table 1.1. The CD4+ T-cell categories are: Category 1 > 500 cells/|lL or mm 3 Category 2 200-499 cells/(lL or mm 3 Category 3 < 200 cells/uL or mm 3 The clinical categories for adults or adolescents are A, B, and C. Clinical categories are divided into A, B, and C (see Table 1.2). Category A consists of one or more of the following Asymptomatic HIV infection Persistent generalized lymphadenopathy (PGL) Acute or primary HIV infection with accompanying illness or history of acute HIV infection (Centers for Disease Control and Prevention, 1992. Category B consists of "symptomatic conditions" not included in Category C (Centers for Disease Control and Prevention, 1992). Examples of conditions in clinical Category B are listed in Table 1.2. Category C includes the clinical conditions listed in the AIDS surveillance case definition as shown in Table 1.3. Once a person has had a category C condition, the person remains in Category C. Because the CDC definition did not adequately address differences seen in Africa, the World Health Organization (WHO) developed a definition for AIDS in Africa. The WHO definition did not include CD4+ cell counts as an essential component partly because

4

THE PERSON WITH HIV/AIDS

TABLE 1.1 1992 Revised Classification System for HIV Infection and Expanded AIDS Surveillance Case Definition for Adolescents and Adults* Clinical categories

CD4+ Cell categories

(A) Asymptomatic, or persistent generalized lymphadenopathy, acute infection

(B) Symptomatic, not (A) or (C) conditions

(C) AIDS-indicator*

< 500/u.L

A1

B1

C1

200-499/u.L

A2

B2

C2

< 200/jiL AIDS-indicator cell count

A3

B3

C3

*The shaded cells illustrate the expansion of the AIDS surveillance case definition. People with AIDS-indicator conditions (category C) are currently reportable to health departments in every state and U.S. territory. In addition to people with clinical category C conditions (categories C1, C2, and C3), person with lymphocyte counts of less than 2007uL (categories A3 or B3) also will be reportable as AIDS cases. **See Table 1.3. Source: Centers for Disease Control and Prevention. (1992). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report, 41, (No. RR-17), 7.

of less availability of technology to determine and follow such counts in individuals over time. A definition of AIDS has also been issued by the Pan American Health Organization. Definitions for epidemiological terms may be useful in reading the literature. Common ones are shown in Table 1.4. ETIOLOGY The etiologic agent of AIDS is the human immunodeficiency virus (HIV) of which there are two types designated as type 1 and type 2 or (HIV-1 and HIV-2). HIV-1 is further subdivided into three groups.

THE ETIOLOGY, EPIDEMIOLOGY, AND TRANSMISSION OF HIV

5

TABLE 1.2 Clinical Categories Category A Category A consists of one or more of the conditions listed below in an adolescent or adult (> 13 years) with documented HIV infection. Conditions listed in categories B and C must not have occurred. Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection Category B Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C and that meet at least one of the following criteria: (1) the conditions are attributed to HIV infection or are indicative or a defect in cell-mediated immunity or (2) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples of conditions in clinical category B include but are not limited to: Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5° C) or diarrhea lasting > 1 month Hairy leukoplakia, oral Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess Peripheral neuropathy For classification purposes, category B conditions take precedence over those in category A. For example, someone previously treated for oral or persistent vaginal candidiasis (and who has not developed a category C disease) but who is now asymptomatic should be classified in clinical category B. Category C Category C includes the clinical conditions listed in the AIDS surveillance case definition (see Table 1.3). For classification purposes, once a category C condition has occurred, the person will remain in category C. Source: Centers for Disease Control and Prevention. (1992). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report, 41(No. RR-17), 3-4.

6

THE PERSON WITH HIV/AIDS

TABLE 1.3 Conditions Included in the 1993 AIDS Surveillance Case Definition Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal Cervical cancer, invasive* Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (> 1 month's duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (> 1 month's duration); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extra pulmonary Isosporiasis, chronic intestinal (> 1 month's duration) Kaposi's sarcoma Lymphoma, Burkitt's (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary* or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent* Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV *Added in the 1993 expansion of the AIDS surveillance case definition. Source: Centers for Disease Control and Prevention. (1992). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report, 47(No. RR-17), 15.

The first is called the major group and is known as M. The second is known as group O (outliers), and the proposed designation for the third group, which was recently reported in 1998 from a Cameroonian patient, is N for either "non M-non O" or "new" (Simon et al., 1998; Wain-Hobson, 1998). Group M consists of at least 10 major subtypes designated as A through J, some of which are very rare

THE ETIOLOGY, EPIDEMIOLOGY, AND TRANSMISSION OF HIV

TABLE 1.4

7

Selected Common Epidemiological Definitions

Case Control Studies—investigation of a group of persons with the disease or condition of interest (cases) compared retrospectively with another group that does not have the condition or disease (control). Cohort—a group of persons who have had a common experience who are followed over a time to determine whether or not the condition or disease of interest develops. Incidence rate—measure of frequency with which a new case of disease or condition occurs in a populous over a period of time. Measures pace of new illness in persons originally without the disease of interest. This is usually presented in a base multiple of 10 as either a percent or a rate per 1,000 or 100,000. Incidence rate = number of new cases of disease over a period x base of 10 total population at risk

Morbidity—departure from a state of health or a specified disease Mortality rate—frequency of occurrence among a specified population in a given time period Prevalence—measure of the number or proportion of persons in a given time period with a specific condition or disease. Prevalence rate =

number of persons with disease in a 9'ven time penod x base of

total population at risk Rate—measure of the occurrence or existence of a condition, disease, or time period. Risk—the probability of the occurrence of a condition, event, or disease Relative risk—refers to the degree of risk for a particular group with a factor of interest compared with the risk of a group without that factor to develop a certain condition or disease. Example: the relative risk for smokers to develop lung cancer is higher than non-smokers incidence rate among exposed Relative risk = incidence rate among non-exposed

(Kanki et al., 1999). They differ from one another in 21% to 31% of their gene sequences (Charneau, Borman, & Quillent, 1994; Jaffe & Schochetman, 1998). These are useful in tracing epidemiological origins and spread. Subtype B is most common in the United States and Europe, whereas subtype E has been most frequently seen in Central Africa (Janssens, Buve, & Nkengasong, 1997). Group O has been mainly seen in Central West Africa. The few persons in the United States possessing group O HIV-1 infection were natives of Africa (Jaffe & Schochetman, 1998). HIV-2 has at least five subtypes,

8

THE PERSON WITH HIV/AIDS

and possibly six (Jaffe & Schochetman, 1998). HFV-1 is responsible for most of the AIDS cases in the world at this time, except in West Africa, where HIV-2 is prevalent. When HIV is referred to in this chapter, HIV-1 is meant unless otherwise specified. HIV-2 is discussed in more detail later in this chapter. Duesberg (1989) has consistently argued that HIV is not the etiologic agent of AIDS. However, his arguments have not found wide support in the scientific community. Other suggested classifications of HIV are as follows: (1) as macrophage-tropic or T-cell line tropic; (2) as syncytium-inducing or nonsyncytium inducing (see chapter 2); and (3) as slow/low or rapid/ high in relation to growth in culture or based on coreceptor affinity such as to either CCR5 (R5 virus), CXCR4 (X4 virus), or both (R5X4 virus) (Berger et al., 1998). Historical Background Clues from epidemiological surveillance first suggested that AIDS was caused by a transmissible agent. These included the following: (1) the AIDS epidemic was new; (2) it appeared first in limited geographic areas and then spread; (3) the initial groups of people affected (homosexual men and intravenous drug users) and later identified groups (hemophiliacs and blood transfusion recipients) were prone to communicable diseases but were socially, economically, and geographically disparate; and (4) clustering of cases suggested common links and contacts. Early patterns of the distribution of affected persons were reminiscent of hepatitis B (Curran et al., 1985; Gallo, Shaw, & Markham, 1985; Scale, 1984). By 1982 the most probable virus candidates appeared to be cytomegalovirus, EpsteinBarr virus, certain adenoviruses, a human parvovirus, and the retroviruses (Fauci et al., 1984). Several lines of thinking began to implicate a retrovirus, particularly one similar to human T cell lymphotropic viruses (HTLV), which are also known as human T cell leukemia viruses. (HTLV-I causes adult T cell leukemia in humans.) These included the knowledge that (1) T-4 lymphocytes were selectively depleted in AIDS, and HTLV had already been shown to have this tropism; (2) HTLV could be transmitted by intimate contact or blood products; (3) HTLV could cause immunosuppression; (4) the retrovirus known

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as the feline leukemia virus could cause a type of cancer (leukemia) as well as immunosuppression leading to opportunistic infections in cats; and (5) there was a high incidence of AIDS among Haitians and Africans. (Both Haiti and Africa are endemic areas for HTLVI.) Later assays of AIDS patients showed that they had evidence of exposure to an HTLV-I related virus (Broder & Gallo, 1985; Essex, Allan, et al., 1985; Fauci et al., 1984; Lane & Fauci, 1985). By 1983 and 1984, respectively, three groups of researchers had isolated, identified, and characterized the virus that was established as the cause of AIDS. Gallo and his group at the National Cancer Institute named it HTLV-III; Montagnier and his associates at the Pasteur Institute in Paris, in cooperation with the CDC, named it lymphadenopathy-associated virus (LAV); and Levy and his group in California named it AIDS-associated retrovirus (ARV) (Barre-Sinoussi et al., 1983; Gelman et al., 1983; Levy et al., 1984). A task force sponsored by the International Committee on the Taxonomy of Viruses was assembled to reach a decision on a name (Norman, 1985c). The name recommended by this committee in May 1986 was human immunodeficiency virus (HIV) (Coffin et al., 1986). This is still the accepted terminology. These named viruses were found to be variants of the same one. However, although these viruses are members of the retrovirus family, they are more closely related to the lentivirus subfamily rather than to the oncovims subfamily, which includes HTLV, and HIV is considered to be a member of the lentivirus subfamily of human retroviruses (Walker, 1998). The importance of determining the cause of AIDS included the ability to identify persons infected with HIV, characterize the viral characteristics, epidemiologically characterize viral transmission and patterns, describe the natural history of infection, and develop the potential for screening, prevention, treatment, and vaccination development. HUMAN IMMUNODEFICIENCY VIRUS TYPE 2 (HIV-2) In October, 1985, Clavel, Montagnier, and their colleagues identified a new human immunodeficiency virus in blood samples from persons with AIDS in Portugal who had lived in western Africa. This virus was also described in asymptomatic West African prostitutes (Centers

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for Disease Control, 1989; Gallo & Montagnier, 1988) and was eventually designated human immunodeficiency virus type 2 (HIV-2). HFV2 is more closely related to the simian immunodeficiency virus than to HIV-1 (Whittle, Ariyoshi, & Rowland-Jones, 1998). This relationship is so close that cross-species transmission is the logical explanation, probably from the sooty mangabey monkey (Wain-Hobson, 1998). When comparing HIV-1 and HFV-2, the most similarity is in the core structure, with most differences occurring in the envelope region. To date HIV-2 has been mainly detected, and is thought to have originated, in western Africa. Countries in Africa where HIV-2 infection has a prevalence of more than 1 % and is considered endemic include Guinea-Bissau, Ivory Coast, Mozambique, Angola, Gambia, Mali, Mauritania, and the Cape Verde islands (Centers for Disease Control and Prevention, 1998b). Its prevalence is 8% to 10% in parts of Guinea-Bissau (Whittle et al., 1998). The first reported AIDS case in the United States due to HIV-2 was diagnosed in December 1987 in New Jersey in a patient who was originally from western Africa (Centers for Disease Control, 1988a). Through December 1997, 77 United States cases of HIV-2 infection had been reported to the Centers for Disease Control and Prevention, 52 of these patients were born in western Africa (Centers for Disease Control and Prevention, 1998b). Based on screening for antibody in frozen sera, it is concluded that HIV-2 may have been present in western Africa since at least 1966 (Kawamura et al., 1989). HIV-2 is transmitted in the same ways as HIV-1, but it appears less transmissible sexually and perinatally. Persons with HIV-2 develop similar opportunistic infections and conditions but progression is slower in HIV-2 infection than in HIV-1 (Whittle et al., 1998). HIV2 testing is indicated for persons who have an illness suggestive of HIV infection but whose HIV-1 test results are not positive and for persons for whom the HIV-1 Western blot exhibits the unusual indeterminate test band pattern of Gag plus Pol in the absence of Env, which are HIV proteins (Centers for Disease Control and Prevention, 1998b). No FDA-licensed HIV-2 viral load assay is available at present, and those assays used for HIV-1 are not reliable for use in patients infected with HIV-2. The best approach to treatment for HIV-2 is still not elucidated. Zidovudine therapy to interrupt perinatal transmission should be considered for HIV-2-infected preg-

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nant women, and therapy for their newborns should be initiated as described later in this chapter and in chapter 11 (Centers for Disease Control and Prevention, 1998b). ORIGIN OF HIV AND AIDS Scientists have remained interested in the origin of the human immunodeficiency virus for various reasons since identifying the origin and how the virus causes disease in other hosts might give clues to control HIV (Essex & Kanki, 1988). Attention has focused on Africa as a possible site of origin for AIDS. It has been postulated that HIV crossed the host-species barrier and spread as a "virgin soil" epidemic. Such an organism may be harmless to its natural host but highly lethal to its new host. Various lines of evidence suggest that the natural host for HIV-1 may be chimpanzees, whereas for HIV-2 the animal host may be the monkey known as the sooty mangabey (Gao et al., 1999; Wain-Hobson, 1998). Researchers have been interested in determining whether or not HIV and/or AIDS had made an appearance before the outbreak of the epidemic. Various data and case reports have now appeared that indicate that HIV infection was at least sporadically present decades earlier. The question has been asked, Where was HIV hiding all these years? (Gallo & Montagnier, 1988). The logical question that follows is, Why did HIV infection and AIDS become rampant at the time that it did? Recently HIV viral sequences from early stored blood samples reveal that HIV-1 and HIV-2 probably diverged from a common ancestor, which they shared in the 1940s or early 1950s. HIV-1 probably was introduced into humans shortly before that time (Zhu et al., 1998). Various case reports and retrospective analysis of stored serum samples suggest the presence of AIDS in 1968 in the United States, and perhaps even earlier, although it has also been suggested that some positive serological results may have been artifacts due to prolonged storage (Garry et al., 1989). At this time, the earliest reported case known was in a Norwegian merchant seaman who was infected in 1961 or 1962 with HIV-1 group O in Cameroon and transmitted it to his wife and daughter. Another early reported case in Africa was that of a female Danish surgeon who contracted the disease while working in Zaire in 1976 and who died in 1977 (Bygbjerg,

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1983). Other early cases appear to have occurred in Kinshasha in 1959 (Hooper, 1997; Nahmias et al., 1986). The subject of the origin of HIV and AIDS became a political one. Currently, it is believed that earlier cases of AIDS were sporadic in the United States and elsewhere, although HIV infection may have existed as an endemic disease in Africa (Garry et al., 1989). The World Health Assembly stated in 1987 that HIV is a "naturally occurring retrovirus of undetermined geographic origin" (Mann, Chin, Piot, & Quinn, 1988, p. 82). HIV PREVALENCE In the United States an estimated 750,000 persons have been infected with HIV and about 6 million new infections occur each year (Baiter, 1999; Cohen, Sande, & Volberding, 1998). Worldwide, 33.4 million persons are thought to be infected (UNAIDS/WHO, 1998). Although AIDS is reportable in all states and the District of Columbia in the United States, HIV infection is not. As of December 1998, HIV infection reporting to CDC was in place for 33 states and territories; of these, 3 have it only for pediatric cases—Connecticut and Texas for all pediatric cases and Oregon only for children under 6 years of age. Alaska, Texas, and New York began in 1999 (Centers for Disease Control and Prevention, 1998b). The prevalence of AIDS cases has increased because mortality rates have decreased and thus persons with HIV infection are living longer (Buve & Rogers, 1998). This trend is attributed to advances in treatment, especially the use of protease inhibitors. The incidence of pediatric AIDS has decreased due to zidovidine effectiveness in preventing perinatal HIV transmission. Whether these epidemiologic trends will continue is unknown at present. Over the years, the CDC and others have conducted various surveys of HIV infection prevalence based on the presence of antibodies to HIV among various population segments. These have included surveys of prevalence among groups at recognized risk such as intravenous/injecting drug users; homosexual/bisexual males; hemophiliacs; heterosexual partners of persons with HIV infection or at recognized risk; selected segments of the general population such as blood donors, military recruits, newborns, pregnant women, and

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sentinel hospital patients; and persons in special settings, including prisoners, prostitutes, and persons with tuberculosis. HIV prevalence has been analyzed by geographic area, race, ethnicity, age, sex, and other variables. Detailed information about HIV incidence and prevalence is beyond the scope of this chapter. A detailed analysis for the United States can be found in the reference by Holmberg (1996). Results vary widely with geographic area and population studied. About 47,000 new HIV cases can be predicted yearly in the United States, with about half occurring in injection drug users (IDU), the majority of whom are located in the Northeast, Miami, and San Juan, Puerto Rico. Overall, HIV infection is declining in men who have sex with men; however, HIV infection rates among younger minority homosexual and bisexual men are two to three times those of older or white homosexual and bisexual men. The profile of the person in the United States who is at high risk for HIV infection is the young, minority, indigent woman who uses crack, has multiple sexual partners, has genital ulcer disease such as herpes simplex virus type 2 or syphilis, who trades sex for drugs, money, or both, and who lives in the inner city of the Northeast or the rural South (Holmberg, 1996). HIV prevalence is discussed further under "Worldwide Patterns." TRANSMISSION To date, HIV has been isolated from a variety of body fluids, cells, and tissues including peripheral blood, lymph nodes, brain tissue, cerebrospinal fluid, tears, bone marrow, cell-free plasma, saliva, retina, cornea, ear secretions, bronchial fluid, semen, breast milk, cervical cells, Langerhans cells of the skin and mucous membranes, synovial fluid, and cervical and vaginal secretions. HIV has not been recovered from sweat (Centers for Disease Control, 1988b; Centers for Disease Control and Prevention, 1997c; Pomerantz et al., 1987; Thiryetal., 1985; Withrington etal., 1987). However, the importance of these fluids, cells, and tissues in transmission varies, as does the concentration of HIV within them. The CDC has recommended standard precautions be applied to the following fluids in addition to blood: semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, pericardial fluid, and amniotic fluid. Standard

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THE PERSON WITH HIV/AIDS

precautions should apply to the following only if visible blood is present: feces, nasal secretions, sputum, sweat, tears, urine, vomitus, and breast milk (Centers for Disease Control, 1988b). Periods of higher infectiousness and transmissibility coincide with higher viral load on the part of the HIV-infected person and increasing immunosuppression. Characteristics of HIV itself such as the viral phenotype and its cellular tropism (macrophage or other) are also important in degree of transmissibility (Vermund, 1997). HIV can survive for a week or more in fluids such as water or blood. Recently, it has been demonstrated that viable HIV can be recovered from inside used syringes when maintained at room temperature (Abdala et al., 1999). The major documented ways that HIV can be transmitted are by intimate sexual contact, both homosexual and heterosexual, with an HIV-infected person; exposure to contaminated blood or blood products either by direct inoculation, sharing of drug apparatus, transfusion, or other methods; and through passage of the virus from infected mothers to their fetus or newborn in utero, during labor and delivery, or in the early newborn period. It has been postulated that HIV could be spread by insects such as mosquitoes, particularly in tropical climates (Blaser, 1986), but no evidence has been found to support this supposition. Presently, it is considered that other transmission modes (e.g., insect vectors or others) for HIV, if they exist, are extremely rare (Centers for Disease Control and Prevention, 1997c; Vermund, 1997). In 1998 the CDC published recommendations for the management of persons who had nonoccupational exposures to HIV. They define a nonsexual, nonoccupational exposure (excluding perinatal exposures) that can place a person at risk for HIV infection as a percutaneous penetration (e.g., a needlestick, injection, piercing, or cut with a sharp object); contact with mucous membranes; or contact with skin (especially when the involved skin is chapped, abraded, or affected by dermatitis; when the contact is prolonged; or when the involved area is extensive) and substances that have been implicated in the transmission of HIV infection (i.e., blood, tissues, or other body fluids when contaminated with visible blood). The Centers for Disease Control and Prevention (1998b) describes a sexual exposure that can place a person at risk for HIV infection as "a discrete penetrative sex act (e.g., acts involving the insertion

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of the penis into the vagina, anus, or mouth) involving vaginal, anal, penile, or oral contact with the sex partner's potentially infectious body fluids, including substances that have been implicated in the transmission of HIV infection (i.e., blood, semen, vaginal secretions, or other body fluids when contaminated with visible blood)" (p. 1). The report stresses that these guidelines should not replace prevention of HIV infection. Prevention should not be considered as a "morning-after pill." Before therapy is begun after nonoccupational HIV exposure, the CDC recommends that "health-care providers may want to provide their patients with a system for promptly initiating evaluation, counseling, and follow-up services" after such high-risk exposure (p. 2). Evaluation should include counseling in relation to risk reduction behaviors and prevention of secondary transmission. Besides potential benefits in using antiretroviral agents for postexposure prophylaxis, there are also risks that include side effects, drug toxicity, acquisition of resistant HIV strains, and cost of therapy. The cost may range from $600 to $1,000 for a 28-day course of antiretroviral therapy. Antiretroviral therapy is not recommended for those with low-risk exposures such as potentially infected body fluid on intact skin, or for persons who seek care more than 72 hours after exposure (Centers for Disease Control and Prevention, 1998b). Considerations in caring for persons and considering initiating antiretroviral therapy after nonoccupational exposure are outlined in Appendix 1. Sexual Transmission In the United States early in the HIV epidemic the most common mode of spread was male-to-male sexual transmission. Men who have sex with men is still cumulatively the major exposure category for men into which nearly half (48%) of the reported United States AIDS cases fall. When the combined category of "men who have sex with men and inject drugs" is added, about 54% of all adult cases of AIDS in the United States fall into this exposure category (Centers for Disease Control and Prevention, 1998h). Heterosexual transmission of HIV can occur both from males to females and from females to males. Male-to-female transmission appears more efficient than female-to-male transmission. Heterosexual transmission is believed

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THE PERSON WITH HIV/AIDS

to occur during both penile-vaginal and penile-anal intercourse, and more rarely through oral-genital contact (Vernazza, Eron, Fiscus, & Cohen, 1999; Vermund, 1997). Because HIV may be transmitted during heterosexual or homosexual rape, some experts have proposed mandatory testing (with counseling) of both victim and presumed assailant. HIV transmission due to artificial insemination from an infected donor has been reported, although efforts to remove HIV from semen for safe artificial insemination have been reported. There have also been reports of female-to-female sexual transmission (Greenhouse, 1987; Marmor et al., 1986; Monzon & Capellan, 1987), but this mode is very rare, and women who have sex with women may also have sex with men, have artificial insemination with sperm, or use injecting drugs (Carroll, 1999). Transmission by oral sex has also been described, but the risk is believed to be very low and result from blood contact (Centers for Disease Control and Prevention, 1997c, 1997d; Rozenbaum, Gharakhanian, Cardon, Duval, & Coulaud, 1988; Spitzer & Weiner, 1989). There have been reports of HIV infection among children who had no risk factors other than sexual abuse (Gellert & Durfee, 1989; Gellert, Durfee, Berkowitz, Higgins, & Tubiolo, 1993). The HIV infection epidemic has exposed an ignorance of the type and frequency of various sexual practices in the United States. Sex researchers have estimated that about 25% of American women occasionally engage in anal receptive intercourse and that about 10% do so on a regular basis for either pleasure or contraception (Boiling & Voeller, 1987). This is considered risky because of the possibility of the tearing of tissue leading to bleeding. Any blood contact during sex increases the risk of HIV transmission (Cohen et al., 1998). Acquisition of HIV may be made easier by genital ulcers, sexually transmitted diseases, or trauma, and the presence of inflammation or exudates that can facilitate virus entry into the cell. Menstruation may facilitate transmission, whereas menopause, resulting in vaginal dryness, may lead to trauma, thereby facilitating HIV transmission. First sexual experiences may be associated with bleeding, and immature vaginal tissue in young girls may be less resistant to trauma and bleeding. Infectious cells such as lymphocytes and macrophages that enter the genital tract because of the presence of one of the above are believed to increase transmissibility. Lack of circumcision in men is believed to result in higher intraurethral

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17

and subprepucal loads of infectious cells that increase transmissibility. Thus having sex with an uncircumcised man may pose a greater risk of HIV transmission than engaging in sex with a man who is circumcised (Vermund, 1997; Vernazza et al., 1999). Social and cultural changes have contributed to sexual experimentation and freedom. These include oral contraceptive availability, decreasing fear of pregnancy, weakening of traditional values, openness about homosexuality, and advances in air transportation, allowing greater intermingling (Haverkos & Edelman, 1988). The consequences of these changes have been an increase in many sexually transmitted diseases and increased infertility. In addition to factors mentioned above and biological factors, sexual transmission of HIV is influenced by the number of different sexual partners likelihood that the sexual partner is infected (e.g., behaviors such as drug use) prevalence of HIV infection in the geographic area number of sexual exposures with an HIV-infected person status of rectal and vaginal mucosa (e.g., whether it is dry or if ulcers are present) presence of sexually transmitted diseases infectiousness of the partner (including viral load and use of

antiviral drugs) immune status of partners use of barriers during sex (e.g., proper use of latex condoms) degree of risky sexual behaviors that are practiced (Vermund, 1997; Vernazza et al., 1999). Transmission between regular sexual partners, only one of whom is HIV-infected (i.e., "discordant"), has been of particular interest for many reasons, including the potential for prevention of spread. This transmission rate has varied among different exposure categories and studies but has been reported as ranging as high as 85% in one study (Pinching, Weiss, & Miller, 1988). (Most studies show lower frequencies.) A review of 26 reported studies of heterosexual partners of persons at risk who do not have identified risk factors themselves showed a range of 0% to 58%, with a median of 24% (Centers for Disease Control, 1989). One study estimated that the risk of

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THE PERSON WITH HIV/AIDS

contracting gonorrhea from an infected female in a single sexual encounter is about 25% (Holmberg, Horsburgh, Ward, & Jaffe, 1989). The risk of acquiring HIV per sexual act with an HIV-infected person has been estimated as follows: receptive anal intercourse (0.008 to 0.032), risk to women of vaginal intercourse (0.0003 to 0.002), and the risk to men of vaginal intercourse (0.0003 to 0.0014) (Cohen et al., 1998). In some cases, infectivity of receptive anal intercourse may be as high as 10% (De Gruttola et al., 1989). In fact, it has been somewhat puzzling that the figures for HIV transmission should be as relatively low as they are. Some persons have multiple continuing exposures to HIV-infected partners without acquiring it. Sexual transmission is further discussed under exposure categories for men who have sex with men and heterosexual contact elsewhere in this chapter. Bloodborne Transmission Transmission of HIV by exposure to contaminated blood or blood products occurs mainly through piercing of the skin with a contaminated needle or sharp object, transfusion from an infected donor to someone requiring blood because of temporary illness or surgery, or chronic illness such as hemophilia or dialysis, or through sharing of needles or other drug-related apparatus, especially among injecting drug users. Injuries from needles and sharp objects to health care workers also falls in this category of transmission, as do using contaminated needles and equipment employed for therapeutic purposes. Tattooing has also been implicated in the spread of HIV (Doll, 1988), as has ear and body piercing. Reports of confirmed HIV transmission during bloody flstfights are rare but possible (Ippolitto, Poggio, & Arice, 1994). Concerns about blood-related spread have resulted in various precautions during contact sports. For example, Nevada requires a mandatory HIV test for boxers, who, if positive, are disqualified. Other states with similar rules include New York, New Jersey, Washington, Oregon, and Arizona, as well as Puerto Rico (Feller & Flanigan, 1997). In some states boxing officials require persons assisting the fighter to wear plastic gloves (Gunby, 1988). Other athletic events are not similarly regulated, and more than HIV would need to be considered in any wide-ranging legislation.

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HIV infection after acupuncture has been described (Vittecoq, Mettetal, Rouzioux, Bach, & Bouchon, 1989), as it has from receiving transplanted organs from an HIV-infected person (Centers for Disease Control, 1987a). While HIV infection from receiving a contaminated unit of blood is now relatively uncommon in the United States, efficiency of transmission is high. Nearly all those receiving an HIVcontaminated unit of blood IV develop infection (Vernazza et al., 1999). HIV transmission through blood is discussed further below. Perinatal Transmission The third major transmission mode is vertical transmission of HIV from an infected mother to her fetus or child in the perinatal period including pregnancy, delivery, and postpartum. Prenatal transmission has been supported due to several lines of evidence. HIV has been isolated from fetal tissue and amniotic fluid and cells, and p24 antigen has been detected in fetal blood obtained by fetal blood sampling (Jovaisas, Koch, Schafer, Stauber, & Lowenthal, 1985; Mundy, Schinazi, Gerber, Nahmias, & Randall, 1987; Viscarello, Cullen, DeGennaro, 8c Hobbins, 1992). In utero infection could occur from transplacental transmission of HIV or of HIV-infected maternal lymphocytes (Maury, Potts, & Rabson, 1989). Around the time of delivery, transmission is thought to take place due to contact with infected maternal blood and tissue, and most perinatal transmission is believed to occur close to the time of childbirth. Postdelivery, breastfeeding has been implicated in transmission of HIV and HIV has been isolated from breast milk (Centers for Disease Control and Prevention, 1998c). Major advances have occurred in preventing HIV transmission from a mother to her child, and transmission rates have decreased to reported lows of 13% in some developed countries (Bryson, 1996). In 1994 results of the AIDS Clinical Trials Group Study 076 were reported. This study demonstrated that perinatal transmission of HIV infection could be markedly (nearly 70%) reduced by the administration of zidovudine to HIV-infected women during pregnancy and delivery and to their infants after birth (Connor et al., 1994). More recently, the CDC has reaffirmed these guidelines and recommended zidovudine in a regimen that might include additional man-

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THE PERSON WITH HIV/AIDS

agement aspects depending upon the woman's illness status, whether or not she had prior therapy, and other factors (Centers for Disease Control and Prevention, 1998c). In addition, it is noteworthy that recent research indicates that even short-term courses of treatment with either zidovudine or nevirapine has been shown to significantly reduce the vertical transmission of HIV (Dobis, Msellati, Meda, Welffens-Ekra, You, Manigart, et al., 1999; National Institute of Allergy and Infectious Diseases, 1999). (See also chapter 11.) These findings are important in efforts to reduce vertical transmission of HIV in developing countries where infected women are often unable to afford lengthy treatment with multiple retroviral agents. In addition to pharmacologic therapy, other measures to decrease perinatal transmission have been suggested based on observed risk factors. For example, an increased risk of perinatal HIV transmission has been reported for first-born twins (possible greater exposure to blood and fluids), duration of ruptured membranes of 4 hours or more, advanced maternal HIV disease, the shedding of cervical virus, low maternal CD4+ T-cell count, maternal viral load, maternal lack of ability to produce autologous neutralizing antibodies, and fetal exposure to blood or trauma during delivery. The premature infant has appeared more vulnerable to infection (Newell, Gray, & Bryson, 1997). Decreased risk has been suggested for caesarean section delivery for which the average risk reduction is said by some to be 20% while others have not found a difference between vaginal and caesarean delivery (Bryson, 1996; Landesman et al., 1996). However, more recent studies suggest that elective caesarean section reduces the risk of mother to child transmission of HIV (European Mode of Delivery Collaboration, 1999; Hudson, 1999; International Perinatal HIV Group, 1999). Therapeutic approaches have included adjustments in obstetric management, such as avoiding scalp electrodes and invasive prenatal diagnosis and using chlorohexidine for vaginal washing before delivery (Bryson, 1996). Vitamin A supplementation has been suggested as a way of reducing perinatal transmission of HIV because HIV depletes vitamin A in some way. Women who had vitamin A deficiency had increased transmission of HIV to infants, and an increase in HIV-DNA has been noted in breast milk (Nduati et al., 1995; Semba, Miotti, & Chiphangwi, 1995). However, this approach needs further evaluation because vitamin A in large doses is teratogenic.

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The strongest data implicating breastfeeding in transmission originally resulted from case reports of women who acquired HIV from postparturn blood transfusions and whose infants were subsequently infected (LePage et al., 1987; Zeigler, Cooper, Johnson, & Gold, 1985). However, other studies have indicated that HIV-infected mothers did not transmit HIV to their infants while breastfeeding (Lifson, 1988). This argument has been resolved with the recovery of HIV-1 DNA from breast milk (Nduati et al., 1995). In developed countries such as the United States, the standard recommendations have been for women to refrain from breastfeeding if they are HIVinfected (Centers for Disease Control, 1985b; Centers for Disease Control and Prevention, 1998f). In developing countries, where perinatal transmission is more prevalent, the restriction on breastfeeding is more complex and can also be a political issue. Breastfeeding had traditionally been advocated by the World Health Organization (WHO) because of concern about infant morbidity and mortality that included an increased risk of infectious diseases, including diarrheal diseases, and poor growth and development (Global Program on AIDS, 1992). Cultural issues in regard to breastfeeding were also at issue, and in addition to an increased disease risk, the purchase of infant formulas represented a financial burden. WHO, United Nations Children's Fund (UNICEF), and UNAIDS support that if safe and affordable alternatives are available, HIV-infected women should not breastfeed. Praetors to consider in the breastfeeding decision in developing countries include the availability of safe water, access to what is needed to prepare sterile feedings, the social implications of not breastfeeding in the culture, affordability, and the understanding of what must be done to prepare safe feedings (Newell et al., 1997). Further complicating the picture is that at present, antiretroviral therapy during and after pregnancy has been recommended for HIV-infected women. Some of these drugs, such as zidovudine, nevirapine, and lamivudine, are detectable in human breast milk when administered to nursing women, and the effects of these on the nursing infant are not yet known (Centers for Disease Control and Prevention, 1998c). Studies suggest that not all HIVinfected mothers transmit HIV to their infants via breastfeeding. A meta-analysis of the literature in this area suggested the average risk has been reported at 30% (Newell et al., 1997). However, one recent study found that the overall postnatal HIV transmission rate for one

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THE PERSON WITH HIV/AIDS

group of infants born to HIV-infected mothers by breastfeeding was about 5% (Leroy et al., 1998). Others have estimated a risk of about 14% to 15% (Dunn, Newall, Ades, & Peckham, 1992; Gray, Maclntyre, & Lyons, 1996). Kuhn and Stein (1997) have pointed out that short-term breastfeeding of under 3 months may allow the advantages of breastfeeding with less of a transmission risk of HIV than longer term breastfeeding would engender. Some children become infected postnatally after maternal antibodies are lost. Thus, early cessation"may prevent these cases (Leroy et al., 1998). In the Ivory Coast (Cote d'lvoire), a recommendation for stopping breastfeeding at 6 months for HIV-infected women has been made. It has also been suggested that HIV transmission in the postnatal period might occur through Langerhans cells of the skin. Cocchi and Cocchi (1988) suggested that infants, because of their thin skin and mucous membranes, might be vulnerable to HIV entry through either intact or denuded skin. Therefore, washing the neonate after birth has been suggested for prevention (Newell et al., 1997). New ways of thinking about infant feeding in developing countries are needed. More information is also needed about vertical transmission and its prevention, especially in developing countries. Other Modes The presence of HIV in body fluids such as saliva and tears has caused concern among the public about the possibility of other modes of transmission, such as kissing, shaking hands, and other casual contacts. For nonsexual contacts of persons with AIDS or persons infected with HIV, the risk for acquiring infection appears very low or nonexistent. Except for those having sexual contact with an infected person, or children born to infected mothers, there is scant evidence of casual or household transmission (Centers for Disease Control and Prevention, 1997c). In one case in which a mother acquired HIV from her infected infant son, she was exposed to numerous secretions and apparently did not always follow recommended precautions (Centers for Disease Control, 1986). Another reported 1986 case suggests that transmission may have occurred between two young siblings via a bite that did not break the skin of the noninfected child (Allen & Curran, 1988). Other cases of apparent

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transmission of HIV during biting incidents with blood presence have been reported (Centers for Disease Control and Prevention, 1997c). In a rare incident, HIV transmission occurred from an HFVinfected dentist to six of his patients (Centers for Disease Control, 1990), and an HlV-infected orthopedic surgeon in France may have infected one of his patients (Lot et al., 1999), but such cases are uncommon. The exchange of saliva during intimate kissing has not been completely exonerated as a route of HIV transmission, although if it exists, its actual occurrence is very rare. Microlesions of the oral mucosa have been demonstrated to occur during passionate kissing (Piazza et al., 1989). A case report of possible transmission in this manner involved the wife of a man who was infected with HIV by blood transfusion and who was impotent but was found to be viremic on one occasion (Haverkos & Edelman, 1988; Salahuddin et al., 1984). It is believed that contact with blood during kissing is needed for transmission of HIV in this manner (Centers for Disease Control and Prevention, 1997d). There may be inhibitory mechanisms in saliva that prevent HIV transmission (Baron, Poast, & Cloyd, 1999). Oro-genital contact has been implicated in the transmission of various viral sexually transmitted diseases including human papillomavirus infection (Cohen et al., 1998). TRANSMISSION AND HEALTH CARE WORKERS Health care workers are exposed to many health and safety hazards in the hospital setting. Many of these involve infectious agents such as HIV, hepatitis A, and hepatitis B. Thus, nurses and other health care workers need to follow recommended safeguards in order to protect themselves and be assertive in being sure that such safeguards are available to them. HIV seroconversion after an accident in the work setting has been a source of concern for health care workers. Early information on this risk came from the CDC Cooperative Needlestick Surveillance group, which consisted of 335 institutions throughout the United States. In the period from August 15, 1983, through April 20, 1989, 1,449 injured health care workers were identified as meeting the study criteria, and 1,172 of these were enrolled in the CDC prospective study (Marcus and the Cooperative

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THE PERSON WITH HIV/AIDS

Needlestick Surveillance Group, 1989). Eighty percent of the injuries resulted from needlestick, 8% from cuts with sharp objects, 7% from contamination of open wounds and 5% from mucous membrane contamination. The overwhelming majority of accidents occurred in the patients' rooms (64%), followed by the intensive care unit (13%). The majority of the health care workers enrolled in this longitudinal study were nurses (63%), followed by physicians (14%). As many as 37% of the exposures were believed to be preventable. The greatest number of the preventable exposures occurred when caregivers either recapped needles or improperly disposed of needles and/or sharp objects. The greatest number of injuries (36%) occurred while manipulating an intravenous, phlebotomy, or arterial needle. Of those health care workers tested at 180 days after exposure, 4 were HIV seropositive, and all of these had received either a needlestick or cut with a sharp object. None of those in this study who had mucous membrane contamination or nonintact skin seroconverted (Marcus and the Cooperative Needlestick Surveillance Group, 1989). Since that time more data have been obtained regarding the risk for health care workers. However, the same basic pattern of the types of objects causing injury remain, and this information should be used in applying prevention and education. It is currently estimated by CDC that the average risk for HIV transmission is approximately 0.3% and 0.09% for percutaneous and mucous membrane exposure to HIV-infected blood respectively (Centers for Disease Control and Prevention, 1998d). Ippolito et al. (1999) estimate risk at below 0.5% for percutaneous or mucous membrane and higher for higher risk exposures. As of June 1997, 52 United States health care workers had documented HIV seroconversion after an occupational exposure to HIV, and an additional 114 were considered as "possible." Of the 52 documented cases, 47 were exposed to HIV-infected blood, 1 to bloody body fluid, 1 to an unspecified fluid, and 3 to concentrated virus in the laboratory. Most exposures (45) were percutaneous, and needles were involved in 41 cases (Centers for Disease Control and Prevention, 1998d). HIV seroconversion was examined, and among those who did seroconvert, 81% had a syndrome like that of primary HIV infection a median of 25 days after exposure; in one analysis the estimated median interval from exposure to seroconversion was 46 days, and the mean was 65 days. These intervals are similar to

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those of persons who acquire HIV infection nonoccupationally (Centers for Disease Control and Prevention, 1998d). It is considered that occupational exposures are underreported (Henderson, 1999). Various factors increase the risk for HIV acquisition after occupational exposure, including exposure to a larger quantity of blood from the source patient, source patients with terminal illness reflecting factors such as the presence of syncytia-inducing strains, and a high viral load, as well as whether the device causing injury was used to enter the patient's blood vessel or had visible blood (Gerberding, 1997). Low viral loads in source patients do not rule out the possibility of transmission. Host factors also influence acquisition of HIV, including immune responses and HIV-specific cytotoxic T lymphocyte (CTL) response when peripheral mononuclear cells in the blood were stimulated in the laboratory with HIV mitogens (Centers for Disease Control and Prevention, 1998d). Current thinking is to try to interrupt or ameliorate HIV infection as soon as possible after exposure. This is presently accomplished through the use of postexposure prophylaxis (PEP) (Buchbinder, 1998). As discussed in chapter 5, it now appears that there is a brief "window of opportunity" that occurs after exposure and before systemic infection. In primate studies, migration of dendriticlike cells containing virus did not occur until 24 to 48 hours after infection. Thus, early counseling and antiretroviral therapy, if chosen, should be accomplished within 24 hours. In one retrospective case control study, the risk for HIV infection among those health care workers who used zidovudine for postexposure prophylaxis was reduced 81% (Cardo et al., 1997). However, failures have also been reported (Jochimsen, 1997). In choosing the regimen that should be followed for PEP, efficacy is one consideration, as is the need for adherence to the regimen; thus, side effects and toxicity are major considerations in maximizing adherence. Employers are required to have exposure control plans, and it is important that health care workers report any exposure immediately. When occupational exposure occurs, the report should include the date and time of exposure, details about what was being performed, details of exposure including duration of contact, amount of fluid or material injected, details about the exposure source or person, and details about counseling, management, and follow-up. After exposure the site should be washed with soap and water immediately (flushed with water for

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THE PERSON WITH HIV/AIDS

mucous membranes). The CDC has a variety of algorithms to follow based on the type of exposure resulting in recommendations for a basic or expanded regimen that also includes consideration of whether the health care worker is pregnant or has any relevant conditions or is taking other medications (Centers for Disease Control and Prevention, 1998d). These are shown in Figures 1.1 and 1.2. Baseline evaluation and HIV testing should be done to establish serostatus at the time of exposure, and subsequent testing at 6 weeks, 3 months, and 6 months is recommended. The basic regimen usually consists of both zidovudine and lamivudine for 4 weeks, while the expanded regimen adds a protease inhibitor, usually either indinavir or nelfinavir, to it (Buchbinder, 1998; Centers for Disease Control and Prevention, 1998d; Gerberding, 1997). NATURAL HISTORY OF HIV INFECTION Much new information about the course of HIV infection has been acquired. Formerly it was believed that after infection with HIV there was a period of latency during which HIV was thought to be quiescent. New knowledge has disproven a period of quiescence, as discussed in chapters 2 and 5. Still, questions remain: Will HIV infection progress to clinical disease and/or AIDS in all cases? What factors influence this progression? Will all who develop AIDS die? After acquisition of HIV, many (but not all) individuals develop an acute illness similar to flu, with symptoms commonly appearing in about 2 to 6 weeks. This initial acute illness represents primary infection and is usually self-limited. After this acute illness, clinically speaking, most persons enter an asymptomatic phase, although in some cases lymphadenopathy may persist or other clinical symptom begin. It is now believed that this postacute period represents a unique opportunity for early treatment. (Primary HIV infection is discussed in chapter 5.) After infection, antibodies to HIV may appear by 3 to 6 weeks and are nearly always present by 3 months postHIV infection, although in some cases seroconversion may take 6 months or longer. This early period, during which the person is infected with HIV but does not demonstrate antibodies, has often been termed the "window period." Rarely, some individuals may not remain HIV seropositive but are still latently infected with HIV

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FIGURE 1.1 Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure: step 1.* Source: Centers for Disease Control and Prevention. (1998). Public health service guidelines for the management of health care worker exposures to HIV and recommendations for postexposure prophylaxis. Morbidity and Mortality Weekly Report, 47(No. RR-7), 14.

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FIGURE 1.2 Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure: steps 2 and 3.* Source: Centers for Disease Control and Prevention. (1998). Public health service guidelines for the management of health care worker exposures to HIV and recommendations for postexposure prophylaxis. Morbidity and Mortality Weekly Report, 47(No. RR-7), 15.

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(Farzadegan etal., 1988). Phases of HIV infection can be conceptualized as the early or acute phase, which lasts for weeks; the middle or chronic phase, which can last for years and during which changes begin to occur; and the final, or crisis, stage, which can last months to years. Another critical question is, What is the time between becoming infected with HIV, developing steadily declining CD4+ cell counts, and manifesting symptoms and conditions, leading eventually to a diagnosis of AIDS? Various observations and projections have been made regarding progression to clinical illness with variations in estimated outcomes. These differences may be due to several factors, including the route by which HIV was acquired; patient factors (e.g., age, immune status, and the presence of other infections), cofactors, viral factors (e.g., the viral dose received and virulence), and assumptions (e.g., estimated rates of disease progression) made in those studies using mathematical models. In examining percentages of HIV-infected persons who progress to AIDS, data also result from observation, mathematical projections, and/or a combination of both. On average, before protease inhibitor therapy, the time between initial infection and the development of AIDS was about 10 to 12 years (Mellors et al., 1996). Persons who acquire HIV infection may be categorized as follows: rapid progressors typical progressors slow or non-progressors Rapid progressors are those whose time between infection and progression to AIDS is within 5 years. Slow progressors are those who will not develop AIDS within 20 years after infection (Mellors et al., 1996). At this time, most researchers believe that the ultimate outcome of AIDS is death. However, the longer that HIV-infected persons can survive without progressing to AIDS, and the longer persons can survive once they develop AIDS, the more hope there is to postpone a fatal outcome. The development, approval, and application of newer drug protocols should contribute to less morbidity and a longer life span. Ongoing vaccine development also holds the potential to prevent HIV infection.

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THE PERSON WITH HIV/AIDS

COFACTORS AND RISK FACTORS IN ACQUISITION AND PROGRESSION While HIV is the etiologic agent of AIDS, other factors may also play a role. Cofactors are elements that may influence acquisition of HIV, efficiency of its transmission, development of specific clinical manifestations of AIDS, disease progression, and/or ultimate survival. Cofactors may act with HIV to modulate clinical expression. Proposed cofactors include those relating to the host, the organism, the environment, and the interaction effect of individual factors. Several factors might act together in producing a common effect, such as subclinical preexisting immune dysfunction occurring because of repeated exposure to antigens; repeated exposure to absorbed semen; exposure to infectious diseases, such as hepatitis B or tuberculosis, as well as chronic infections or parasitic diseases such as malaria; use of immunosuppressant drugs; pregnancy; malnutrition; and genetic susceptibility or even stress. The extent of the importance of such susceptibility factors and determinants remains speculative in many instances. Some factors associated with sexual transmission, such as genital ulcer disease due to both syphilis and herpes simplex virus, have been discussed. The consistent recovery of HIV from genital herpes simplex lesions suggests these lesions increase efficiency of sexual transmission of HIV (Schacker et al., 1998). As discussed in the section on natural history, increased age appears to be a major determinant in rapidity of disease progression. Behavioral factors such as types of sexual practices and the use of drugs and alcohol may play a role. These might act through the induction of immunosuppression or by reducing inhibition resulting in risky behavior. Amyl and butyl nitrites used during anal intercourse may cause vasodilation or may result in more vigorous intercourse and tearing, leading to a higher risk of HIV transmission (Cohen etal., 1998). Various host genes have been noted to play roles both in susceptibility to HIV and in progression to AIDS. The major ones of interest currently are the major histocompatibility genes such as HLA and genes determining receptors for chemokines as well as those for mannose-binding protein. The HLA complex is the major histocompatibility locus in humans and is located on chromosome 6. Meaning ful HLA associations are known for a variety of other diseases, such

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as narcolepsy and ankylosing spondylitis. The exact nature of disease associations and HLA has remained unclear, although various theories exist that are related to the immune system. Persons can possess various combinations of the HLA genes which are present as a haplotype. For a review of HLA, see Lashley (1998). The haplotypes most associated with faster progression to AIDS are HLA Al-Cw7-B8-DR3DQ2 and HLA All-Cw4-B35-DRl-DQl. Association with faster progression to AIDS has also been demonstrated for A23, A24, A26, B21, and B38, whereas delayed progression has been shown for B17, B27, B51, B57, DR4, and DR7. Interactions between tumor antigen protein (TAP) alleles and HLA combinations may take place as well. Genes coding for complement are also in the HLA region. Complement C4A and C4B null alleles result in impaired antibody responses and have been demonstrated to be associated with rapid progression to AIDS (Roger, 1998). SDF1 chemokine gene variants may also influence progression (Maglerowska et al., 1999). In the process of HIV infection, HIV enters the cell by interaction with its viral envelope glycoprotein (gp!20) and cell surface molecules CD4+ and various coreceptors. The most important coreceptors are the (3 (or CC) chemokine receptor, CCR5, expressed mainly in peripheral blood mononuclear cells (PBMC) and macrophages, and the a (or CXC) chemokine receptor, CXCR4 found in PBMC, macrophages and also other tissues and cells (Sol et al., 1997). Some HFV1 strains can use both or additional chemokine receptors such as CCR3 and CCR2b. Some persons have a specific mutation in CCR5 that involves a deletion of 32 nucleotides (532-CCR5) that results in a loss of activity. This mutation occurs in about 1 % of the Caucasian population and is rare in others. Those who are homozygous (have two copies) of this mutant allele appear to be resistant to HFV-1 infection, although there are exceptions to this (Bid et al., 1997; Malo et al., 1998; Roger, 1998; Theodorou et al., 1997). In some studies those who were heterozygous (had one mutant allele and one normal allele) demonstrated slower progression to AIDS and had a slower rate of decline of CD4+ T cells and/or lower viral loads (Phair, 1999). This understanding does not fully explain long-term survival, since the majority of long-term survivors do not have this mu tation. Other mutations of CCR5 may also result in protection (Quillent et al., 1998). A specific polymorphism (CCR2b-64I) apparently does

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THE PERSON WITH HIV/AIDS

not influence susceptibility to HIV infection but may result in slower progression to AIDS in both the heterozygous and homozygous state in both Caucasians and African Americans (Phair, 1999). There may be both independent and interactive effects. Mannose-binding protein activates complement and phagocytosis and is an opsonic factor. Certain variant alleles in the homozygous state appear to confer greater susceptibility to HIV infection (Roger, 1998). Characteristics of HIV itself appear to influence disease progression. HIV is replicating throughout the course of infection, even when the person is clinically asymptomatic; thus, while virus levels in the blood may appear stable, HIV is actually rapidly turning over (Fauci, 1996). The steady state of virus in the blood that is established early in HIV infection predicts rapidity of progression, as discussed in chapter 5. Some other viral factors influencing progression include viral replication, cellular tropisms, cytopathicity, and the propensity to mutate. However, these viral factors interplay with host factors and the environment. Viral replication occurs most efficiently in activated cells; thus, when the immune system is activated with a concurrent infection such as TB or chronic parasitic infections, HIV replication is increased. HIV-inducing cytokine expression also occurs. There are macrophage tropic HIV strains and those that are T cell tropic that do not usually infect macrophages and are usually syncitium inducing. Various strains may influence cell infections, and long-term nonprogressors often show a dominance of M strains (Fauci, 1996). HIV-1 subtypes may also differ in the rate of progression to AIDS (Kanki et al., 1999), but this has not been a consistent finding (Hu et al., 1999). Various studies have examined progression to AIDS in HlV-infected individuals. Some earlier studies had suggested progression differences among exposure categories, whereas others did not (Carre, Deveau, Balange, et al., 1994; Chaisson, Keruly, & Moore, 1995). Recent studies suggest that if age is considered as a covariate, there are no significant differences among various exposure categories in progression to AIDS. Age at seroconversion, however, does appear to be a major factor and more rapid progression has been noted in older individuals regardless of exposure categories or sex (Darby, Ewart, Giangrande, Spooner, & Rizza, 1996; Pezzotti et al., 1996; Rezza, 1998). Other associations with progression is that those who have symptomatic acute primary infections progress faster than

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others and that early antiretroviral treatment retards progression (Rezza, 1998). Kaposi's sarcoma is said to accelerate the clinical course of HIV infection (Brodt, Kamps, Helm, Schofer, & Mitrou, 1998). Among male and female IDUs, progression to clinical AIDS was associated with crack-cocaine use (Webber et al., 1999). STATISTICAL PATTERNS IN THE UNITED STATES By December 31, 1998, 688,200 cases of AIDS had been reported to the Centers for Disease Control and Prevention (CDC). Of these, 679,739 cases occurred in adults or adolescents (13 years of age or over). The number of pediatric (under 13 years of age) cases reported was 8,461. The case fatality rate from before 1981 to December 1998 was about 60%. Among adults, 83.9% of cases occurred i males; among children under 13 years of age, approximately 51.5% were male (Centers for Disease Control and Prevention, 1997b, 1998h). Table 1.5 shows the distribution of cases by age group. A decrease of about 25% in deaths among persons with AIDS in the United States was noted in 1995 and 1996 (Centers for Disease Control and Prevention, 1997b); in 1997 the death rate from AIDS TABLE 1.5 U.S. AIDS Cases by Age at Diagnosis Reported to CDC through December, 1998 Age at diagnosis (years)

Number

Percentage*

Under 5 5-12 13-19 20-29 30-39 40-49 50-59 60+

6,574 1,887 3,423 117,717 310,196 176,239 52,437 19,724

1.0 0.27 0.5 17.1 45.1 25.6 7.6 2.9

Total

688,200

*May not add up to 100.0% due to rounding error. Source; Centers for Disease Control and Prevention. (1998). HIV/AIDS Surveillance Report, Vol. 10, No. 2, 1-43.

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in the United States decreased almost 50%. In 1997 AIDS was the 14th cause of death in the United States (Perlman, 1998). Distribution by exposure category is discussed later in this chapter. The total number of persons living with AIDS has increased and the number of deaths decreased in 1997. These findings have been attributed to the use of combinations of antiretroviral therapy, including protease inhibitors and prophylaxis for opportunistic infections (Centers for Disease Control and Prevention, 1998h). There has not been a concomitant decline in the number of newly diagnosed HIV cases among young people. In 1999 AIDS was the second leading cause of death for Americans between 25 and 44 years of age and is the leading cause of death for African-Americans in this age group (Centers for Disease Control and Prevention, 1998g; Perlman, 1998). Geographic Distribution AIDS has been reported in all 50 states plus the District of Columbia (Centers for Disease Control and Prevention, 1998h). Since the onset of the epidemic, shifts in the geographic distribution of AIDS have occurred. Before 1983, New York, New Jersey, and Pennsylvania reported 63% of all AIDS cases in the United States, whereas as of the end of 1997, they accounted for only about 27% (Centers for Disease Control, 1989; Centers for Disease Control and Prevention, 1998h). As of December 31,1998, the highest cumulative percentage of AIDS cases (both adult and pediatric) was from New York state, which had about 19% of the total number. California reported the second highest, about 16%, followed by Florida (10.2%), Texas (7.0%), and New Jersey (5.6%). Those states having the lowest numbers of AIDS cases were North Dakota, South Dakota, Wyoming, Montana, Vermont, and Idaho. An examination of AIDS annual incidence rates per 100,000 population for states in 1998 reveals that Washington, D.C., had the highest rate, followed by New York, Florida, Maryland, New Jersey, Delaware, Louisiana, Connecticut, South Carolina, and Texas (Centers for Disease Control and Prevention, 1998h). Standard Metropolitan Statistical Area (SMSA) data regarding cases of AIDS by residence showed the greatest cumulative totals in

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1998 reported in New York, Los Angeles, San Francisco, Miami, Washington, D.C., Chicago, Houston, Philadelphia, and Newark. The highest AIDS incidence rates per 100,000 population for 1998 in SMSAs with populations of 500,000 or more were New York (85.9), Miami (73.3), San Francisco (57.6), Fort Lauderdale (55.6), San Juan, Puerto Rico (53.1), and Jersey City (58.9) (Centers for Disease Control and Prevention, 1998h). In some rural areas, HIV and AIDS are increasing, especially in the South (Voelker, 1998). Sex Distribution As of December 31, 1998, the cumulative number of female cases of AIDS reported to the CDC was 109,311, accounting for 15.9% of all reported adult cases. Females also accounted for nearly half of reported pediatric cases. For new cases of AIDS in 1998 in the U.S., women accounted for 23% (Centers for Disease Control and Prevention, 1998h). The rates of AIDS in U.S. women have been rising. Between 1991 and 1995, the number of women reported with AIDS increased by 63%, more than any other group (Wortley & Fleming, 1997). For women, the major exposure category is IDU, accounting for about 43% of reported cases, followed by heterosexual contact (about 39%). When the category of IDU and the subcategory of "sex with IDU" is added, then about 60% of all AIDS cases in women are known to be related to IDU in some way (Centers for Disease Control and Prevention, 1998h). AIDS continues to have a disproportionate impact on minority women. In terms of prevalence, AIDS in women is as follows: Black, non-Hispanic 56.6%; White, non-Hispanic 22.4%; and Hispanic 20.1%; with the remainder in other groups. However, the 1998 AIDS incidence rates for U.S. women show the following: Black, non-Hispanic, 61.6%; Hispanic, 18.7%; and White, non-Hispanic, 18.5%, with the rest distributed as "other" (Centers for Disease Control and Prevention, 1998h). The majority of women with AIDS live in urban areas of the Northeast, but there has been a rapid increase in cases in women who live in the South (Wortley & Fleming, 1997). As discussed below, the proportion of new cases of AIDS in younger women is increasing. These trends indicate directions for future prevention, as discussed in chapter 3. There is no separate category for women who have

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THE PERSON WITH HIV/AIDS

sex with women. Through 1996, of women with AIDS who reported that they had sex only with other women, 97% had another risk factor such as injecting drug use. This supports the proposition that woman-to-woman transmission of HIV is not common. However, education that includes the premise that sexual identity does not always predict behavior must be included in prevention (Centers for Disease Control and Prevention, 1997a).

Age Distribution In regard to age, the peak age range for reported AIDS cases at diagnosis cumulatively for males is 30 to 39 years of age, with abou 86% falling between the ages of 25 and 49 years. For females, the cumulative peak age range is also 30 to 39 years, with about 80% falling between the ages of 25 and 49 years. However, in looking at the year 1997, the proportion of women with AIDS is highest for the age group of 13 to 19, a finding similar to that for men (Centers for Disease Control and Prevention, 1998g). Persons 60 years of age and older account for about 3% of both male and female cases (Centers for Disease Control and Prevention, 1998h). Although this number is small, too often sexual practices in older persons are not discussed. A recent study showed that nearly half of those over 60 years of age engaged in sex at least once a month (Leary, 1998). Older people may also engage in IDU or have greater medical needs involving transfusion or transplant (Cohen, 1995). HIV was reported in a woman of 89 years of age (Rosenzweig & Fillit, 1992). Nonmonogamous sexual relationships are becoming increasingly common in the elderly, and they may not be engaging in safer sex such as condom use (Chiao, Ries, & Sande, 1999). Health care professionals often do not discuss safer sex or assess injecting drug use in elderly patients (Cohen, 1995). As discussed earlier, adolescents may be at particular risk for HIV acquisition. Adolescence is a time of risky behavior and exploring, with a high use of alcohol and experiments with drugs and sex. Data pertaining to adolescents from the Youth Behavior Survey are discussed later in this chapter. Gay adolescents who are first recognizing their homosexuality may engage in more risky behavior, and

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adolescents who are alienated may engage in risky sex in exchange for money for living or for drugs. Racial/Ethnic Distribution The approximate racial composition of the United States is about 72% White non-Hispanic, 12% Black non-Hispanic, 11% Hispanic, and 5% other (U.S. Census Bureau, 6/23/99). However, AIDS cases in adults at the end of 1998 was distributed ethnically as follows: White, non-Hispanic persons, 44.5%; Black, non-Hispanic persons, 36.3%, and Hispanic persons, 18.1%. For pediatric cases of AIDS the distribution was Black, non-Hispanic persons, 58.3%; Hispanic persons, 23.1%; and White, non-Hispanic persons, 17.6% (Centers for Disease Control and Prevention, 1998h). (Pediatric AIDS is further discussed in chapter 12.) For all exposure categories, reported persons with AIDS in the United States are disproportionately Black and Hispanic. These differences have been attributed to such factors as nutritional status and social and economic conditions (e.g., access to quality health care) rather than race per se. When examined by exposure categories, there is particular disproportion in the category of injecting drug use for both men and women, with Black nonHispanic persons accounting for 53.3%, Hispanic persons for 26.0%, and White, non-Hispanic persons for 20.0% of individuals with AIDS in this category at the end of 1997 (Centers for Disease Control and Prevention, 1998h). It has been suggested that this reflects higher prevalence of injecting drug use in these same ethnic groups. For men who have sex with men (MSM), the racial/ethnic distribution at the end of 1997 was as follows: White, non-Hispanic persons, 63.0%; Black, non-Hispanic persons, 22.2%; and Hispanic persons, 13.4%, with others comprising the rest. In the category of heterosexual transmission at the end of 1997, the racial/ethnic distribution was also disproportional and was as follows: Black, non-Hispanic, 55.7%; Hispanic, 22.5%; and White, non-Hispanic, 20.7%, with the remainder comprised of others (Centers for Disease Control and Prevention, 1998h). New cases of HIV infection in the categories of MSM, IDU, and heterosexual contact appear to be occurring at disproportionately higher rates in minorities. The annual adult AIDS incidence rates per 100,000 by racial/ethnic group overall for 1998

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were Black, non-Hispanic, 84.7; Hispanic, 37.8; White, non-Hispanic, 9.9; Asian, Pacific Islander, 4.8; and American Indian/Alaska Native, 9.7 (Centers for Disease Control and Prevention, 1998h). These data are useful in planning prevention programs. WORLDWIDE STATISTICS AND PATTERNS As of the end of 1998, about 33.4 million people worldwide were living with HIV/AIDS (UNAIDS/WHO, 1999). For many countries in the world, the reporting of AIDS may be less than reliable, and the definitions used to define AIDS may vary; however, accuracy has increased over the years. Of the 33.4 million people currently estimated to be living with HIV/AIDS, the distribution is as follows: Adults: 32.2 million Women: 13.8 million Children under 15 years of age: 1.2 million Worldwide, about 13.9 million persons, including 3.2 million children, have died of AIDS since the beginning of the epidemic. The number of AIDS orphans (children who lost their mother or both parents to AIDS when they were under the age of 15 years) since the beginning of the epidemic is about 8.2 million. When the worldwide AIDS epidemic was first examined, various geographic patterns were described on the basis of predominate exposure categories seen. These are not currently used, because the spread of the epidemic is complicated even within continents. Nearly 90% of people with HIV live in sub-Saharan Africa or Asia (UNAIDS/WHO, 1999). The toll has been tremendous, particularly in the developing countries of Africa, Asia, and Latin America. The worldwide AIDS statistics are shown in Table 1.6. The number of people living with HIV/ AIDS is shown in Table 1.7. Asia did not experience a major HIV epidemic until the late 1980s. As of June 1998, the greatest number of Asian AIDS cases has been reported by Thailand, followed by India, Myanmar (formerly Burma), Japan, Malaysia, and Vietnam (World Health Organization, 1998). The total number of AIDS cases for Asia reported to the World Health Organization as of June 1998 was 101,429. The distribution of

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TABLE 1.6 Reported AIDS Cases Worldwide as of June 20, 1998 Area Africa Americas Asia Europe Oceania Total

Number 686,256 889,465 101,429 107,890 8,744 1,893,784

Source: World Health Organization. (1998). Global AIDS surveillance. Weekly Epidemiological Record, 73, 193-200.

TABLE 1.7 Adults and Children Living with HIV/AIDS Worldwide, December, 1998 Region

Number

Sub-Saharan Africa North Africa & Middle East South & South-East Asia East Asia & Pacific Latin America Caribbean East Europe & Central Asia Western Europe North America Australia & New Zealand

22.5 million 210,000 6.7 million 560,000 1.4 million 330,000 270,000 500,000 890,000 12,000

Total

33.4 million

Source: UNAIDS/WHO. AIDS epidemic update: December, 1998. UNAIDS Joint United Nations Programme on HIV/AIDS, 1-17.

these cases by transmission category varies by country. For example, in Thailand, about 75% of cases fall into the heterosexual transmission category, as do about 85% of cases in Laos, 78% of cases in India, and 77% in the Republic of South Korea. In China, about 53% are reported as due to IDU, as are about 71% in Myanmar, all in Vietnam, and 44% in Malaysia. The classification of "homosexual" is applied to about 52% of cases from Hong Kong, 51 % in Indonesia, 56% in Singapore, 37.1% in the Philippines, and 23.5% in Malaysia

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THE PERSON WITH HIV/AIDS

(Li & Yeoh, 1996). India is said to have about four million people living with HIV, the largest number of HFV-infected persons of any country in the world. HIV prevalence varies across India. In Pondicherry, the rate of HIV infection in pregnant women was about 4%. A study of HIV prevalence in truck drivers in Madras showed an increase from 1.5% in 1995 to 6.2% in 1996. In Thailand, in 1996, about 2.3% of adults were estimated to be HlV-infected. The incidence of HlV-infection among sex workers appears to be falling in part due to educational measures, but among IDUs the prevalence has stabilized at about 40%. In studies of HIV prevalence in Cambodia, the following were found: 1 in 30 pregnant women, 1 in 16 soldiers and police, and almost 1 in 2 sex workers tested HIV positive. In Myanmar, HIV infection among sex workers in 1996 was about 20%, and about two thirds of that country's IDUs are HlV-infected (UNAIDS/WHO, 1998). In the Americas, about 890,000 cases were reported as of June 20, 1998. Without including the United States, this total is 248,417 (World Health Organization, 1998). The country reporting the highest number of cases was Brazil, followed by Mexico, Argentina, Colombia, Canada, Honduras, and Haiti. The incidence rate per 100,000 for 1996 was highest in the Bahamas (1,335.7), French Guiana (478.1), Jamaica (213.8), Grenada (190.9), Guyana (170.6), Antigua and Barbuda (168.8), Dominica (168.7), Honduras (137.0), Barbados (494.3), Belize (171.9), and Brazil (101.3). Looking by region, the highest incidence is for the Caribbean (246.2), followed by Central America (75.6). There are variations seen in transmission categories by subregions. Homosexual transmission is highest in the Andean area (58.7%), followed by Mexico (55.8%). IDU is highest in the southern cone (29.3%). Heterosexual transmission is highest in the Caribbean region (77%), followed by Central America (64%) and the Andean area (34.8%) (Cohen et al., 1998). In Brazil, about 20% of the HlV-infected adults are women, and about half of IDUs are HlV-infected, as is also seen in Argentina. In Haiti and the Dominican Republic about 8% of all pregnant women are HIVinfected (UNAIDS/WHO, 1998). Western European countries, Canada, Australia, and New Zealand share many commonalities in the patterns of HIV infection. As a group, the largest proportion of cases was among homosexuals, while the second greatest percentage was among IDUs. Within most

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countries in western Europe, among the earliest diagnosed cases, a high proportion originally lived in central Africa or Haiti (Centers for Disease Control, 1985b; Mann et al., 1988). Overall in western Europe, new HIV infections appear to be decreasing, as evidenced by a 38% drop in 1997 (Harriers, Downs, Infuso, & Brunet, 1998). Many new infections are concentrated among IDUs in southern Europe in countries such as Greece and Portugal. In 1997 fewer than 500 children were newly infected with HIV (UNAIDS/WHO, 1998). In Europe, the highest number of cases of AIDS is reported in Spain, closely followed by France and Italy (World Health Organization, 1998). The incidence rate is highest in Spain, followed by Italy, Portugal, France, and Switzerland. In Australia, most (nearly 90%) of AIDS cases remain reported among homosexual/bisexual men; this is true for Canada as well (71%). Within western Europe there are regional differences. In northwestern European countries, AIDS has remained mostly in the homosexual/bisexual male population, whereas France and Switzerland report nearly equal proportions between MSM and IDU categories. IDUs and heterosexual contact are more important modes in Spain, Italy, and France. Within countries there may also be variation. For example, in Italy the prevalence of HIV infection among IDUs at one time was higher than 70% in Milan but never exceeded 10% in Naples (Hamers et al., 1998). In eastern Europe, low rates of HIV infection existed until 1994. But this has drastically changed. For example, in the Ukraine in 1994, 44 people were reported to test positive for HIV. By 1997, 15,000 new HIV infections were identified. In eastern Europe, most HIV infections are currently concentrated among IDUs. However, various signs point to the potential heterosexual spread of HIV. For example, a dramatic rise has been noted in sexually transmitted diseases (STDs), and in Kaliningrad, one third of the sex workers were IDUs. Four out of five women testing positive for HIV disease at the registered AIDS center were sex workers (UNAIDS/WHO, 1998). Spread among IDUs has also been high in Poland. There have been several exceptions to the current patterns. For example, Romania experienced nosocomial spread through the use of improperly sterilized needles and syringes, and about 10,000 children were infected (Hamers et al., 1998). Both HIV-l and HIV-2 infection are seen in Africa. HIV-2 is largely confined to western Africa. HIV is presently considered endemic in

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central Africa, and about 70% of the worldwide cases of AIDS occur in sub-Saharan Africa. In Francistown, Botswana, 43% of pregnant women tested HIV positive in 1997. In the Cote d'lvoire, Djibouti, Central African Republic, and Kenya, 1 in 10 adults live with HIV. In Botswana, Namibia, Swaziland, and Zimbabwe, between 20% and 26% or persons aged 15-49 years are living with HIV/AIDS. Nigeria has an estimated adult prevalence of 4.1%, or 2.2 million HFVinfected persons. Uganda, which has been extremely active in education and counseling programs, has shown a decrease in HIV prevalence rates over time (UNAIDS/WHO, 1998, 1999). The impact of AIDS has been severe, and many medical units in hospitals are largely filled with persons with AIDS. AIDS in Africa and in other developing countries such as the Caribbean has the following characteristics: 1. Heterosexual contact seems to be the major mode of transmission. 2. Males and females are affected in nearly equal ratios. 3. Perinatal transmission is common, leading to larger numbers of HIV-infected children than are seen elsewhere. Cultural, social, and political events may have had an impact on AIDS in Africa. Factors, such as the weakening of traditional family structures, the emigration of young persons from rural to urban areas, and prostitution as a way to earn a living, all have had an impact (Pela & Platt, 1989). In some areas, HIV infection patterns follow the path of the major trucking routes. However, some researchers claim that cultural and social changes that differed from traditional village practices actually occurred decades ago and are not relevant to the spread of HIV (Vail, 1988). Cultural practices that might contribute to the type of HIV infection pattern seen in Africa have been discussed by anthropologists. For example, some anthropologists have explained the heterosexual spread by postulating a culturally normal period of homosexuality among young central African males before marriage (Weber, 1984). It is also possible that the practice of female genital mutilation practiced in some cultures may result in tearing and bleeding during vaginal intercourse and recourse to anal intercourse, thus allowing contact with blood during intercourse among heterosexuals in Africa. Other practices that have been proposed to contribute to HIV

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infection in Africa have been "blood brotherhood" rituals, medicinal blood letting and use of unsterile needles, shared instruments, ritual scarification, genital tattooing, and group circumcision. To date, heterosexual transmission with a higher frequency of sexually transmitted diseases and a greater number of partners seems to be the most important factor in transmission (UNAIDS/WHO, 1998). Yet little is known about sexual behavioral patterns in many of the ethnic groups in Africa (Larson, 1989). In examining Africa in a cultural perspective, one must take into consideration the fact that Africa consists of many different countries with different cultures and subcultures. African women have been heavily affected by HIV. Four of five HFV-infected women live in Africa, as do about 87% of HFV-infected children. There are several reasons noted for the high proportion of HlV-infected children in Africa: 1. The large number of HlV-infected women of childbearing age. 2. African women have more children on the average than women in other countries, so an infected woman may pass HIV to more children. 3. Most African children are breastfed, and breastfeeding accounts for a substantial proportion of vertical transmission of HIV. 4. Drugs that can reduce perinatal HIV transmission are less accessible in Africa and in other developing countries than in industrialized ones (UNAIDS/WHO, 1998). It has been difficult to collect accurate data in many countries, and therefore accurate information is still somewhat limited, especially from developing countries. Cooperation has increased, however, and in 1998, 197 countries contributed data (World Health Organization, 1998). There remain many disparities in the HIV epidemic across the world in regard to the availability of HIV education, counseling, testing, and state-of-the-art treatment. EXPOSURE CATEGORIES FOR AIDS Terminology to describe epidemiological groupings of AIDS cases has undergone various transitions over the years. Since the switch

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in March 1989 by the CDC to a monthly, instead of a weekly, update on AIDS cases, epidemiologic data reporting formerly entitled "transmission categories" became known as "exposure categories." This change superseded a previous revision that occurred in August 1986, when the hierarchy of risk factors for AIDS was revised and entitled "transmission categories" instead of "patient groups." The single exposure categories are still ordered in a hierarchical, mutually exclusive manner; thus, cases with multiple characteristics who belong in more than one exposure category are assigned to the group that is listed first. In hierarchical order in adults/adolescents, these currently are men who have sex with men; injecting drug use; men who have sex with men and inject drugs; hemophilia/coagulation disorder; heterosexual contact; receipt of blood transfusion, blood components, or tissue; and other risk not reported or identified. AIDS cases are also now reported by risk factor combinations as well as by single risk factors (Centers for Disease Control and Prevention, 1998h). By slightly changing the terminology used, behaviors were more emphasized rather than membership within a certain group. The distribution of all adult and adolescent (age 13 years and over) cases of AIDS according to these categories is shown in Table 1.8. Exposure categories for pediatric cases, in hierarchical mutually exclusive order, currently are as follows: hemophilia/coagulation disorder; mother with/at risk of HIV infection; receipt of blood transfusion, blood components, or tissue; and risk not reported or identified (see Table 1.9; Centers for Disease Control and Prevention, 1998h). Among the major changes that have occurred over time in exposure categories were the removal of Haitians as a separate group in 1985; the change in terminology for male homosexual/ bisexual contact to men who have sex with men; the addition of the group known as heterosexual contacts (also called "cases" at various times); the change from IV drug use to injecting drug use; the inclusion of other coagulation disorders to the group originally designated as hemophilia A, and the renaming of the "none of the above" group to "other/undetermined," and eventually to "risk not reported or identified." The separate category of male homosexual/bisexual contact who were also intravenous drug abusers was added in August 1986, and later the title was changed to men who have sex with men and inject drugs. For a period of time Haitians were considered to be a distinct high-risk group for the development of AIDS, but

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TABLE 1.8 United States Adult/Adolescent AIDS Cases by Exposure Category as Reported to CDC through December, 1998 Adult/adolescent exposure categories

Number

Percentage*

Men who have sex with men Injecting drug use Men who have sex with men and inject drugs Hemophilia/coagulation disorder Heterosexual Sex with injecting drug user Sex with bisexual male Sex with person with hemophilia Sex with transfusion recipient with HIV infection Sex with HIV infected person, risk not specified Recipient of blood transfusion, blood components, or tissue Risk not reported or identified

326,051 173,693 43,640 4,911 66,490 26,246 3,132 429 935

48.0 25.6 6.4 0.73 9.8 3.9 0.46 0.06 0.14

35,748

5.3

8,382

1.2

56,572

8.3

Total

679,739

Source: Centers for Disease Control and Prevention. (1998). HIV/AIDS Surveillance Report, Year-end edition, Vol. 10, No. 2, 1-43. *May not add to 100.0% due to rounding error.

Haitians have been moved in regard to epidemiologic group placement. In 1985, when they were removed as a separate risk group, they were placed into the "other/none of the above" group. In August 1986 they were placed into the heterosexual cases category, now called "heterosexual contact"; eventually they were categorized in the same manner as other persons. In 1985 it was stated that it does not appear that "being of Haitian extraction by itself, in isolation from other risk factors, increases the relative risk of being exposed to HTLV-III" (Landesman, Ginzburg, & Weiss, 1985). Information about each exposure category is discussed below. MEN WHO HAVE SEX WITH MEN (MSM) There are about 1.7 million homosexual and bisexual men in the United States (Holmberg, 1996). AIDS was first identified among

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TABLE 1.9 Pediatric AIDS Cases in the United States as Reported to CDC through December, 1998 Pediatric (< 13 years) exposure categories

Number

Percentage*

Hemophilia/coagulation disorders Mother with/at risk for AIDS/HIV infection: Injecting drug use Sex with an injecting drug user Sex with bisexual male Sex with person with hemophilia Sex with transfusion recipient with HIV infection Sex with HIV-infected person, risk not specified Receipt of blood transfusion, blood components, or tissue Has HIV infection, risk not specified Receipt of blood transfusion, blood components, or tissue Risk not reported or identified

234 7,687 3,032 1,400 165

2.8 90.8 35.8 16.5 2.0 0.34 0.30

Total

8,461

29 25 1,137

13.4

154

1.8

1,745 378

20.6 4.5

162

1.9

Source: Centers for Disease Control and Prevention. (1998). HIV/AIDS Surveillance Report, Year-end edition, Vol 10, No. 2, 1-43. *May not add to 100.0% due to rounding error.

homosexual men presenting with Kaposi's sarcoma and Pneumocystis carinii; pneumonia (Centers for Disease Control, 1981a, 1981b). In 1982 the CDC reported the occurrence of unexplained persistent generalized lymphadenopathy among homosexual males. It was recommended that such individuals be followed periodically (Centers for Disease Control, 1982a). Other clinicians noted the occurrence of such a syndrome as early as 1977 in some regions and 1979 in others (Abrams, Lewis, Backstead, Casavant, & Drew, 1984; Miller et al., 1984). A cluster of cases of autoimmune thrombocytopenic purpura in homosexual men was diagnosed in New York after November 1980. These reports suggested that sexually active homosexual men might be developing disorders of immune regulation (Morris, Distenfeld, Amorosi, & Karpatkin, 1982). Why AIDS first surfaced in large numbers among the homosexual population is not known. The first appearance of AIDS in recogniz-

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able proportions among this group, however, provoked varying public reactions from lack of interest to condemnation to accusations to feelings that it was deserved. Persons in this exposure category, men who have sex with men (MSM), still comprise the largest percentage of cases of adult AIDS in the United States. As of December 31, 1998, MSM accounted for about 48% of the total adult cases of AIDS in the United States, and the category of "MSM and inject drugs" accounted for about another 6%, totaling about 54% (Centers for Disease Control and Prevention, 1998h). Studies to identify risk factors for HIV infection identified large numbers of different male sexual partners as the most important risk factor for HIV acquisition. In regard to the sexual practices studied, the ones most frequently associated with increased risk for infection were frequent receptive anal intercourse and "fisting" (a practice involving the insertion of a hand or fist into the rectum) (Vermund, 1997). These studies have provided important information for the development of educational programs and counseling geared at prevention, as described in chapter 3. Many homosexual males, especially in California and New York, became leading activists in the field of AIDS. Their extensive efforts in education and prevention of HIV infection have apparently had notable success. These have involved changes in behavior, including less promiscuity and increased condom use (Martin, 1987). Others are less optimistic about the success of behavioral interventions. Initially, MSM were demonstrating safer sexual behaviors. But by the 1990s younger homosexual men were noted to have higher levels of sexual risk taking (De Wit, 1996). In a report from San Francisco of homosexual men between 18 and 29 years of age, an HIV prevalence of about 18% was found and 27% of the group said they had unprotected anal sex in the year before participating in the study (Cohen et al., 1998; Osmond et al., 1994). A study reporting on about 2,100 homosexual men ages 15 to 22 years across the United States found a median HIV prevalence of 7%; in a Boston study, 26% of White male homosexuals reported unprotected anal sex (De Wit, 1996). In the Young Gay Men's Cohort study in the Netherlands, there was a 4.3% HIV prevalence; 38% reported that they engaged in unprotected anal sex in the six months before the study began (De Wit, 1996). While homosexual men are well educated about HIV, their behavior does not always reflect the understanding of risk

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factors. Reasons have been attributed to the person's social norms, perceived attitude toward the behavior, and their assessment of whether they can carry out the particular behavior (de Wit, 1996). Thus, many preventive efforts are focusing on young homosexual men, as discussed in chapter 3. Clinically, Kaposi's sarcoma has a far greater prevalence among homosexuals with AIDS than in other groups, although it has been reported in all exposure categories. This is at least partly due to the fact that KS is caused by a herpes virus that is transmitted sexually (see chapter 5). Injecting Drug Use (IDU) In 1991, the CDC changed the terminology from "intravenous drug use" to "injecting drug use" to describe the use of needles for selfinjection of drugs not prescribed by a physician. These include those who share needles and apparatus, skin pop, and take unprescribed anabolic steroids, vitamins, or other medications by injection. It is estimated that about 36% of all cases of AIDS reported in 1997 were directly or indirectly associated with IDU (Centers for Disease Control and Prevention, 1998f). Furthermore, heterosexual partners of IDUs accounted for about 40% of the cumulative total cases in the exposure category of heterosexual contact at the end of 1998. Injecting drug use in females and heterosexual males accounts for about 26% of adult AIDS cases, whereas use in the category of MSM/IDU is approximately 6%, as shown in Table 1.8 (Centers for Disease Control and Prevention, 1998h). The highest rates of IDU-associated AIDS cases were in the Northeast, Puerto Rico, and Miami (Holmberg, 1996). AIDS in IDUs appears to have disproportionately affected Blacks and Hispanics. Of the AIDS cases in IDUs reported to CDC as of December 31, 1998, about 53% occurred in Black, non-Hispanic persons and about 26% were Hispanic (Centers for Disease Control and Prevention, 1998h). In the Youth Risk Behavior Study, 2.1% of adolescents surveyed said they had injected illegal drugs in their lifetime, and 8.2% used some form of cocaine (Centers for Disease Control and Prevention, 1998f). This distribution adds to the social challenge of HIV-infection in IDUs. IDUs represent, however, a heterogenous group of people whose behaviors vary, a

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fact that influences both seroprevalence rates and the success of intervention strategies. IDU accounts for 44% of reported AIDS cases in Europe. Countries reporting rapid increases in HIV infection among IDUs include Ukraine, Vietnam, northern Thailand, and Vancouver. Higher numbers of IDUs are found in countries where drug traffic is heavy, such as southeast Asia, western Africa, parts of South America, and Myanmar (Burma), and in some Middle Eastern countries, such as Iran. Areas of high IDU are at risk for outbreaks of HIV and other viral diseases such as hepatitis B and hepatitis C. However, it has been noted that HIV may spread rapidly among IDUs for a time, such as was seen in Edinburgh, Scotland, in the early 1980s, then decrease and become more stable (Strathdee et al., 1998). In addition to comprising the second-largest exposure category for AIDS, IDUs are considered a bridge to heterosexuals and to HlV-infected children. Of the AIDS cases associated with perinatal transmission reported through 1997, mothers who injected drugs or their sexual partners accounted for nearly 58% of the cases reported (Centers for Disease Control and Prevention, 1998h). The CDC (1998d, 1998f) estimated that the risk for HIV transmission per episode of IV needle or syringe exposure is 0.67%. Many drug abusers share drug paraphernalia with others and often use unsterilized, contaminated needles and syringes. It is currently believed that AIDS is transmitted among drug users through the transfer of small amounts of blood during the sharing of needles, syringes, or other drug-related apparatus such as cookers, water used to prepare injections, and cotton (Strathdee et al., 1998). The latter three may initially become contaminated through the use of contaminated syringes (Jones & Vlahov, 1998). In addition, some of the substances that drug users use have been shown to have intrinsic immunosuppressive properties, which may enhance the effects of HIV. IDUs often inject themselves with drugs, some more than 1,000 times per year (Centers for Disease Control and Prevention, 1998F). This behavior is not compatible with using clean needles. In one report, those IDUs who were HIV seropositive were more likely to have injected drugs daily and shared needles with 4 or more persons. Many of the HIV seropositive group (41.5%) reported having no sexual partners in recent months, possibly due to diminished libido;

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34.2% reported 11 or more partners, possibly because they were exchanging sex for drugs (Raymond, 1988). A study reported by researchers in New York showed that IDUs infrequently sterilized their works, although recognizing the risk of HIV infection. There were several reasons for this. These included strong and immediate desires to use drugs, believing their friends "would be insulted" if they sterilized equipment, inadequate sterilization techniques when they were used, choosing a partner whom they believed was "safe," economic pressures, not owning or wanting to carry drug-injecting equipment with them, and desires to please their partner (particularly in women) (Magura et al., 1989). Those who had been incarcerated were more likely to share syringes. In one study involving 12,323 IDUs in 19 sites in the United States, McCoy, Metsch, Chitwood, Shapshak, and Comerford (1998) found that 42.0% did not use needles, syringes, cookers, cotton, or water used by another IDU, but only 12.6% used new needles or syringes. In another study, Diaz et al. (1998) found that those who knew they had been infected with HIV for more than a year were less likely to share drug apparatus than those who knew about it one year or less. In one study in New York City, HIV prevalence was 11% among those who had been injecting 1 to 3 years and 18% for those injecting 4 to 6 years. Those who were more likely to be HIV-infected were African Americans, Hispanics, females, and men who engaged in male to male sex (Des Jarlais et al., 1999). Preventive activities with injecting drug users have been difficult. Drug users tend to be a less conspicuous group than the other groups at high risk for the development of AIDS. They tend not to have advocates in the general population, nor do they generally form advocacy and support groups among themselves. New York state researchers from the Division of Substance Abuse Services found some impediments to prevention that included limitations on the perception of risk by such individuals due to the long latency period in the development of severe AIDS, the difficulty in distinguishing AIDS from other narcotic-related deaths, and the ambiguity of some of the symptoms of AIDS. In addition, needle sharing may have associations with communal feeling and socialization in the drug subculture (Black et al., 1986). There are also economic motivations for sharing injection equipment. Syringe exchange programs have proliferated in the United States and Europe. There are 113 pro-

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grams in the North American Syringe Exchange Programs. Many of these programs not only offer needle and syringe exchange but also offer other services such as HIV counseling and testing, TB testing, STD screening, and primary health care. IDUs participating in these programs increase the proportion of sterile syringes used for singleuse injections, thus decreasing potential contamination. IDUs participating in these programs have lower rates of HIV incidence compared to other IDUs (Centers for Disease Control and Prevention, 1998f). Another approach is to allow the purchase of sterile syringes over the counter in pharmacies, as is done in Connecticut. One concern has been injury, especially to children, from improperly disposed of needles and syringes. A variety of community-based programs have been developed to address this (Jones & Vlahov, 1998). Others have proposed the use of single-use or difficult-to-reuse syringes to decrease multiple use (Desjarlais, 1998). Multiple drug and alcohol use is common to persons who are IDUs, and some unique clinical characteristics have been noted. Clinically, a broader range of opportunistic infections are seen in IDUs with AIDS than in other groups. Particularly frequent infections noticed are STDs, bacterial pneumonias, bacterial endocarditis, and tuberculosis (Contoreggi, Rexroad, & Lange, 1999) (see chapter 5). Furthermore, lower socioeconomic status and malnutrition may contribute to poor general health, affecting clinical presentation. IDUs may also be less likely to seek health care. IDUs can be difficult for health care professionals to care for because of their negative feelings toward them. In a study of registered nurses across the United States, Cohen, Durham, and Smith (1988) found that negative and neutral feelings reported by respondents were 69.3% and 22.9%, respectively, with only 7.8% reporting positive feelings. Hemophilia/Coagulation Disorder In July 1982 the CDC first published reports of three cases of Pneumo cystis carinii pneumonia (PCP) among three hemophiliacs who had no other underlying disease. The first case was identified in January 1982, and the others were found through surveillance of the use of drugs to treat PCP. All were heterosexual without a history of intravenous drug abuse, and all had received factor VIII concentrates

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(Centers for Disease Control, 1982b). As of December 31, 1998, the CDC had received reports of 4,911 adult and 234 pediatric cases of AIDS in persons with hemophilia or another coagulation disorder, representing about 1% of the adults with AIDS and about 3% of children with AIDS (Centers for Disease Control and Prevention, 1998h). Of these, the majority had hemophilia A, whereas the rest had hemophilia B, von Willebrand disease, or other blood coagulation defects. Hemophilia A or factor VIII deficiency is a genetic disorder of blood coagulation that is inherited in an X-linked recessive manner and is the classical type of hemophilia. Hemophilia B (Christmas disease) is a genetic disorder due to deficiency of clotting factor IX. It is also inherited in an X-linked recessive manner. It is only about one fifth as frequent as hemophilia A (Lashley, 1998). They are nondistinguishable clinically. Hemophilia B tends to be somewhat less severe than hemophilia A. Von Willebrand disease is a genetic disorder of coagulation that is usually inherited in an autosomal dominant manner but may also be inherited in other ways. Part of the management of these disorders includes the administration of clotting factors. Pooled plasma was traditionally used in making these clotting factor concentrates, and each vial could contain material from between 2,500 and 25,000 blood or plasma donors (Levine, 1985). The majority of persons with hemophilia in the United States became HIV seropositive between 1979 and 1982 and before 1985, when the screening of donated blood was implemented and the prevalence of HIV infection in adults with hemophilia A and hemophilia B was about 80% and 50%, respectively, of those who had been treated with factor concentrates (Rosenberg & Goedert, 1998). Older hemophiliacs have been more likely to be HIV-infected. Most of this group became infected with hepatitis C as well. Although the total case number of AIDS is small in persons with coagulation disorders, it does represent an important cause of mortality for this group. AIDS now exceeds hemorrhage as the leading cause of death among hemophiliacs (Pierce et al., 1989). Not using coagulation factor concentrates, however, would mean a return to the preclotting factor concentrate days, when death due to hemorrhage caused hemophiliacs to have a life expectancy that was less than half that of unaffected persons (Levine, 1985) and bleeding into joints

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caused considerable morbidity (Cahill & Colvin, 1997). Viral inactivation techniques using heat and other methods have been developed. The cloning of the factor VIII gene allowed recombinant factor concentrates and monoclonally purified concentrates to be developed. Recombinant factor IX concentrates have become available more recently (Cahill & Colvin, 1997). Sexual partners of hemophiliacs are at increased risk for HIV infection through sexual activity. Various education programs have been introduced in hemophilia treatment centers to prevent spread by this method. Reported cases of AIDS resulting from sex with a person with hemophilia or a coagulation disorder accounted for only 0.65% of cases within the heterosexual contact category and 0.0063% of the total adult cases of AIDS in the United States (Centers for Disease Control and Prevention, 1998h). In one study of male hemophiliacs between the ages of 12 and 24 years, self-reported sexual behavior in the past 6 months revealed that 13% had intimate touch only, 21% had intercourse always with condoms, and 13% had unsafe intercourse. The rest did not report sexual activity in that time period. Thus, 87% of this group abstained or had safer sex. The "unsafe sex" group was older and more angry and anxiou than the others (Remafedi, Parsons, Schultz, & Schulz, 1997). In other studies, only about 20% of female sex partners of hemophilic men with HIV infection became infected. Those who did had partners with higher viral loads than those who did not (Ragni, Faruki, & Kingsley, 1998). Clinically, there are some aspects particular to the hemophilia group. KS and lymphomas are rare in persons with hemophilia. Most (about two thirds) present with Pneumocystis carinii pneumonia, followed by esophageal candidiasis and extrapulmonary cryptococcosis (Cohen, Sande, & Volberding, 1998). HIV-infected persons with hemophilia A with antibodies against factor VIII and persons with hemophilia B showed faster progression to AIDS than did HIV-infected persons with hemophilia B (Roosendaal et al., 1999). Heterosexual Contact This group includes all individuals who do not fit into one of the exposure categories listed first in the hierarchy (men who have sex

54

THE PERSON WITH HIV/AIDS

with men, injecting drug use, men who have sex with men and inject drugs, hemophilia/coagulation disorder). The following subcategories have been identified: (1) sex with injecting drug user; (2) sex with bisexual male; (3) sex with person with hemophilia; (4) sex with transfusion recipient with HIV infection; (5) sex with HIVinfected person, risk not specified. As of December 31, 1998, there were 66,490 reported adult AIDS cases in the heterosexual contact category, representing about 10% of the total adult cases. Of these, the largest subcategories were sex with "HIV-infected person, risk not specified" (35,748, or 53.8% of the cases in this category) and injecting drug user (26,246 cases, or 39.5% of the cases in this category) (Centers for Disease Control and Prevention, 1998h). (See Table 1.8.) There is racial/ethnic disproportion in this category, as described earlier. Geographically, the majority of cases in the heterosexual exposure category are concentrated in four states— New York, Florida, New Jersey, and California. In January 1983 the CDC published two cases of women with immunodeficiency who were the sexual partners of men with AIDS. One of these men was an intravenous drug abuser and one was a bisexual. The women themselves had no recognized risk factors (Centers for Disease Control, 1983a). Other cases began appearing in the literature (Harris et al., 1983), including the report of a previously healthy 71-year-old wife of a 74-year-old hemophiliac who developed Pneumocystis carinii pneumonia, developed AIDS, and died. Her only apparent risk factor was infrequent sexual contact with her husband when he was asymptomatic (Pitchenik, Shafron, Glasser, & Spira, 1984). Varying percentages of regular sexual partners of HIV-infected persons show evidence of HIV infection depending upon the study and factors related to the host (e.g., viral load) and the virus as well as whether there has been proper and consistent use of barrier protection. As with homosexual men, receptive anal intercourse may place women at increased risk, as discussed earlier, but HIV may be transmitted by both vaginal and anal intercourse (Cohen et al., 1998; Vermund, 1997). Although most of the initial reports emphasized the transmission of disease from males to females, it is bidirectional. In addition, cervical and vaginal tissues and secretions have been shown to contain HIV.

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Heterosexual contact is an important exposure category for women. Females account for about 65% of all AIDS cases in this classification, and heterosexual contact is the second highest exposure category for women (IDU is first) (Centers for Disease Control and Prevention, 1998h). The category of heterosexual contact is complex. Women may be exposed to HIV through trading sex for drugs, money, or protection or may be unaware of, or choose to ignore, their partners' risky sexual practices such as promiscuity, IDU, or bisexuality for many reasons (Cohen & Durham, 1995b). Men may also be unaware of their partners' risky sexual activities. Men who seek sexual gratification with a commercial sex worker have a greater risk of acquiring HIV infection. Preventive efforts as discussed in chapter 3 focus on education, the proper and consistent use of condoms, access to appropriate health care, and womancontrolled prevention. RECEIPT OF BLOOD TRANSFUSION, BLOOD COMPONENTS, OR TISSUE Perhaps no other mechanism for the transmission of AIDS has been as frightening as that of receipt of blood transfusion, blood-components (e.g., plasma, platelets), or tissue. As of December 31, 1998, 8,382 adult and 378 pediatric cases were linked to receipt of blood transfusion and reported to the CDC, representing about 1.2% and 4.5% of the total cases, respectively (Centers for Disease Control and Prevention, 1998h). These figures do not include hemophiliacs who were in a separate category. The cases in this category ranged in age from newborns to more than 80 years of age (Centers for Disease Control, 1986). Most of the cases of AIDS now being diagnosed as a result of transfusion are in those who received blood or components before widespread screening was implemented in 1985; however, some have resulted from receiving HFV-infected blood that tested as negative for HIV antibody at the time of transfusion. Transfusion appears to be an effective transmission method for HPV7, as it is estimated that 95% of recipients of a single transfusion of HFVinfected blood became infected (Centers for Disease Control and Prevention, 1998c). Progression does not appear to be different than in persons in other exposure categories.

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The first case of AIDS associated with a blood transfusion was reported by the CDC in December 1982. The White male infant, who was delivered by cesarean section in March 1981, had erythroblastosis fetalis resulting in hyperbilirubinemia. He received exchange transfusions, whole blood, platelets, and packed red cells during his month of hospitalization following birth. These blood and blood products were from 19 different donors and had been irradiated. After 1 month the infant appeared well and was discharged from the hospital. At 4 months of age he showed splenomegaly. By 7 months he developed opportunistic infections and showed evidence of unexplained cellular immunodeficiency. The infant ultimately died of Pneumocystis carinii pneumonia at 20 months of age. His parents were heterosexual, not intravenous drug users, and were not Haitian. Subsequent investigation of the blood products received by this infant revealed that one of the 19 donors of blood and blood products had been reported to the CDC later as having developed AIDS. This donor died in August 1982. At the time of this initial report the cause of AIDS was unknown, and thus it gave further support to the idea that AIDS was caused by an infectious agent. It also suggested that the agent could be present in the blood before causing symptomatic illness and that the incubation period could be a long one (Centers for Disease Control, 1982c), speculation that has since been verified. A major concern was that of protecting the nation's blood supply. In 1983 the United States Public Health Service (USPHS) recommended that blood and/or plasma not be donated by persons with signs and symptoms of AIDS, by sexual partners of AIDS patients or of persons at increased risk for AIDS, or by any other members of groups at increased risk for AIDS, as an interim measure to protect transfusion recipients until specific tests were available. The USPHS also recommended that physicians "adhere strictly to the medical indications for transfusion" (p. 103), and they encouraged autologous blood transfusions (Centers for Disease Control, 1983b). In 1985 testing of potential donors by enzyme-linked immunosorbent assay (ELISA) became possible. ELISA is sensitive, but it is estimated that of 8 million blood donors per year, 40,000 will be falsely positive using ELISA alone. Confirmatory tests, however, increase expense. The possibility of false negatives due to testing error and to latency between exposure to the virus and subsequent develop-

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ment of antibody is also of concern. The combination of testing with voluntary deferral has proved effective but not entirely so. The HIV-infected blood of persons who are HIV-infected but who have not yet developed antibody and seroconverted would not be identified as HIV-infected when using ELISA (or a similar test) for screening. Thus, in 1996, the FDA recommended the use of the p24 antigen assay to screen all donated blood in the United States. Both HIV-1 and HIV-2 are tested for in U.S. blood donations. The risk for receiving an HIV-infected blood transfusion has been reduced markedly in the United States but not completely eliminated, because some persons at risk for HIV infection still donate blood; moreover, not all persons who are HIV-infected may be presently detected with tests in current use, although most will be. It has been estimated that, in the United States, 1 in 450,000 to 1 in 660,000 transfusions transmit HIV-1 per year (Cohen et al., 1998). This figure may be higher in urban areas such as San Francisco and New York, and lower in certain rural areas in low HIV prevalence states. In developing countries, the risk of HIV infection probability is markedly higher and is estimated overall at 1 in 50 to 1 in 100 blood transfusions (Lackritz et al., 1998). The possibility of transfusionassociated HIV transmission has affected clinical practice, including the revision of many criteria for administering blood transfusions and increased caution in making the decision to administer transfusions. Methods have been introduced to reduce blood loss during surgery. More consumers are requesting autologous blood donation provisions or designated donor programs or are requesting female donors. New screening techniques are expected to further reduce risk (Moor etal., 1999). ' Risk Not Reported or Identified Until November 1986 this category was known as "none of the above." Persons classified in this group are those with no reported history of HIV exposure through any of the routes listed in the hierarchy of exposure categories. "Risk not identified" cases include persons who are currently under investigation, those lost to follow-up through death, those who refused to be interviewed or other reasons, those for whom investigation is complete but no exposure mode was identi-

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fied, and health care workers without identified risks (two as of April 30, 1990). As of December 31, 1998, about 8.3% of adult and about 2% of pediatric AIDS cases reported to CDC fell into this exposure category. Upon identification of an exposure mode, persons in this category are reclassified into the appropriate one (Centers for Disease Control and Prevention, 1998h). CDC investigations through 1999 have not identified the existence of any additional transmission modes. Some cases are included in this category because of delays in investigation. Failure to reclassify persons into other exposure categories is probably due to nonrecognition of contributing factors, especially heterosexual contacts. For example, an infected person might not know that his or her sexual partner is a bisexual or an IDU or that he or she has had contact with a prostitute or a sexual partner who has not been monogamous. A study following up on a group of unclassified cases in this category found that risk may not have been documented because of denial of risk, lack of awareness of risk, fear of discrimination or losing insurance, lack of assessment by health care provider because of lack of training, desire not to offend the patient, or assumptions that their patients are not at high risk (Elevens et al., 1999). Exposure Categories for Pediatric AIDS The pediatric exposure categories in hierarchical order, as shown in Table 1.9, are hemophilia/coagulation disorder; mother with/at risk for HIV infection; receipt of blood transfusion, blood components, or tissue; and risk not reported or identified. All have been discussed above, except for mother with/at risk for HIV infection. This category is the one into which the majority of the pediatric AIDS cases fall. As of December 31, 1998, 7,687 cases, or about 91% of all reported U.S. pediatric cases of AIDS, fell into this exposure category. The subcategories in descending order of frequency were IDU (39.4%); has HIV infection, risk not specified (22.7%); sex with IDU (18.2%); sex with HlV-infected person, risk not specified (14.8%); sex with bisexual male (2.2%); receipt of blood transfusion, blood components, or tissue (2.0%); sex with a hemophiliac (0.38%); and sex with transfusion recipient with HIV infection (0.33%). Thus, nearly 60% of the perinatally acquired cases of AIDS are attributable

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in some way to injecting drug use (Centers for Disease Control and Prevention, 1998h). In the United States between 1992 and 1996, perinatally acquired AIDS declined 43%; in 1997 there was a 30% decline (Centers for Disease Control and Prevention, 1998f). A full discussion of perinatal transmission of HIV was presented earlier and is in chapter 11. CONCLUSION Studies of epidemiological aspects of the AIDS outbreak have contributed enormously to the identification of the involved etiological agent and its transmission. Yet many questions remain. Additional research is needed to further define and clarify the role of cofactors and their influence on both the development of AIDS and its progression. Further data are also needed on the natural history and consequences of HIV infection, seroconversion, immunosuppression, what the determinants for rapid and slow progression are and how they can be modified, and the spectrum of disease. In developed countries, the death rate has slowed and more people are living with HIV. However, infection is increasing explosively in Africa and parts of Asia and is still on the increase in developed countries. Further information is still needed on effective methods of education and behavior change. REFERENCES Abdala, N., Stephens, P. C., Griffith, B. P., & Heimer, R. (1999). Survival of HFV1 in syringes. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 20, 73-80. Abrams, D. I., Lewis, B. J., Beckstead, J. H., Casavant, C. A., & Drew, W. L. (1984). Persistent diffuse lymphadenopathy in homosexual men: Endpoint or prodrome? Annals of Internal Medicine, 100, 801-808. Adib, S. M., Joseph, J. G., & Ostrow, D. G. (1991). Relapse in sexual behavior among homosexual men: A 2-year follow up from the Chicago MACS/CCS. AIDS, 5, 757-760. Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179-211. .Allen, J. R., & Curran, J. W. (1988). Prevention of AIDS and HlV-infection: Needs and priorities for epidemiologic research. American Journal of Public Health, 78, 381-386.

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2

The Pathogenesis of HIV Infection Janice M. Zeller and Barbara Swansan

nfection with the human immunodeficiency virus (HIV) induces defects in both cell-mediated and humoral immune responses, thus rendering the host susceptible to opportunistic infections and neoplasms. The pathogenesis of HIV infection is highly complex, involving interactions among multiple viral and host factors. In recent months, substantial progress has been made in elucidating the mechanisms underlying HIV infection and replication dynamics. In concert with the development of protease inhibitors, these findings have led to cautious optimism that sustained inhibition of HFV-1 replication will be achieved in the future. In this chapter, we summarize current knowledge pertaining to the pathogenesis of HIV infection.

I

CHARACTERISTICS OF HIV-1 Classification HIV is a retrovirus. Retroviruses demonstrate a reversal in the usual flow of genetic information during their life cycle (Stine, 1997). That is, their genetic material is contained within ribonucleic acid 75

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(RNA), rather than deoxyribonucleic acid (DNA). Following entry into a target cell, they use an enzyme, reverse transcriptase, to transcribe their RNA into DNA, which is then integrated into the host genome. Using host cell enzymes, the integrated DNA, or provirus, is transcribed into messenger RNA (mRNA), which directs the synthesis of new viral particles (Pavlakis, 1997). HIV is a member of the family of retroviruses known as lentiviruses Lentiviruses typically infect cells of the immune system, resulting in immunodeficiency. They escape clearance by the immune system and cause persistent infections characterized by long incubation periods. Examples of other lentiviruses include visna virus, a neurotoxic virus that infects sheep, and simian immunodeficiency virus (SIV), a primate virus that induces an AIDS-like syndrome (Pavlakis, 1997). Viral Structure HIV is spherically shaped and measures 1/10,000 mm in diameter (Stine, 1997). It consists of an outer envelope composed of a phospholipid bilayer that is "studded" with two glycoproteins: gp41, which spans the phospholipid bilayer, and gp!20, which is attached to the top of gp41 and lies outside the viral envelope. Lying directly beneath the lipid bilayer and lining the inner surface of the virus is the pi 7 matrix protein, which helps stabilize the particle. The center of the virus is a cone-shaped core that is composed of the major capsid protein (p24). The core contains enzymes necessary for viral replication and two copies of genomic RNA bound to the nucleocapsid proteins (p9 and p7) (Hahn, 1994; Levy, 1994) (see Figure 2.1). Viral Genes The HIV provirus consists of approximately 8.5 kilobases of proteincoding information flanked on each side by identical sequences of nucleotides known as long terminal repeats (LTRs). The LTRs are produced during reverse transcription and thus are only present in the DNA copy of the viral genome (Hahn, 1994). These LTRs contain binding sites for host transcription factors and regulate the expression of viral proteins (Parslow & Hope, 1994; Stine, 1997). Similar to all known retroviruses, HIV has three genes that encode for its structural proteins: env, pol, and gag. The env gene encodes

THE PATHOGENESIS OF HIV INFECTION

FIGURE 2.1

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HIVvirion.

Note. From The Medical Management of AIDS (5\h ed.). Edited by M. A. Sande & P. A. Volberding, 1997, Philadelphia: W. B. Saunders Company. Copyright 1997 by W. B. Saunders Company. Reproduced with permission.

for gplGO, a precursor to the envelope glycoproteins. The gplGO precursor is cleaved by a cellular protease into its subunits, gp!20 and gp41. The pol gene encodes for three viral enzymes necessary for replication: reverse transcriptase, integrase, and protease. The grtggene encodes for a polyprotein that is cleaved by the viral protease into the viral matrix (pi7), capsid (p24), and nucleocapsid proteins (p7 and p9) (Lew, 1994; Young, 1994). Additional genes, unique to HIV, encode for three proteins that regulate viral replication. One protein, Tat, binds to a region in the LTR known as the Tat responsive element (TAR). Binding of Tat to TAR has been shown to upregulate viral replication by 1,000fold (Stine, 1997), possibly by initiating and elongating proviral transcription (Folks & Hart, 1997). A second regulator}' protein, Rev, binds to the Rev regulatory element located in the env gene of the viral mRNA (Folks & Hart, 1997). Rev is involved in transporting mRNAs for the gag, pol, and env genes from the nucleus to the cytoplasm, where they are translated into proteins (Hahn, 1994). The third regulatory protein, Nef, has diverse functions. Nef has been shown to downregulate surface expression of CD4+ on infected

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1911s (Aiken, Konner, Landau, Lenburg, & Trono, 1994). This downregulation of CD4+ prevents the reinfection of target cells and promotes viral spread to uninfected cells. Thus, Nef appears to confer a survival advantage to the virus (Hahn, 1994). Evidence also suggests that Nef regulates viral virulence. A small cohort of Australians infected in the 1980s with a Nef-deleted viral mutant has shown no evidence of immunodeficiency to date (Dyer et al., 1997). Furthermore, it has been shown that Nef is required for viral replication and the development of disease in macaques infected with SIV (Kestler et al., 1991). Cellular Tropism HIV strains can be categorized on the basis of their tropism, or ability to infect different cell types. Tropism is determined by variations in the V3 loop of gp!20. All viruses isolated from infected persons are capable of infecting CD4+ T lymphocytes (Fauci, 1996). Some isolated viruses are also capable of infecting macrophages and are known as macrophage tropic strains (M tropic), while other isolates only infect T lymphocytes or transformed T cell lines and are known as T cell tropic strains (T tropic). For unknown reasons, M tropic strains predominate in the early, asymptomatic stages of infection, regardless of route of transmission, while T tropic strains predominate at later stages (Fauci, 1996). HIV strains are also categorized by their ability to induce the formation of syncytia in vitro. Syncytia are clusters of fused lymphocytes that form when cell cultures are infected with certain viral strains. These viral strains, termed syncytium-inducing (SI), predominate in later stages of infection and are associated with a decline in CD4+ T lymphocyte counts and progression to AIDS. In contrast, non-syncytium-inducing (NSI) strains can be found at all stages of infection. Generally, T tropic strains are SI, whereas M tropic strains are NSI (Weiss, 1994). HIV LIFE CYCLE HIV Receptors HIV infects cells that express the CD4+ receptor on their surface. CD4+ is a 58-kd transmembrane glycoprotein that belongs to the

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immunoglobulin (Ig) superfamily. CD4+ assists in T cell recognition of antigen by binding to major histocompatibility complex (MHC) class II molecules expressed on the surface of antigen-presenting cells. CD4+ cells that are targets for HIV infection include the helper subset of T lymphocytes, monocytes and macrophages (including microglial cells in the brain), and dendritic cells (follicular dendritic cells in the lymph node and Langerhans cells in the skin) (Cunningham, Dwyer, Mills, & Montagnier, 1996; Pavlakis, 1997). For years, it had been recognized that CD4+ is necessary but insufficient to permit infection of target cells and that unknown coreceptors were likely involved in viral binding and entry. Recently, it was observed that chemokines, chemoattractant cytokines released during inflammation, suppressed infection of CD4+ target cells. This observation led to the identification of chemokine receptors as coreceptors for HIV infection (Fauci, 1996). Chemokine receptors have seven transmembrane segments and are coupled to signal transducing G proteins (Feng, Broder, Kennedy, & Berger, 1996). Ligand binding activates signals that mediate leukocyte extravasation and migration (Wu et al., 1997). Two major chemokine receptors have been identified as the coreceptors for HIV infection: CXCR4, which mediates entry of T tropic strains, and CCR5, which mediates entry of M tropic strains (Unutmaz & Littman 1997). Variations in these affect resistance to HIV infection and progression to AIDS. See chapter 1 (Lane, 1997; Wu et al., 1997). Binding and Entry Upon entry into the host, HIV attaches to the CD4+ molecule via gp!20. This binding induces conformational changes in both the viral envelope and CD4+ that permit binding of other gp!20 epitopes to either CXCR4 or CCR5. This second binding event moves the viral envelope closer to the cell surface and leads to the fusion of gp41 with the target cell membrane. Following fusion, the virus enters the cell, the core uncoats, and the core contents (two strands of RNA and reverse transcriptase) are released into the cytoplasm (Levy, 1996). Reverse Transcription, Translocation, and Integration Reverse transcriptase (RT) is a polymerase that acts in concert with a second enzyme, RNAse, to copy the viral RNA into DNA. The RT

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polymerase transcribes the two RNA strands into two strands of DNA, while the RNAse separates the DNA copies from the RNA (Brennan & Porche, 1997). T;«e mutations characteristic of HIV are generated during reverse transcription. The RT polymerase lacks a "proofreading" mechanism to correct for misincorporated nucleotides. These transcription errors underly the genetic diversity of viral strains worldwide, enable the virus to elude immune clearance, and select for antiretroviral-resistant mutants (Folks & Hart, 1997). The double-stranded DNA, in association with the gag matrix proteins and integrase, is transported across the nuclear pore and into the nucleus. This translocation is mediated by nuclear localization signals contained within the gag matrix proteins. Upon entry into the nucleus, the integrase enzyme trims the viral DNA, cuts the host chromosomal DNA, and inserts the viral DNA into the host's chromosomes (Folks & Hart, 1997). Some viral DNA does not become integrated into the host's chromosomes and remains in the cytoplasm. The accumulation of unintegrated DNA has been shown to be associated with cell death in animal models of retrovirus infection (Weller, Joy, & Temin, 1980). However, it is not known if this is a mechanism associated with the progression of HIV infection in humans.

Viral Transcription and Synthesis Provirus transcription and subsequent viral synthesis occurs most efficiently in activated cells. Activation stimuli, such as opportunistic pathogens or immunizations, induce the elaboration of cytokines that promote proviral transcription and subsequent viral replication. For example, cytokines activate a DNA binding protein, known as nuclear factor-kappa B (NF-KB), that is present in the cytoplasm of T lymphocytes. NF-KB binds to receptors present in the interleukin2 (IL-2) promoter gene region, thus promoting IL-2 production by activated cells. The HIV-LTR also contains receptors that can bind NF-KB, and binding of these receptors activates provirus transcription (Fauci & Rosenberg, 1994). Because HIV infection is associated with chronic immune activation, the infected host provides a permissive environment for viral replication (Pantaleo et al., 1997).

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Upon cellular activation, the provirus is transcribed into strands of RNA. Some of the strands are spliced by cellular enzymes to become the messenger RNA (mRNA) that serves as the template for the synthesis of new virus particles. The strands left unspliced are the genomic RNA that will be packaged in the core of new viral particles (Stine, 1997). Following proviral transcription, the Rev protein binds to the RNA transcripts and delivers them to ribosomes in the cytoplasm. At the ribosome, the mRNA is translated into polyproteins that will serve as the structural and regulatory proteins of new virus particles. The viral polyproteins accumulate at the plasma membrane, and the two genomic RNA copies become encapsidated by the gag proteins. The viral particles begin to bud from the host cell and acquire their lipid envelopes from the plasma membrane. During and immediately after budding, the viral protease cleaves the polyproteins into individual active proteins, thus creating mature, infectious new virions (Folks & Hart, 1997; Stine, 1997). VIRAL REPLICATION DYNAMICS After entering the host, HIV is rapidly disseminated to the lymphoid tissues (Fauci, Pantaleo, Stanley, & Weissman, 1996). During this period of initial infection, also known as primary infection, there is a burst of viremia, as demonstrated by a high plasma viral load (up to 107 copies of HIV RNA per 1 milliliter of plasma), and a depletion of CD4+ T lymphocytes (Pantaleo & Fauci, 1996). After a period of a few weeks, the host develops an immune response to the virus, resulting in a down regulation of plasma viral load and a partial restoration of absolute CD4+ T lymphocyte numbers, although both parameters frequently fluctuate for the next 6 months (Ffrench, Stewart, Penny, & Lew, 1996). Viral load in regard to treatment is discussed in chapter 7. The immune response does not completely eliminate the virus from the host. Viral particles can be found in the lymphoid tissue, which serves as the reservoir for as much as 99% of the total viral burden in the body. Most of the lymphoid tissue-associated virus is contained within follicular dendritic cells (FDC) (Patel, Hale, & Haynes, 1996). Latent, yet replication-competent virus, has also been found in quiescent, CD4+ T lymphocytes

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in the peripheral blood of patients who have been taking highly active antiretroviral therapy (HAART) for up to 30 months. This finding suggests that peripheral lymphocytes constitute a second, albeit smaller, viral reservoir (Finzi et al., 1997). Approximately 6 months after infection, CD4+ T lymphocyte counts and plasma viral load stabilize. The stable viral load is known as the "viral setpoint" and is predictive of long-term clinical outcomes, with higher viral load associated with more rapid progression to AIDS (Staprans & Feinberg, 1997). The initiation of antiretroviral therapy during primary HIV infection may lower the viral setpoint and thus delay disease progression, although there are insufficient data to confirm this (Carr & Cooper, 1997). See chapter 5. After the period of primary HIV infection, there is a clinically asymptomatic phase that can last for several years. During this period of clinical latency, HIV is actively and continuously replicating. It is estimated that 1.1 x 108 virus particles are produced daily, with the majority of virus produced from continuous rounds of de novo infection, rather than from chronically infected cells or latently infected cells that become activated (Wei et al., 1995). Because the half-life of virus-producing cells is only 2 days, a tremendous reconstitution of infected cells is necessary to sustain steady-state levels of viral replication. The daily turnover rate of CD4+ T lymphocytes in HIV infection is estimated to be 2.6 x 109 cells. It is hypothesized that the persistent reconstitution demands eventually exceed the immune system's finite capacity for regeneration, resulting in immunodeficiency and disease progression (Ho et al., 1995). MECHANISMS OF VIRAL ESCAPE FROM THE IMMUNE RESPONSE Shortly after infection, the host mounts vigorous, anti-HIV cell-mediated and humoral responses resulting in a decline of the initial viremic burst (Haynes, Pantaleo, & Fauci, 1996). However, for unknown reasons, these responses are insufficient to completely eliminate the virus from the infected host, although both virologic and immunologic factors are probably involved. Putative virologic factors include (1) the formation of large pools of latently infected cells, (2) the trapping of viral particles in the FDC network leading to

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continuous rounds of de novo infection of resident CD4+ T lymphocytes and/or activation of these cells rendering them susceptible to infection, and (3) the continual emergence of viral mutants that can escape HlV-specific cytotoxic T lymphocyte (CTL) responses. Immunologic factors include (1) virally induced quantitative and qualitative defects in immune cells, (2) the egress of HIV-1-specific CTLs from the lymphoid tissue, the primary site of viral replication, and (3) the clonal deletion of HlV-specific CTLs (Pantaleo & Fauci, 1996). CD4+ LYMPHOCYTE DYNAMICS Naive and Memory Cells Over the course of HIV infection, there is a steady decline in the number of CD4+ lymphocytes. Phenotypic analysis of CD4+ T lymphocytes has revealed that naive cells are preferentially depleted, with a relative sparing of memory subsets. By end-stage disease, it is postulated that only memory cells remain (Lane, 1997). HAART is associated with an expansion of both naive and memory subsets, although memory subsets expand preferentially early in the course of therapy. After several months of therapy, there is a slow increase in naive cells. Therefore, although HAART is associated with clinically significant improvements in immune function, only partial restoration of the immune system is achieved in the first year (Powderly, Landay, & Lederman, 1998). Th-1 and Th-2 Responses Imbalances involving immunoregulatory subsets of CD4+ T lymphocytes have been postulated to contribute to HIV disease progression (Staprans & Feinberg, 1997). Immune responses are regulated by the helper subset of CD4+ T lymphocytes, of which there are two major phenotypes: (1) type-1 cells (Th-1) that produce interferony and induce cell-mediated immune (CMI) responses, and (2) type2 cells (Th-2) that produce interleukin-4 (IL-4) and induce humoral

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responses. CMI responses activate effector cells that are capable of killing intracellular pathogens such as viruses. Humoral responses involve the elaboration of antibody to neutralize pathogens and are effective in clearing bacterial infections (Allen & Maizels, 1997). Th-1 responses appear to inhibit HIV disease progression, whereas Th-2 responses appear to be relatively ineffective (Clerici & Shearer, 1994). It has been suggested that HIV disease progression is associated with a switch from a predominantly Th-1 response to a Th-2 response. The mechanisms underlying this phenotypic switch remain unclear, although it may be influenced by the temporary upregulation of IL-4 production that occurs in the first year of HIV infection (Shearer & Clerici, 1996). Studies to confirm this hypothesis have yielded conflicting findings, calling into question the validity of this hypothesis (Allen & Maizels, 1997; Graziosi et al., 1994). HIV in Lymphoid Tissue During primary infection and throughout the period of clinical latency, the greatest concentration of HlV-infected cells is found in the lymphoid tissue. This includes the lymph nodes, adenoids, tonsils, and the spleen (Staprans & Feinberg, 1997). The high concentration of actively replicating virus in lymph nodes, and the subsequent immune activation, underlie the lymphadenopathy commonly seen in the early stages of HIV infection (Saag, 1997). Histological analysis of lymph node tissue throughout the course of HIV infection reveals characteristic changes that correlate with plasma viral load, CD4+ T lymphocyte count, and clinical status. In early HIV infection (CD4+ count > 500/mm3), virus particles are trapped by the network of follicular dendritic cells (FDC) located in lymph node germinal centers. FDCs are major antigen presenting cells in the lymph node. They can trap HIV that is bound to antibodycomplement complexes via complement receptors expressed on their surface (Patel et al., 1996). This trapping leads to immune cell activation, infection of target cells in the lymph node, and follicular hyperplasia. Moreover, trapping of virus particles by the FDC network sequesters virus in the lymph node. In the early stages of infection, viral load in the lymphoid tissue exceeds that in the plasma by one to three logs (Pantaleo et al., 1997).

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As HIV infection progresses to intermediate stages (CD4+ T lymphocyte counts between 200 and 500/mm s ), plasma viral load increases to levels that are more comparable with levels found in the lymph node. Although this increase in plasma viremia reflects HIVinduced immune suppression, it also reflects progressive histopathological changes in lymphoid tissue (Pantaleo et al., 1997). During this time, lymph nodes show involution with hypocellular germinal centers, loss of FDCs, and increased vascularity. These changes lead to a gradual loss of viral trapping by the FDC network and increased plasma viral load (Patel et al., 1996). In the final stages of HIV infection (CD4+ lymphocyte counts < 200/mm s ), there is a profound destruction of normal lymph node architecture. Lymph node germinal centers are involuted and depleted of lymphocytes and FDCs. The remaining cells are predominantly histiocytes and plasma cells. These histopathological changes are associated with high plasma viral load, the development of opportunistic infections, and death (Pantaleoetal., 1997; Patel etal., 1996). PROFILES OF DISEASE PROGRESSION Typical Progressors, Rapid Progressors, Long-term Nonprogressors Although it was initially estimated that all persons who had become infected with HIV would die within a few years of exposure to the virus, it soon became clear that there was tremendous diversity in outcomes postinfection. In observing the immunological, virological, and clinical changes occurring in HFV-infected persons, three patterns of disease progression have emerged. The majority (80% to 90%) of HFV-infected persons are categorized as typical progressors. They tend to develop AIDS within 10 years of initial infection (Pantaleo et al, 1997). Rapid progressors, representing 5% to 10% of infected persons, progress to AIDS within 2 to 3 years of HIV infection. The remaining 5% of infected persons (long-term nonprogressors) remain clinically asymptomatic for 7 to 10 years following infection and show no decline in CD4+ T lymphocyte counts. To gain a better understanding of the factors that sup-

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port an effective host response to HIV infection, attempts have been made to characterize the genetic, immunological, and virological correlates of disease progression in these populations (Pantaleo et al, 1997). The majority of typical progressors manifest acute clinical symptoms within 3 to 6 weeks of primary infection. During this period, high serum viral liters can be detected, but in most cases there is no indication of elevated antibody liters to HIV. At 9 to 12 weeks, individuals enter into a period of clinical latency that correlates with the appearance of both humoral and cell-mediated immune responses to the virus, reduction in plasma viremia, and resolulion of clinical symptoms. Allhough viral levels in ihe peripheral blood remain low during the period of clinical latency, active viral replication occurs within lymphoid organs. CD4+ T lymphocyle counls decline and clinical disease becomes apparenl after approximately 8 to 10 years. The onset of clinical disease occurs in the face of continuous viral replication, progressive deslruclion of lymphoid lissue, and profound immune dysregulalion. Rapid progressors differ from typical progressors in that they fail lo develop a compelenl immune response lo primary infeclion. Rapid progressors show low HIV anlibody lilers, poor suppression of HIV replication by CD8+ CTLs, and persistency high plasma viral load. Later stages of the disease are characterized by inappropriate immune activation, as evidenced by elevated serum levels of neoplerin, p2-microglobulin, and soluble IL-2 receptors. This inappropriate immune aclivation is associated with progressive exhaustion of the immune response and accelerated clinical disease progression. Long-term nonprogressors have captured the interesl of clinicians and researchers alike, as iheir clinical course may shed light on how best to promote a favorable host response to HIV. This small group of individuals has been shown to maintain stable CD4+ T lymphocyte counts for greater than 7 years postinfection, despite lack of antiretroviral iherapy. Their immune funclion remains intact, as they continue to generate slrong humoral as well as cell-mediated responses lo HIV and show no signs of inappropriate immune activation. Absolute numbers of CD8+ CTLs are higher than those seen in typical progressors, and fewer CD8+ CTLs show signs of inappropriate activation. Although long-term nonprogressors demonstrate low levels of viral load in plasma and mononuclear cells in the peripheral blood

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and lymph nodes, viral replication persists. Despite the persistence of viral replication, lymph node architecture is preserved and no evidence of AIDS-associated clinical symptoms is noted for at least 7 years following primary infection. A number of factors have been proposed as contributory to the varying rates of disease progression in HIV-infected individuals. Although there is evidence that virus isolated from long-term nonprogressors is infectious and replication-competent, it is plausible that these viral strains exhibit lower levels of pathogenicity than those infecting persons with more rapidly progressing disease (Pantaleo et al., 1997). In support of this hypothesis, strains of virus bearing Nef deletions have been isolated from long-term nonprogressors (Korchhoff, Greenough, Brettler, Sullivan, & Desrosiers, 1995). Host genetic factors have also been associated with varying rates of HIV disease progression. Those genes encoded by the major histocompatability (MHC) loci, MHC class I and MHC class II, determine the strength and specificity of cellular and humoral immune responses. Certain MHC alleles have been postulated to promote long-term survival in persons with HIV infection by facilitating effective clearance of HIV-infected cells during early stages of infection (Haynes et al., 1996). Also, the expression of MHC class I antigens on HIVinfected cells may regulate their susceptibility to lysis by natural killer cells (Haynes et al., 1999b). The observation that long-term nonprogressors have strong CTL responses to certain HIV epitopes has focused attention on these cells in the design of HIV immunotherapeutic strategies (Haynes et al., 1996). Resistance to Infection Of perhaps even greater interest to the research community than long-term nonprogressors are those individuals who have been repeatedly exposed to HIV but nevertheless show no clinical evidence of chronic infection. There is reason to believe that these individuals were acutely infected at some point, as they demonstrate vigorous CTL responses to HIV antigens (Haynes et al., 1996). Although currently there is no explanation for the ability of certain individuals to effectively clear the infection, host genetics, such as that involving alleles of the CCR5 gene, may play a role (Fauci, 1996). This molecule

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may be an important target in planning disease prevention strategies (Fauci, 1996). See chapter 1. CHARACTERISTICS AND MECHANISMS OF HIV-RELATED IMMUNE DEFICIENCY Decline in CD4+ Cell Numbers Virtually all components of the immune system are altered during the course of HIV infection. This may be the result of direct infection of immune cells with HIV or alternatively may occur in response to altered patterns of cytokine expression associated with the disease (reviewed in Zeller, McCain, & Swanson, 1996). The cell most markedly influenced by HIV infection is the CD4+ T lymphocyte. Functional defects in CD4+ T lymphocytes occur early in infection, even when CD4+ cell numbers remain high (Clerici & Shearer, 1992). Over the course of illness, there is a progressive decline in the ability of these cells to respond to recall antigens, followed by a loss of responsiveness to alloantigens, which is followed by a failure to respond to nonspecific activators, such as mitogens (Shearer & Clerici, 1992). The rate of decline of CD4+ T lymphocyte numbers has proven to be an important prognostic indicator of HIV-disease progression. The maintenance of an adequate pool of functionally intact CD4+ T lymphocytes is dependent upon maintaining a steady-state balance between cell loss and cell renewal (Ffrench et al., 1996). In HIV disease, reduced CD4+ T cell numbers have been attributed to impairments in cell renewal capabilities coupled with increased cell losses. Impairment in T Cell Renewal CD4+ T lymphocytes are derived from bone marrow cells that undergo maturation within the thymus gland. T lymphocytes normally encounter antigen and continue to differentiate and proliferate within peripheral lymph nodes (Janeway & Travers, 1994). Over the course of HIV infection there is evidence of direct infection and lytic destruction of thymocytes (immature T lymphocyte

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precursors), as well as disruption of the stromal network within the thymus gland, which provides a microenvironment for thymocyte maturation. Additionally, as HIV disease progresses, there is marked involution and atrophy of peripheral lymphoid organs (Fauci, Pantaleo, Stanley, & Weissman, 1996; Pantaleo & Fauci, 1996). Loss of the network relevant MHC class II antigen-presenting cells within this environment is instrumental in reducing the renewal of an antigen-specific T helper cell population (Heeney, 1995). At late stages of HIV disease, pluripotent bone marrow stem cells, identified by the CD34 surface marker become infected with the virus. Although in vitro infection of CD34+ bone marrow stem cells is cytopathic, it remains uncertain whether these cells are destroyed in vivo or whether they serve as a viral reservoir in HIV-infected individuals (Fauci et al., 1996). Anergy, diminished capacity for clonal expansion following cell stimulation, may also contribute to reduced cell renewal in persons with HIV disease. It has been postulated that gp!20 from the virus binds to CD4+ on T cell surfaces, rendering these cells refractor)"' to further stimulation (Heeney, 1995). Enhanced Loss of CD4+ T Lymphocytes T cell destruction in HIV disease has been attributed to both virologic and nonvirologic mechanisms. Direct virologic mechanisms include single-cell lysis and cell fusion, resulting in syncytia formation. CD4+ T lymphocytes infected with HIV can undergo loss of viability due to disruption of cellular function and loss of membrane integrity in association with budding of newly synthesized virions (Garry, 1989). Syncytia formation occurs when gp!20 on the surface of HIV-infected cells binds to free CD4+ on uninfected cells. This process of cell engagement, which is facilitated by cell adhesion molecules (Hildreth 8c Orentas, 1989), results in membrane fusion and the generation of rnultinucleated giant cells. Although both direct cell killing and syncytia formation have been observed in HIV-infected cells in culture, it remains controversial whether these mechanisms play a major role in CD4+ T lymphocyte depletion in vivo (Pantaleo et al.," 1997). Nonvirologic mechanisms proposed to contribute to cell loss in HIV infection include apoptosis, cell stimulation by superantigens,

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and cell killing by immunologic mechanisms (Pantaleo et al., 1997). Apoptosis, also referred to as programmed cell death, is a process used by multicellular organisms to maintain a homeostatic balance between cell proliferation and cell loss (Thompson, 1995). Apoptotic cell death is characterized by intracellular release of digestive enzymes, DNA fragmentation, and plasma membrane disruption (Thompson, 1995). The observation that mature T lymphocytes can undergo apoptosis following activation (Kabelitz, Phol, & Pechhold, 1993) supports the hypothesis that programmed cell death may contribute to cell loss associated with HIV infection (Ameisen, 1992). It has been reported that soluble gp 120 binding to the CD4+ receptor renders lymphocytes more susceptible to apoptosis (Oyaizu & Pahwa, 1995). Given that infection is not required for this event to occur, apoptosis may explairi, at least in part, the loss of large numbers of T lymphocytes in HIV disease, more than can be attributed to direct infection with the virus. To date, it has not been demonstrated that apoptosis is closely correlated with HIV disease progression (Meyaard & Miedema, 1995). Superantigens are molecules that have the potential to bind to antigen receptors on certain subsets of T lymphocytes (Janeway, 1991). Engagement of these receptors may lead to cell loss either by inducing anergy or by directly destroying the stimulated cell. Microbial-derived superantigens have been implicated in the pathogenesis of a number of diseases (Johnson, Torres, & Soos, 1996). Although it has been reported that certain HIV components can function as superantigens (Garcia et al., 1996), it remains controversial whether this property of the virus significantly contributes to the loss of T lymphocytes in HFV-infected individuals (Pantaleo et al., 1997). A number of immune mechanisms may contribute to the decline of CD4+ T lymphocyte numbers over the course of HIV disease. As described earlier, CTLs have been proposed to exert a beneficial role in HIV disease by controlling viral load (Pantaleo & Fauci, 1996). For example, it has been reported that intact CTL responses are more long-lived in long-term nonprogressors than in rapid progressors (Pantaleo et al., 1997). CTLs are able to reduce viral load by directly lysing cells that are the source of new virions, such as CD4+ T lymphocytes. CD8+ CTLs recognize foreign antigen on the surface of infected cells in the context of the MHC class I molecule.

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Lytic destruction occurs due to CTL release of perforin, a poreforming molecule, and cytokines such as tumor necrosis factor-alpha. Alternatively CTL binding can trigger programmed cell death in HIV-infected cells (reviewed in Rowland-Jones, Tan, & McMichael, 1997). Because, under certain conditions, CTLs can lysis both HIVinfected cells and uninfected cells (Weinhold et al., 1989; Zarling et al., 1990), the potential for massive cell destruction by this mechanism is great. There is evidence that CD8+ T lymphocytes can also control viral production in HIV-infected cells using noncytotoxic mechanisms (Levy, Mackewicz, & Barker, 1996). By suppressing viral replication with a soluble factor that does not destroy cells, this mechanism may protect the host from harmful consequences of CTL-mediated cell lysis (Levy et al., 1996). The interplay of cytotoxic and noncytotoxic mechanisms utilized by CD8+ T lymphocytes in controlling HIV viral load warrants further investigation. CONCLUSION Since the early years of the HIV epidemic, tremendous progress has been made in understanding the nature of the infectious virus, the mechanisms it utilizes to decimate the immune system, and how it manages to circumvent normal host defense mechanisms. This information, taken together with current insights into the tremendous variability of the disease course as well as host and viral factors that may influence clinical outcomes, offers promise for the development of new treatment strategies. While many of these new approaches may involve the use of immune-derived products to prevent HIV entry into uninfected cells, others will focus on the development of vaccines to either prevent or attenuate the disease. Recent information that nutritional factors (Guenter et al., 1993; Snyder & Sigal, 1994) and neuroendocrine-derived products (McCain & Zeller, 1996) alter immunity and perhaps the course of HIV infection suggest that nonpharmacologic approaches to disease management should also be considered when planning treatment strategies.

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Folks, T. M., & Hart, C. E. (1997). The life cycle of human immunodeficiency virus type 1. In V. T. Devita, S. Hellman, & S. A. Rosenberg (Eds.), AIDS: Biology, diagnosis, treatment, and prevention (4th ed., pp. 29-43). Philadelphia: Lippincott-Raven. Garcia, S., Dadaglio, G., Cilote, V., Chenal, H., Bondurand, A., & Gcmgeon, M. L. (1996). Evidence for an in vivo superantigenic activity in human immunodeficiency virus-infected persons. Blood, 88, 2151-2161. Garry, R. F. (1989). Potential mechanisms for the cytopathic properties of HFV. AIDS, 3, 683-694. Graziosi, C., Pantaleo, G., Gantt, K. R., Fortin, J. P., Demarest, J. F., Cohen, O. J., Sekaly, R. D., & Fauci, A. S. (1994). Lack of evidence for the dichotomy of Thl and Th2 predominance in HIV-infected individuals. Science, 265, 193-194. Guenter, P., Mtuirahainen, N., Simons, G., Kosok, A., Cohan, G. R., Rudenstein, R., & Turner, J. L. (1993). Relationships among nutritional status, disease progression, and survival in HIV infection. Journal of Acquired Immune Deficiency Syndromes, 6, 1130-1138. Hahn, B. H. (1994). Viral genes and their products. In S. Broder, T. C. Merigan, & D. Bolognesi (Eds.), Textbook of AIDS medicine (pp. 21-43). Baltimore: Williams & Wilkins. Haynes, B. F., Pantaleo, G., & Fauci, A. S. (1996); Toward an understanding of the correlates of protective immunity to HIV infection. Science, 271, 324—327. Heeney, J. L (1995). AIDS: A disease of impaired Th-cell renewal? Immunology Today, 16, 515-520. Hildreth, J. E. K., & Orentas, R. J. (1989). Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation. Science, 244, 1075-1078. Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., & Markowitz, M. (1995). Rapid turnover of plasma virions and CD4 lymphocytes in HFV-1 infection. Nature, 373, 123-126. Janeway, C. (1991). Mis: Makes a little sense. Nature, 349, 459-461. Janeway, C. A.. Jr., & Travers, P. (1994). Immunobiology: The immune system in health and disease. New York: Garland. Johnson, H. M., Torres, B. A., & Soos, J. M. (1996). Superantigens: Structure and relevance to human disease. Proceedings of the Society for Experimental Biology and Medicine, 212, 99-109. Kabelitz, D., Pohl, T., & Pechhold, K. (1993). Activation-induced death (apoptosis) of mature peripheral T lymphocytes. Immunology Today, 14, 338-339. Kestler, H. W.. Ringler, D. J., Mori, K., Panicali, D. L., Sehgal, P. K., Daniel, M. D., & Desrosiers, R. C. (1991). The importance of the ne/gene for maintenance of high virus loads and for development of AIDS. Cell, 65, 651-662. Korchhoff, F., Greenough, T. C., Brettler, D. B., Sullivan, L., & Desrosiers, R. C. (1995). Brief report.: Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. New England Journal of Medicine, 332, 228-232. Lane, H. C. (1997). HIVpathogenesis. Improving the Management of HIV Disease, 5, 4-7. Levy, J. A. (1994). HIV and the pathogenesis of AIDS. Washington, DC: ASM Press. . (1996). Infection by human immunodeficiency virus—CD4 is not enough. New England Journal of Medicine, 335, 1528-1530.

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Levy, J. A., Mackewicz, C. E., & Barker, E. (1996). Controlling HIV pathogenesis: The role of the noncytotoxic anti-HIV response of CD8+ T cells. Immunology Today, 17, 218-224. McCain, N. L., & Zeller, J. M. (1996). Psychoneuroimmunological studies in HIV disease. Annual Review of Nursing Research, 14, 23-55. Merigan, T. C., & Bolognesi, D. (Eds.). Textbook of AIDS medicine. Baltimore: Williams & Wilkins. Meyaard, L., & Miedema, F. (1995). Programmed death of T cells in HFV infection: Result of immune activation? Current Topics in Microbiology and Immunology, 200, 213-221. Oyaizu, N., & Pahwa, S. (1995). Role of apoptosis in HIV disease pathogenesis. Journal of Clinical Immunology, 15, 217-231. Pantaleo, G., Cohen, O., Graziosi, C., Vaccarezza, M., Paolucci, S., Demarest, J. F., & Fauci, A. S. (1997). Immunopathogenesis of human immunodeficiency virus infection. In V. T. Devita, S. Hellman, & S. A. Rosenberg (Eds.), AIDS: Biology, diagnosis, treatment, and prevention (4th ed., pp. 75-88). Philadelphia: Lippincott-Raven. Pantaleo, G., & Fauci, A. S. (1996). Immunopathogenesis of HIV infection. Annual Review of Microbiology, 50, 825-854. Parslow, T. G., & Hope, T.J. (1994). Structure and expression of the HIV genome. In P. T. Cohen, M. A. Sande, & P. A. Volberding (Eds.), The AIDS knowledge base (2nd ed., pp. 3.2-1 to 3.2-9). Boston: Little, Brown. Patel, D. D., Hale, L. P., & Haynes, B. F. (1996). HIV in lymph node and thymus. In S. Gupta (Ed.), Immunology of HIV infection (pp. 95—121). New York: Plenum. Pavlakis, G. N. (1997). The molecular biology of human immunodeficiency virus type 1 regulatory genes. In V. T. Devita, S. Hellman, & S. A. Rosenberg (Eds.), AIDS: Biology, diagnosis, treatment, and prevention (4th ed., pp. 45-74). Philadelphia: Lippincott-Raven. Powderly, W. G., Landay, A., & Lederman, M. M. (1998). Recovery of the immune system with antiretroviral therapy. The end of opportunism? fournal of the American Medical Association, 280, 72-77. Rowland-Jones, S., Tan, R., & McMichael, A. (1997). Role of cellular immunity in protection against HFV infection. Advances in Immunology, 65, 277-346. Saag, M. S. (1997). Quantitation of HIV viral load: A tool for clinical practice? In M. A. Sande & P. A. Volberding (Eds.), The medical management of AIDS (5th ed., pp. 57-74). Philadelphia: W. B. Saunders. Shearer, G. M., & Clerici, M. (1992). T helper cell immune dysfunction in asymptomatic, HFV-1-seropositive individuals: The role of TH1-TH2 cross regulation. In R. L. Coffman (Ed.), Regulation and functional significance of T-Cell subsets (pp. 21-43). Basel, Karger. . (1996). Type 1 and type 2 responses in HIV infection and exposure. In S. Gupta (Ed.), Immunology of HIV infection (pp. 229-241). New York: Plenum. Snyder, B. K. & Sigal, L. H. (1994). Aging, nutrition and the immune system: B. nutrition and immunity. In L. H. Sigal & Y. Ron (Eds.), Immunology and Inflammation:. Basic mechanisms and clinical consequences (pp. 509-517). New York: McGraw-Hill.

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Staprans, S. I., & Feinberg, M. B. (1997). Natural history and immunopathogenesis of HFV-1 disease. In M. A. Sande 8c P. A. Volberding (Eds.), The medical management of AIDS (5th ed., pp. 29-55). Philadelphia: W. B. Saunders. Stine, G. J. (1997). AIDS update 1997. Saddle River, NJ: Prentice Hall. Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science, 267, 1456-1462. Unutmaz, D., & Littman, I). R. (1997). Expression pattern of HIV-1 coreceptors on T cells: Implications for viral transmission and lymphocyte homing. Proceedings of the National Academy of Science, 94, 1615-1618. Wei, X., Ghosh, S. K., Taylor, M. E., Johnson, V. A., Emini, E. A., Deutsch, P., Lifson, J. D., Bonhoffer, S., Nowak, M. A., Hahn, B. H., Saag, M. S., & Shaw, G. M. (1995). Viral dynamics in human immunodeficiency virus type 1 infection. Nature, 373, 117-122. Weinhold, K. J., Lyerly, H. K., Stanley, S. D., Austin, A. A., Matthews, T. J., & Bolognesi, D. P. (1989). HIV-1 gp!20-mediated immune suppression and lymphocyte destruction in the absence of viral infection. Journal of Immunology, 142, 3091-3097. Weiss, R. A. (1994). The virus and its target cells. In S. Broder, T. C. Merigan, & D. Bolognesi (Eds.), Textbook of AIDS medicine (pp. 15-20). Baltimore: Williams & Wilkins. Weller, S. K., Joy, A. E., & Temin, H. M. (1980). Correlation between cell killing and massive second-round superinfection by members of some subgroups of avian leukosis virus. Journal of Virology, 33, 494—506. Wu, B. L., Paxton, W. A., Kassam, N., Ruffing, N., Rottman,J. B., Sullivan, N., Choe, H., Sodroski, J., Newman, W., Koup, R. A., & McKay, C. R. (1997). CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV1, in vitro. Journal of Experimental Medicine, 185, 1681—1691. Young, J. A. T. (1994). The replication cycle of HIV-1. In P. T. Cohen, M. A. Sande, & P. A. Volberding (Eds.), The. AIDS knowledge base (2nd ed., pp. 3.1-1 to 3.1-12). Boston: Little, Brown. Zarling, J. M., Ledbetter, J. A., Sias,J., Fultz, P., Eichberg, J., Gjerset, G., & Moran, P. A. (1990). HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4+ cells. Journal of Immunology, 144, 2992-2998. Zeller, J. M., McCain, N. L., & Swanson, B. (1996). Immunological and virological markers of HIV disease progression. Journal of the Association of Nurses in AIDS Care, 7(1), 15-27.

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3

Preventing HIV Infection Barbara Berger and Vida M. Vizgirda

Tien the HIV epidemic first emerged, little was known regarding effective disease prevention programs in general, and the finer points of transmission behaviors were yet to be elucidated. Currently, much more information is available about how these transmission behaviors interact with social, cultural, and personal factors in determining an individual's risk of HIV infection. Effective prevention programs must not only address the specific behaviors linked to transmission of HIV, but must also tailor that information to the various contexts within which these behaviors may occur. This chapter reviews the behaviors that place an individual at risk for HIV infection and ways in which context can influence transmission and adoption of risk reduction measures. Information on prevention programs will focus on those characteristics most associated with successful risk reduction and decreased HIV seroconversion. Much of the information on how to protect oneself from HIV is straightforward, but questions of skill, motivation, and access to prevention resources continue to complicate HIV prevention.

w

SEXUAL TRANSMISSION OF HIV Modes of Transmission The risk of HIV transmission during sex is entirely related to the exchange of body fluids. The relative risk of transmission appears 97

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to vary with the type of activity. Body fluids known to contain and transmit HIV include ejaculate, vaginal secretions, breast milk, and blood. Although HIV has been recovered from saliva, only saliva contaminated with blood from oral lesions or gum disease has been implicated in HIV transmission (Centers for Disease Control and Prevention, 1997a). There is a theoretical possibility of HIV transmission during "passionate" kissing, although kissing in the absence of oral lesions or bleeding is considered generally safe (Marzili, 1989; Woolley, 1989). Cases of HIV transmission during oro-genital sex, with and without ejaculation, have also been reported (Edwards & Carne, 1998). Anal and vaginal intercourse are associated with higher risk of HIV transmission compared to oral sex (European Study Group on Heterosexual Transmission of HIV, 1992; Seidlin, Vogler, Lee, Lee,&Dubin, 1993;Voeller, 1991). Bleeding during intercourse has also been associated with increased risk of sexually transmitted HIV, both to male and to female partners (European Study Group; Lazzarin, Saracco, Musicco, Nicolosi, & Italian Study Group on HIV Heterosexual Transmission, 1991; Seidlin et al.). Sexual Practices Most adults are sexually active, with a range of sexual practices that may include vaginal, oral, and anal intercourse. Each of these practices carries some risk of HIV transmission if one's partner is infected, although the degree of risk differs across behaviors. For example, it appears that unprotected anal intercourse is more likely to transmit HIV than unprotected vaginal intercourse (European Study Group, 1992; Padian, Shiboski, & Jewell, 1990). Thus, in evaluating the risk associated with sexual activities, the prevalence of specific sexual behaviors must be taken in to account. Reviewing information on sexual behaviors collected by several major surveys of American health and family life, Seidman and Rieder (1994) found that 91% of males between ages 25 and 59 are heterosexually active. Of these, 25% had 20 or more lifetime partners, and 55% had 2 to 19 lifetime partners. In the National Health and Social Life Survey, Laumann, Gagnon, Michael, and Michaels (1994) interviewed a probability sample of men and women of all ages. This more inclusive sample reported an overall median of 3

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partners (median number of sexual partners for men was 6 and for women was 2), with nearly 20% reporting more than 10 lifetime sexual partners. The most important demographic predictors of multiple partners were marital status (unmarried), gender (male), age (< 30), and race (Black) (Laumann et al., 1994; Seidman & Rieder, 1994). These findings are consistent with those in adolescents ages 14 to 19 (Kegeles, Adler, &Irwin, 1988), i.e., that 53% of females and 72% of males had more than 1 sex partner over a 1-year period. Similarly, the 1995 Youth Risk Behavior Survey of 10,904 high school students (Centers for Disease Control and Prevention, 1996c) found that 52% of Black males, compared to 15% of White males, had had 4 or more sex partners in their lifetime. The number of partners for homosexual men may be higher than for exclusively heterosexual men, but not at a statistically significant level. For example, men with only female partners averaged nearly 2 partners in the past year, compared to 3 partners in the past year for men who selfidentified as homosexual or bisexual (Laumann et al., 1994). In general, the age at first intercourse has been decreasing. For example, White females born 1963-1967 had intercourse approximately one year earlier than those born 1933-1942 (Laumann et al., 1994). Laumann and colleagues found that half of Black males had had intercourse by age 15, compared with age 16 1/2 for Hispanic males and nearly 17 for White males. Half of Black females had had intercourse by age 17, compared to approximately age 18 for White and Hispanic females. By age 19, over 75% of females and over 80% of males had engaged in sexual intercourse (Seidman & Rieder, 1994). According to the Centers for Disease Control and Prevention (1996c), 9% of high school students nationwide had sex by age 13. However, in groups with higher risk of HIV infection, these figures may be even more extreme. In a survey of high risk 9to 15-year-olds living in public housing, 12% of 9-year-olds (both boys and girls) claimed to have had sex; by age 15, all boys and more than 80% of girls reported having sex (Romer et al., 1994). Among men ages 17 to 22 who had sex with men in the San Francisco area, 85% reported first having anal intercourse at or before age 19, and 22%) were age 14 or younger (Lemp et al., 1994). In this sample, younger age at first anal intercourse was also associated with higher rates of HIV infection (15.2% among those age 14 oryounger,

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11.6% among 15- to 19-year-olds, and 3.8% among those age 20 and older). Nearly all adults (95% of men and 97% of women) reported having vaginal intercourse at some time in their lives (Laumann et al., 1994). The remaining 5% and 3% included those who may not yet have begun to have intercourse or who may have had no opportunity or desire to engage in vaginal intercourse. Oral sex, including fellatio (performed on a male) and cunnilingus (performed on a female), was practiced by many, though not as regularly or frequently as vaginal intercourse. While 76% to 79% of men and 67% to 73% of women reported having oral sex in their lifetimes, only 19% to 27% of men and 20% to 28% of women reported oral sex during their last sexual episode (Laumann et al.). Among men who have sex with men (MSM) and women who have sex with women (WSW), oral sex was highly prevalent within the past year (90% to 95%) (Laumann et al., 1994). The prevalence of anal intercourse is less clearly defined. Up to one quarter of heterosexuals reported having had anal intercourse (Seidman & Rieder, 1994). Similarly, Laumann and colleagues (1994) found that, across all sexually active adults, 26% of men and 20% of women reported having participated at some time in anal intercourse. For those with opposite-gender partners, 10% of men and 9% of women reported practicing anal intercourse in the past year (Laumann et al., 1994), although only 2% of men and 1% of women had done so during their last sexual encounter. These findings are consistent with Seidman and Rieder's (1994) and Voeller's (1991) conclusion that 10% is a conservative estimate of the number of sexually active Americans who engage in heterosexual anal intercourse with some regularity. Although anal intercourse is more common among MSM, it is not universally practiced even by those who identify themselves as exclusively homosexual. Of men who had male sex partners in the past year, 21% to 23% did not include anal intercourse in their repertoire of practices (Laumann et al., 1994). Factors Modifying Risk of Sexual Transmission Sexually transmitted diseases (STDs), whether ulcerative or nonulcerative (de Vincenzi, 1994; Hook et al., 1992; Laga et al., 1993; Lazzarin etal., 1991; Plummeretal., 1991) and whether existing in the person

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with HIV or in their HlV-uninfected partner (Centers for Disease Control and Prevention, 1997b), have been associated with increased risk of HIV transmission. Ulcerations that provide a portal of entry for HIV and inflammatory processes that concentrate infectable cells at a site of virus deposition or that increase the concentration of HIV being deposited may contribute to the link between STDs and HIV transmission (Levine et al., 1998). Because HIV infection has been associated with nonulcerative STDs such as chlamydia and gonorrhea in younger (adolescent) women, researchers have speculated that the immature cervical epithelium may facilitate HIV transmission in these cases (Stein, 1995). Because STDs are associated with unsafe sexual practices such as having multiple partners or unprotected intercourse (Centers for Disease Control and Prevention, 1997c), STD rates may be viewed as proxies for HIV risk behavior. The high rates of STDs among adolescents, whether from heterosexual or homosexual activity, increase concerns about HIV transmission among this population. STD rates in general decreased over the period from 1990 to 1996. However, the rates for chlamydia and gonorrhea in women remained highest among those ages 15 to 19, and for men the gonorrhea rate was highest among 20- to 24-year-olds, closely followed by 15- to 19year-olds (Centers for Disease Control and Prevention, 1997c). A link between STDs and HIV infection has been demonstrated in young MSM. Two separate studies found HIV seroprevalence rates of 23% to 25% among young MSM with a history of an STD, whereas only 3% to 6% of those with no history of STD were HIV-positive (Lemp et al., 1994; Ruiz, Facer, & Sun, 1998). Sexual transmission of HIV can also be modified by the consistent use of condoms. Studies among HFV-discordant couples (couples in which only one partner is infected with HIV) have demonstrated that using condoms with every episode of intercourse is effective in preventing HIV transmission. Deschamps, Pape, Hafner, and Johnson (1996) reported one seroconversion among 42 Haitian couples who always used condoms, compared to a seroconversion rate of 6.8/100 person-years among those who intermittently or never used condoms. De Vincenzi (1994) found 0 seroconversions among 124 couples who always used condoms in 15,000 protected vaginal and anal sexual contacts. Among those who did not consistently use condoms, HIV seroconversions occurred at a rate of 4.8/100 person-

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years. De Vincenzi also found no difference in the number of seroconversions between couples who used condoms for less than half of their sexual encounters compared to those using condoms for more than 50% but not 100% of encounters. Condoms are clearly effective in preventing transmission of HIV, if used during every sexual encounter. Use of drugs, including alcohol, that affect judgment and motivation can increase the likelihood of exposure to HIV during sexual activity. Whether legal or illegal, injected, ingested, or inhaled, any substance that decreases inhibitions or alters consciousness can interfere with decision-making related to whether, how, and with whom to engage in sex. For example, heterosexual female and homosexual male respondents in Trocki and Leigh's (1991) survey of San Francisco adults reported being less likely to use a condom for vaginal or anal intercourse when feeling intoxicated. The effects of drug use on sexual behavior is a particular concern with adolescents. According to the National Institute on Drug Abuse (National Commission on AIDS, 1994), 89% of high school seniors have used alcohol, 40% reported using marijuana, and 9% have tried cocaine. Nationwide, 24.8% of sexually active high school students reported using alcohol or drugs at last sexual intercourse (Centers for Disease Control and Prevention, 1996c). Sixteen percent of Hingson, Strunin, Berlin, and Heeren's (1990) random sample of adolescents reported using condoms less often after drinking. In two studies of young MSM, both Ruiz and colleagues (1998) and Remafedi (1994) found that the prevalence of unprotected anal intercourse was significantly higher for those reporting recent drug use during sex. By increasing the likelihood that sexual activity will be unsafe, drug use increases the risk of HIV transmission. The particular sexual practices, age at onset of sexual relations, and number of sexual partners over time all influence the risk of HIV infection via sexual activity. Other significant factors include STDs, condom use, and concomitant drug use. Information about the risks associated with all types of sexual activities should be addressed with all audiences in HIV prevention programs. Methods Protecting against Sexual Transmission of HIV There are several ways to protect against sexual transmission of HIV, some of which participants will find more practical or acceptable

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than others. Which method of protection is best will depend on the people involved, their values and beliefs related to sex, the context or circumstances in which they are acting, and their access to resources. By understanding the different options for protection during sexual activity, the individual will be better able to choose and modify sexual behaviors in ways that minimize the risk of HIV transmission. Abstinence offers complete protection from HIV and other sexually transmitted diseases. While abstinence is an effective strategy and may be encouraged especially among adolescents, it is not realistic as the sole option for avoiding HIV. Abstinence is seldom a viable approach to lifelong HIV prevention. Furthermore, intending to abstain from sex without considering other possible methods of protection may leave the person entirely unprotected, should abstinence fail. Given data about sexual activity of adolescents and adults, abstinence appears not to be an option for many persons. Monogamy can prevent sexually transmitted HIV if both partners are monogamous, neither is HlV-infected, and neither partner participates in other activities (such as injection drug use) through which he or she may acquire HIV. This method of protection requires an understanding of the difference between lifetime monogamy (one partner throughout one's life) and serial monogamy (one partner at a time, but several partners over time), and recognition that HIV tests are not infallible. For example, either partner may test negative for HIV during "the window period" before antibodies are detectable, yet be infected with HIV and able to transmit it through sexual behavior to the partner. Outercoune is a term for any nonpenetrative sexual activity that involves contact with intact skin but does not result in an exchange of potentially infectious body fluids. Such activities include masturbation, frottage, petting, massage, and cuddling. Use of sex toys is safe as long as they are not shared between partners, since sharing can expose one partner to the other's secretions. For some people, outercourse can be a satisfactory alternative to more conventional penetrative sex. However, because outercourse activities may lead to penetrative sexual activity, partners must be clear about the point beyond which additional protection is required to avoid exchanging body fluids.

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Barriers include the male latex condom and the dental dam, a thin latex or polyurethane film that protects the oral mucosa during cunnilingus. Latex condoms have been shown to be highly effective in preventing HIV transmission when used correctly, and experience with condoms results in greatly decreased failure rates (Gates Be Stone, 1992). In prospective studies in developed countries (Albert, Warner, Hatcher, Trussell, & Bennett, 1995; Centers for Disease Control and Prevention, 1993a) condom breakage rates ranged from 0.5% to 3.7% during vaginal and anal intercourse. Similarly, slippage rates ranged from 0.6% to 5.4%. Strategies to optimize condom performance are presented in Table 3.1. Latex allergy may limit condom use by some people. A male polyurethane condom is also available in the United States. This type of condom has been shown to be significantly more likely to break than latex condoms. In one large clinical trial, the overall condom failure rate (combining breakage and slippage) was 1.7% for latex condoms and 10.8% for polyurethane male condoms (Frezieres, Walsh, Nelson, Clark, & Coulson, 1998). However, male partners reported less discomfort and better sensation with the polyurethane condoms compared to latex condoms. The female condom is a prelubricated polyurethane sheath with an external ring, which holds the opening against the vulva, and a free internal ring, which helps position the sheath in the vagina. Laboratory studies have shown the female condom to be impervious to HIV, and 1-year pregnancy rates of 5% to 11% when used consistently and correctly have been reported (Centers for Disease Control and Prevention, 1993a; Farr, Gabelnick, Sturgen, & Dorflinger, 1994). Advantages of the female condom include a softer polyurethane material that conducts heat better than latex, the ability to put it in place prior to erection and use it with partners who may have trouble sustaining an erection, and the increased ability for women to control the use of protection when a partner refuses to wear male condoms. The female condom is also an alternative to latex condoms for people with latex hypersensitivity. The female condom is somewhat more expensive than conventional male latex condoms. Among women who have tried the female condom, its acceptability is fairly high. In Farr and colleagues' study, 80% of the women reported that they liked the female condom and would recommend

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TABLE 3.1 of HIV

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Proper Use of Condoms to Prevent Sexual Transmission

About male condoms: Use latex condoms only. Lambskin or natural membrane condoms have pores through which hepatitis B virus, and possibly HIV, can pass. Condoms come in many sizes and shapes. If one type is not comfortable, try others. Protect condoms from heat. Do not leave in the car or carry in your wallet for long periods of time. Do not use after the expiration date, or if brittle, sticky, or discolored. Open the package carefully, being sure not to puncture or tear the condom. Do not unroll the condom to inspect it before use, since this is associated with increased rates of condom breakage. Use only water-soluble lubricants such as KY jelly. Avoid oil-based products, including vaseline, mineral oil, and hand lotion, since they can cause rapid (within 60 seconds) deterioration of the latex. Saliva is not recommended as a lubricant because it may contain infectious material. Some condoms come with the spermicide nonoxynol-9 already in the tip. Because high doses of nonoxynol-9 have been associated with genital irritation, it is no longer routinely recommended to prevent HIV transmission. If either partner has a rash or genital irritation, any genital contact will be unsafe. Using a male condom: Use a new latex condom with each act of oral, vaginal, or anal intercourse. Before opening the condom, inspect the wrapper for punctures or defects, and discard if not intact. Pinch 1/2 inch at the tip of the condom to squeeze air out and to leave room for the semen. Unroll the condom onto the erect penis before beginning penetrative intercourse. If uncircumcised, pull the foreskin back before putting on the condom. Use additional water-soluble lubricant on the outside of the condom if your partner is not well lubricated—sex without adequate lubrication increases the likelihood that the condom will break. Monitor the condition of the condom throughout intercourse. If the condom breaks or slips, immediately stop and put on a new condom. Change condoms during prolonged intercourse. Refrain from rough or vigorous sex. Hold on to the rim of the condom during withdrawal to avoid spilling any fluid. Dispose of the used condom in the trash. Flushing a condom down the toilet is bad for the plumbing. Wash the genital area thoroughly with soap and water to remove all secretions before cuddling. (continued)

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TABLE 3.1

(continued)

Using a female condom: The female condom may be applied well before either partner is aroused, since it does not require an erect penis. Inspect the condom for tears or punctures, and discard if any defects are visible. Lubricant, either water- or oil-based, should be used, both on the outside to help hold the condom in place against the vaginal wall, and on the inside to protect against tears and to decrease displacement. To insert the female condom, pinch the inner ring at the closed end with the thumb and middle finger, and insert into the vaginal canal. Then put your index finger inside the condom and push the inner ring up behind the pubic bone, similar to a diaphragm. Be sure the sheath is not twisted. The large ring stays outside, covering the labia. Avoid penile misrouting/penetration by the penis outside the outer ring. If the female condom tears or slips, immediately stop and put on a new condom with additional lubricant. To remove the female condom, squeeze and twist the outer ring to prevent spillage, and pull gently. Dispose of the used condom in the trash, not in the toilet. Use a new female condom with each act, and remove it promptly after ejaculation. It is not recommended to use a male latex condom and the female condom at the same time, since friction between the two materials may cause tears or slippage of either condom. Adapted from Gates & Stone (1992), Centers for Disease Control and Prevention (1993a), Gollub & Stein (1993), Joffe (1993), and Reality® product information [online], available at http://www.femalehealth.com/yourquests.html.

it to friends. In a small sample of female staff and patients, 73% of respondents, and 44% of their male partners, preferred the female condom compared to male condoms (Gollub, Stein, & El-Sadr, 1995). About 15% to 20% experienced some malfunction, including displacement of the condom or "penile misrouting," that could have placed them at risk for HIV infection. In a sample of MSM using condoms for anal intercourse, 86% indicated that they would use the female condom again, and 54% preferred it to male condoms (Gibson, McFarland, Wohlfeiler, Scheer, & Katz, 1999). However, although 86% of female sex workers were willing to recommend the female condom to others, only 24% preferred it to male condoms (Witte, El-Bassel, Wada, Gray, & Wallace, 1999). Focus groups of men have demonstrated a wide range of attitudes towards the female condom (Seal & Ehrhardt, 1999), although attitudes following actual

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experience with the female condom were more positive (El-Bassel, Krishnan, Schilling, Witte, & Gibert, 1998). In general, attitudes toward the female condom appear to be more favorable among people who have experience with using the device. Although the higher failure rates with both male and female polyurethane condoms are a concern in terms of HIV prevention, these products do offer an alternative for people who are allergic to latex. Information on how to use the female condom is included in Table 3.1. Those techniques that do not reliably protect against pregnancy, such as coitus interruptus, douching after sex, and the rhythm method, are entirely ineffective against HIV. Other techniques that do prevent pregnancy may not reliably decrease the risk of contracting HIV. For example, hormonal contraceptives, including birth control pills and injectable or implantable contraceptives such as Norplant, do not protect against HIV, and may even increase the risk of transmission because of their effects on the vaginal environment (European Study Group, 1992; Plummer et al., 1991). Intrauterine devices, sterilization, and hysterectomy are other methods that prevent pregnancy but are not effective against HIV. The diaphragm and cervical cap are latex barriers that cover the cervix, acting as physical barriers to HIV infection through the cervix. However, neither the diaphragm nor the cap is considered adequate protection against HIV transmission, since HIV can also enter the body through the vaginal mucosa. Spermicides and virucides have been considered as methods of preventing sexual transmission of HFV. Using nonoxynol-9 is no longer recommended, since the vaginal irritation associated with frequent use and high doses may actually increase HIV transmission (Howe, Minkoff, & Duerr, 1994). There is some evidence that lower concentrations of nonoxynol-9 may be protective (Zekeng, Feldblum, Oliver, & Kaptue, 1993), but the role of nonoxynol-9 in preventing sexual transmission of HIV remains unclear (Wittkowski, Susser, 8c Dietz, 1999). "Partner history" refers to the past sexual and drug use activities of either participant in a sexual encounter. By knowing a potential partner's risk behaviors, people may believe they can judge how likely that person is to have become infected with HIV. Unfortunately, there is ample evidence that partners are not always forthright about their past sexual and drug experiences. Among bisexual men,

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fewer than half disclosed the fact that they also had male partners to their female partners (Wold et al., 1998). In a study of sexually active HIV-seropositive men (Marks, Richardson, 8c Maldonado, 1991), 52% had not told at least one of their sexual partners, and the more partners they had, the less likely they were to disclose their HIV status. Similarly, Stein and colleagues (1998) found that 40% of their sexually active HIV-positive respondents admitted not disclosing their HIV status to all sexual partners in the preceding 6 months, and, of that 40%, 57% did not consistently use condoms. Even among men who used condoms, 13% failed to disclose condom breakage to their partners, potentially resulting in unintended pregnancy or delayed treatment for disease (Warner, Boles, & Goldsmith, 1997). Information on preventing sexual transmission of HIV is available to the general public over the Internet and through various other sources such as popular magazines and radio. Although these sources have been very helpful in getting prevention messages to the public, consumers must be aware that some safer sex information available through the media, including the Internet, may not be entirely correct. Consumers can be very confident about information from a reputable source or Internet site, such as the Centers for Disease Control and Prevention (http://www.cdc.gov), the National AIDS Clearing House (Centers for Disease Control and Prevention National AIDS Clearing House at 800-458-5231), or a university or other major medical center, but should be more skeptical of information from unknown individuals or organizations.

Safer Sex Recommendations on safer sex have been widely disseminated to the general public over the past decade. Sex practices that are considered always safe include abstinence and nonpenetrative sexual behaviors that do not involve the exchange of body fluids. Sexual behaviors that are unsafe include any of the following performed without a latex barrier: penetrative vaginal or anal intercourse, fellatio or cunnilingus, heavy petting, and sharing of sex toys. Each of these unsafe behaviors becomes safer with the use of a latex barrier such as a condom. However, if the condom or barrier fails (breaks, leaks, falls off), that activity poses a risk for HIV transmission. Increasingly

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rough sexual activities that lead to mucosal trauma or bleeding, such as "fisting" or rough anal intercourse, are considered very unsafe. Even when latex barriers are used, these activities carry some risk, since the roughness of the activity may damage the protective barrier. The range of possible sexual expressions is limited only by the human imagination, making it impossible to identify every possible behavior and its associated risk of HIV transmission. However, knowing the extremes of safe and unsafe activities, and understanding how a safer behavior can turn into an unsafe activity, allows the individual to judge the degree of risk involved with a particular act. An informed participant can determine where a given behavior would fall along the continuum from safe to unsafe, depending on the likelihood of exposure to body fluids. Motivational Aspects of Sexual Prevention Knowing how to avoid sexually transmitted HIV does not guarantee that prevention methods will be used in every sexual encounter. The reality is that condoms are not used 100% of the time. Even among couples who know they are HFV-discordant, less than 50% always used condoms (de Vincenzi, 1994; Deschamps et al., 1996). In the general U.S. population, levels of consistent condom use, though increased over rates in the 1970s and early 1980s, remain low. Studies of representative samples of adults in the United States indicate that approximately 23% to 36% of those with multiple partners consistently used condoms with their secondary partners (Binson, Dolcini, Pollack, & Catania, 1993; Catania et al., 1995; Leigh, Temple, & Trocki, 1993), and approximately 22% of these respondents always used condoms with their primary partners. Among a group of inner city women considered at risk for sexually transmitted HIV, 30% reported always using condoms and 51% reported never using condoms in the previous 6 months (Heckman et al., 1996). In the Youth Risk Behavior Survey (Centers for Disease Control and Prevention, 1996c), 54% of adolescents reported using a condom during their last sexual encounter. Similarly, nearly half of a group of runaway adolescents in New York City reported condom use at last intercourse, but less than 20% reported always using condoms (Rotheram-Borus 8c Koopman, 1991).

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So what can account for these low rates of barrier protection use among people who are at some risk of sexually transmitted HIV? A number of factors interfere with consistent condom use. Although evidence of the effectiveness of condoms is available (Centers for Disease Control and Prevention, 1993a), many people believe that condoms are not effective, or not adequately effective, in preventing HIV transmission. For example, over half the respondents to a telephone survey believed condoms might fail during intercourse (Choi, Rickman, & Catania, 1994). Others, though their behavior clearly involves some risk for HIV transmission, do not consider themselves at risk for HIV, perhaps because they feel they know their partner, because they are not part of the "risk groups" identified with AIDS early in the epidemic, or because they are uninformed about how HIV can be transmitted sexually (St. Lawrence, 1993). Particularly for adolescents, who are well known for their feelings of invulnerability (Stiffman, Earls, Dore, & Cunningham, 1992), the threat posed by a virus that may not cause illness for a decade may seem too intangible to bother about (Joffe, 1993). Many people have negative attitudes toward condoms. Leonard (1990) found a general dislike of condoms among male clients of prostitutes, often to the extent of refusing intercourse if the woman insisted on a condom. In a probability sample of heterosexual adults (Choi et al., 1994), 41% believed that using a condom interferes with sensation and sexual pleasure, and 21% reported that putting condoms on was uncomfortable. Others believe that a condom makes it more difficult to maintain an erection (Ames, Atchinson, & Rose, 1995). Buying condoms is embarrassing (Choi et al., 1994; Hingson et al., 1990; Sacco, Rickman, Thompson, Levine, & Reed, 1993), particularly for women and adolescents, and may be inconvenient if stores are not open when a condom is needed (Wight, 1992). Access to condoms may also be more difficult for individuals with marginal finances, such as runaway adolescents (Rotheram-Borus & Koopman, 1991) or people in developing countries. Sexuality and sexual behavior can carry powerful, pervasive, and primal messages that tap into deeply held beliefs about sexual identity, masculinity, and power and dominance. For some men, using a condom diminishes their feelings of virility and potency (Campbell, 1995; Wight, 1992). For some, condoms are associated only with prostitutes and are not to be used with the decent women in their

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lives (Marin, Marin, & Juarez, 1988). Frank and open discussions of sexuality and condom use may also violate cultural norms calling for female naivete regarding all sexual topics (Mays & Cochran, 1988). Not using condoms for intercourse may also be considered an affirmation of the legitimacy of gay sex (Ames, Atchinson, & Rose, 1995). Women may be concerned that carrying condoms or having frank discussions about sex will be interpreted as evidence of their own promiscuity (Airhihenbuwa, DiClemente, Wingood, & Lowe, 1992; Hillier, Harrison, & Warr, 1998; Wight, 1992). When negotiating for condom use, women often find themselves at a disadvantage (Fullilove, Fullilove, Haynes, & Gross, 1990; Sacco et al., 1993; Wight, 1992). As Wight (1992) noted, gender-related power decisions can make insisting on condoms a lose-lose proposition for women—the woman can insist on condoms at the expense of the relationship, or not insist and risk being exposed to HIV. Women may find it especially difficult to negotiate condom use in abusive relationships (Wingood & DiClemente, 1997). Women who are dependent on their sexual relationship for status or financial support may see themselves as having more to lose by insisting on condoms (Wight, 1992). The effects of drugs and alcohol on judgment and motivation can interfere with condom use. Kelly and colleagues (1995) speculated that the association between patronizing bars and high-risk sexual behaviors could be attributed at least in part to the disinhibiting effects of alcohol. Among adolescents in Massachusetts, 25% reported using condoms less often when taking drugs, and 16% used condoms less often when drinking alcohol (Hingson et al., 1990). Male street youth who used marijuana daily were less likely to use condoms (Clements, Gleghorn, Garcia, Katz, & Marx, 1997). Differential condom use, that is, using condoms more often with one type of sex partner than another, occurs in various contexts. Prostitutes are more likely to insist on, or at least request, condoms with their commercial clients, while with emotionally intimate partners, the norm is not to use condoms (Campbell, 1995; McKeganey, 1994). Male sex workers in Australia, for example, demarcate work sex, casual sex, and personal sex based in part on whether a condom is used (Browne & Minichiello, 1995). As McKeganey (1994) noted, norms regarding condom use with clients may vary widely over a

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fairly small geographic region, but this pattern of using condoms less often in personal as opposed to commercial sexual encounters persists. This general pattern is also seen with condom use among heterosexuals who have secondary partners in addition to a single primary partner. Typically, condoms are used more frequently with the secondary partners, though even there the level of condom use tends to be low. In a representative sample of young urban heterosexuals with multiple partners, 36% always used condoms with secondary partners, while 23% consistently used condoms with their primary partner (Binson et al., 1993). A representative national sample of African-Americans was more likely to use condoms with secondary partners compared to condom use with primary partners, though 45% reported never using condoms at all (Grinstead, Peterson, Faigeles, & Catania, 1997). Anderson et al. (1999) found that only 19% of a nationally representative sample reported using condoms in their last sexual encounter with an on-going partner, while 62% who had recently had sex outside their main relationship reported condom use. Condom use can be particularly problematic among men who have sex with both men and women. Bisexuals in Boston were more likely to engage in unprotected sex with their female partners than with male partners (Wold et al., 1998). Nongay-identifying men who had sex with men tended to deny any increased risk of HIV for themselves or for their female partners, and this was reflected in their very low rates of condom use with either male or female partners (Goldbaum, Perdue, & Higgins, 1996). One of the most difficult aspects of sexual behavior to reconcile with condom use is the desire to trust one's partner. This impulse to trust is directly at odds with consistently protecting oneself, especially from a partner who is not known to have HIV. Indeed, many people worry that merely asking to use condoms will cost them their partner's trust (Choi et al., 1994). Wight (1992) noted that as adolescents' relationships become more committed, continued use of condoms may be interpreted as distrust. Similarly, Ames and colleagues (1995) reported that for gay men, not using condoms is a sign of trust and may indicate a special, more intimate meaning to the relationship that is contradicted by insisting on condoms. Successfully changing behavior to prevent sexual transmission of HIV will require "finding

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the proper mix between protection from infection, satisfying sexual desire, and building emotional and loving bonds" (Ames etal., 1995, P- 71). INJECTING DRUG USE AND HIV TRANSMISSION Modes of Transmission HIV can be transmitted by reusing injection equipment that has previously been used by someone with HIV. Injecting drug users (IDUs) who share injection equipment such as syringes and needles, filters, and water may be at particular risk due to practices such as "backloacling," "frontloading," and "booting." Backloading and frontloading (Grund, Kaplan, Adriaans, Blanken, & Huisman, 1990) are techniques for transferring drug between two syringes in order to divide the drug or to mix two drugs together. Booting, which appears to be more common with cocaine injection compared to heroin injection (Greenfield, Bigelow, 8c Brooner, 1992), involves aspirating blood into the syringe to mix with the drug just before injecting, a practice that is believed to intensify the drug's effects. Any equipment, including spoons or bottle caps for mixing drug, cotton through which drug is filtered, or rinse water from a communal jar, can become contaminated with HIV, and can pass HIV along to the next user (Wiebel et al., 1996). Sharing these types of equipment is common. Booth, Koester, Brewster, Wiebel, and Fritz (1991) reported that "cookers" were shared by 86% of IDUs in their sample, and that 70% shared needles, similar to the 71% of IDUs in a Baltimore sample who reported sharing needles without cleaning them (Latkin, Mandell, Vlahov, Oziemkowska, & Celentano, 1996). However, IDUs who do not share any equipment or supplies can continue to inject drugs without risking HIV infection from their injection practices. Other practices in which needles could be reused, such as injecting vitamins or steroids, tattooing or body piercing, and medical care in situations in which sterile equipment is scarce (Centers for Disease Control and Prevention, 1996a), may also carry transmission risk.

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Modifying Factors The actual risk of contracting HIV due to injection practices that involve sharing varies according to a number of factors. One important aspect of IDU culture is the network, the group of people involved in drug-related activities, including obtaining drugs and equipment and injecting together. Although these networks may provide emotional, financial, and informational support that the IDU cannot obtain from other sources, they may also draw the IDU into environments with greater risk for HIV transmission. An increased prevalence of HIV in the IDU's network of injectors will increase the likelihood that sharing equipment will include sharing HIV (Alcabes & Friedland, 1995). Smaller networks tend to be associated with fewer sharing partners and relatively private venues for injecting, compared to more public settings such as shooting galleries (Walters, 1989). Injecting drug use in shooting galleries has been associated with an increased risk of HIV (Celentano et al., 1991), perhaps because of the increased likelihood of using HIV-infected equipment (Latkin et al., 1996; Neaigus et al., 1994) and the increased prevalence of HIV infection in that environment. The network may also be influential in establishing and maintaining behavioral norms for its members. These norms often set expectations for sharing drugs and injection equipment, but may also include sharing other commodities such as food and housing (Grund, Kaplan, & Adriaans, 1991). These exchanges not only provide material support, but also symbolize social bonds that develop among the network members. For example, Singer (1991) refers to needle sharing as "a core rite of intensification" (p. 268) in the IDU subculture. The affective component of this type of support is also visible in Mays and Cochran's (1988) account of allowing another IDU to "wash" (diluting and injecting the residue from a recently used syringe to postpone withdrawal symptoms) as an expression of friendship and loyalty. The IDU's injection experience also appears to make a difference in injection-related HIV transmission. HIV prevalence has been found to be higher among younger and new-onset injectors in Baltimore (Alcabes & Friedland, 1995). Van Ameijden, van den Hoek, van Haastrecht, and Coutinho (1992) also reported an increased risk of HIV seroconversion among novices, that is, those who first injected

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within the previous 2 years. Grund and colleagues (1991) provide several cases illustrating how more experienced IDUs are able to anticipate problems and make adjustments to keep their injection behavior safe. Novices, on the other hand, found themselves in situations where their only alternative to unsafe injection was not to inject at all, generally not an acceptable option. The increased risk of HIV associated with failing to plan for unsafe injection conditions can be exacerbated by drug craving, the desire to inject as soon after scoring as possible (Barnard, 1993; Grund et al., 1991). Injection frequency and equipment sharing have been linked to the type of drug being injected, with cocaine tending to increase both frequency of injection and sharing, and consequently the risk of acquiring HIV (Alcabes & Friedland, 1995; Grund et al., 1991). Sharing of injection equipment occurs when an IDU has limited access to dean equipment. Where injection equipment can be purchased through pharmacies or obtained at needle exchanges, sharing is less likely (Barnard, 1993; Calsyn, Saxon, Freeman, & Whittaker, 1991). There may be a protective effect to having legal access to clean injection equipment. Nelson and colleagues (1991) found significantly lower rates of HIV infection in diabetic IDUs (9.8%) compared to their nondiabetic counterparts (24.3%). However, in most states in the United States, legal access to injection equipment is complicated by legislation that prohibits the sale, distribution, or possession of devices that can be used to inject illicit drugs (Gostin, Lazzarini, Jones, & Flaherty, 1997). Such legislation has also prevented widespread development of needle or syringe exchange programs (NEPs or SEPs) in this country. In addition, for IDUs who are incarcerated, the barriers to obtaining clean equipment may be overwhelming (Polonsksy et al., 1994). Gender may also have some effect on sharing behaviors. Women may be more reluctant to obtain clean needles and syringes from pharmacies or NEPs (Barnard, 1993) because they are afraid that being known to inject drugs could be used as a lever to take away their children. Female IDUs are also more likely to have IDUs as primary sex partners, so that sharing syringes becomes an additional expression of intimacy (Dwyer et al., 1994). Dwyer and colleagues also found that women were more likely to report being unable to inject themselves than men. As a result, women were less likely to

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inject alone, leaving them vulnerable to the unsafe injection practices of others. Methods Protecting against HIV Transmission during Injection Drug Use The harm reduction or harm minimization perspective is the framework upon which many HIV prevention efforts with IDUs are based. Programs operating from this perspective work with IDUs to make their behaviors safer without requiring them to stop or reduce their drug use (Des Jarlais, Friedman, & Ward, 1993). Although harm reduction acknowledges the detrimental aspects of drug use, it does not define IDUs solely by their drug use. Instead, it sees them as individuals who will make rational choices to change specific behaviors that place them at risk. Rather than insisting on a drug-free ideal, the harm reduction approach focuses on pragmatic short-term goals to minimize the negative impact of injection drug use on the IDU and others. To be most effective, harm reduction requires a multidimensional approach, not just a single type of program (Brettie, 1991; Paone, Des Jarlais, Gangloff, Milliken, & Friedman, 1995; Stryker et al., 1995). Prevention efforts appropriate to a harm reduction approach include street outreach work teaching safer injection and safer sex techniques, NEPs, HIV counseling and testing programs, and drug treatment programs, including methadone treatment. The following set of easy-to-remember recommendations on safer injection techniques (Broadhead, 1991) incorporates harm reduction principles as it moves hierarchically from safest to least safe behaviors. Don't use drugs. If you do use drugs, don't shoot. If you do shoot, don't share equipment. If you do share, use bleach. Each of the steps of the risk reduction hierarchy that acknowledges drug use also offers an option that can make that activity safer by avoiding HIV. Clearly, in terms of HIV transmission, the riskiest injection behavior is sharing equipment, that is, injecting oneself

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with equipment that another person has already used. Yet even that behavior can be made safer by cleaning the syringe with bleach. When first developed, a typical bleaching protocol called for using full-strength bleach twice, then rinsing twice with water, with the total procedure taking less than 15 seconds (Broadhead, 1991). Different cities and outreach programs developed their own specifications for bleaching injection equipment. In 1993 questions arose regarding whether those bleach protocols were adequate to kill HIV (Centers for Disease Control and Prevention, 1993b). Responding to these concerns, Shapshak and colleagues (1994) demonstrated that both bleach concentration and exposure time were important in disinfecting syringes. Being exposed to full-strength bleach for 30 seconds was sufficient to inactivate HIV, but full-strength bleach for 15 seconds or 10% diluted bleach for 30 seconds was not. Flynn and associates (1994) had similar findings regarding use of fullstrength bleach. However, although both groups concluded that disinfecting injection equipment with full-strength bleach for at least 30 seconds effectively inactivated HIV in syringes, they concurred that using only sterile equipment is a safer practice. Flynn's group also identified corrosion of the needle and loss of smooth plunger movement after about 20 washings as disadvantages of bleaching. A further concern about cleaning with bleach was whether IDUs were following the cleaning procedures they had been taught. McCoy and associates (1994) found that 90% of IDUs who had been instructed in bleaching techniques 6 to 12 months earlier could still perform the basic steps of using bleach and rinsing with water, but only 36% completely filled the syringe with bleach twice, as they had originally been taught. When Gleghorn, Doherty, Vlahov, Celentano, and Jones (1994) videotaped IDUs performing their cleaning procedures, 58% used full-strength bleach, but 46% of those who used bleach had less than 30 seconds of contact time between the bleach and the syringe. IDUs also reported that they were cleaning for about twice as long as they actually were. Ongoing reinforcement of bleaching techniques may be necessary to maintain IDUs' skills at an effective level. Safer injection can also be accomplished by avoiding social pressures to share equipment. IDUs who have internalized HIV prevention messages against sharing injection equipment may handle requests to share bv earning a spare syringe that they are willing to give

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away, since refusals to share can be interpreted as believing that the requesting IDU has HIV (Barnard, 1993). Techniques to avoid sharing include giving equipment away rather than loaning it, or denying having any syringes on hand (Barnard, 1993). These techniques give IDUs the opportunity to protect themselves without disrupting their social connection with the requesting IDU. For those who continue to inject, the safest practice is to use sterile equipment each time. Having access to sterile supplies has been shown to significantly decrease risky injection practices, and concerns that increased access to needles may encourage drug use or initiate new users have not been borne out (National Institutes of Health, 1997; Paone et al., 1995). By decreasing the time a needle is in circulation, NEPs decrease the number of IDUs who use it (Alcabes & Friedland, 1995). NEPs may also be cost-effective. Gold, Gafney, Nelligan, and Millson's (1997) economic analysis of an NEP in Hamilton estimated that the cases of HIV prevented by the NEP would result in a net saving of $1.3 million over 5 years. In many countries syringes are available at legally sanctioned NEPs or can be purchased without a prescription at pharmacies. In the United States, however, most states have some regulations prohibiting the sale and/or possession of injection equipment without a prescription (Gostin et al., 1997). Indeed, the political opposition to providing IDUs access to sterile supplies has been sufficient to outweigh the conclusions of numerous scientific panels and reports that NEPs are beneficial and warranted in HIV prevention (Lurie, 1995). Despite these obstacles, over 100 NEPs were operating in the United States in 1996 (Centers for Disease Control, 1997d). By offering other services in addition to needle exchange, such as referral to drug treatment programs, instruction in safer sex and safer injection techniques, HIV testing and counseling, tuberculosis testing, primary medical care, and STD screening and prevention, NEPs can make themselves more valuable to their IDU clients and more politically acceptable. Ultimately, the most effective approach to HIV prevention for IDUs may be to stop using drugs altogether. Drug treatment programs work with IDUs to help them stop drug use, especially injecting drug use, stop using unclean equipment, and stop high-risk sexual practices (Holtgrave et al., 1995). Longshore, Hsieh, and Anglin (1994) suggest that sexual risk reduction may be more likely as IDUs

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disengage from sex work and increase their perceived self-efficacy. IDUs who do not initially succeed in stopping all drug use may still benefit from the risk reduction practices they learn in treatment. Sex by Drug Interaction As previously discussed, use of any mood-altering substance can lessen the motivation to use risk reduction behaviors. Although alcohol may be the most common drug to impair judgment and expose its users to HIV risk, illicit drugs, particularly smokable cocaine ("crack"), have also been implicated in high-risk sexual behavior. Crack users experience brief but intense highs, followed immediately by craving for more drug (Edlin et al., 1994). In these circumstances of addiction and craving, safer sex practices are not a priority for the user. Edlin and colleagues found that crack use was widespread among both males and females, and in both sexes was associated with high-risk sexual behaviors. Nearly half of men using crack reported 50 or more sex partners, and significantly more male crack users had anal sex with other men. More than two thirds of female crack users had engaged in sex work, often without condoms. Crack use has also been associated with greater numbers of partners, less consistent condom use, higher rates of new STDs among HFV-infected women (Wilson, Minkoff, DeHovitz, Feldman, & Landesman, 1998), and increased rates of HIV infection (Chiasson et al., 1991), particularly among women (Edlin et al., 1994). Edlin and colleagues attributed this increased prevalence of HIV among crack users entirely to their high-risk sex practices. The risk of HIV infection associated with injection drug use may pose an unrecognized threat to the sexual partners of IDUs. Many male IDUs have non-IDU female sex partners (Dwyer et al., 1994; Kane, 1991). These female non-IDU partners may be unaware that their partner injects drugs until the relationship is well established (Kane, 1991). Developing rules within the relationship to minimize the intrusiveness of the partner's drug use may increase the risk of HIV by making it easier to ignore the increased potential for sexual transmission. Although there is evidence that IDUs are adopting safer injection practices, use of safer sex practices has lagged behind. In the United

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States, Booth and colleagues (1991) found that unprotected sex was the norm among IDUs, with 66% reporting that they never used condoms whereas only 6% always did. Only 4% practiced both safer sex and safe injection. Among HIV-infected European IDUs, about two thirds reported using safer injection techniques and not giving away used needles, but only slightly over one third reported consistent condom use (Desenclos, Papaevangelou, & Ancelle-Park, 1993). Those who tested negative for HIV showed a similar pattern of risk reduction, with two thirds or more practicing safe injecting but less than 10% always using a condom. More recently, the proportion of IDUs in Chicago who reported injection risk behavior decreased from 100% to 14%, while those reporting high-risk sexual behaviors decreased from 71% to 45% over a 4-year period (Wiebel et al., 1996). Rhodes, Stimson, and Quirk (1996) suggested that the lack of change toward safer sex practices may be due to IDUs' perceiving less risk from sex than from injection, difficulties applying knowledge of sexual risk reduction to actual situations, and responsibility norms that are tied primarily to injection behaviors rather than sex behaviors for IDUs. OTHER METHODS OF TRANSMITTING HIV Transfusions HIV infection due to transfusing infected blood or blood products, including coagulation factors used to treat hemophilia, was a significant problem until a screening test for HIV antibody became available in 1985. The "window" period between when a person becomes infected with HIV and when that infection can be identified may narrow further as more sensitive methods of detecting HIV become feasible. Recent estimates of the risk of HIV from transfusion in the United States range from 1 in 450,000 (Lackritz et al., 1995) to 1 in 680,000 units transfused (AuBuchon, Birkmeyer, & Busch, 1997). Blood supplies in the United States, Australia, New Zealand, Canada, Japan, and western European countries are tested for HIV antibody (Centers for Disease Control, 1996a). However, people living or traveling in countries with less rigorously screened blood supplies should consider postponing elective medical procedures until they

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can be transported to a locale with reliable testing of the blood supply. Vertical (Mother-to-Child) Transmission Transmission of HIV to young children occurs almost entirely while in utero, during birth, or during breastfeeding, with most perinatal transmission taking place near or during childbirth (Centers for Disease Control and Prevention, 1998a). Before antiretroviral drugs were available, about 25% of infants born to mothers with HIV were also infected with HIV. In 1994 preliminary results from Pediatric AIDS Clinical Trials Group Protocol 076 (PACTG 076) demonstrated that, for HIV-infected mothers with CD4 counts above 200 cells/|oL who had not received antiretroviral therapy earlier in the pregnancy (Centers for Disease Control and Prevention, 1994), administering zidovudine (ZDV) to the mothers during pregnancy and delivery, and to infants for 6 weeks after birth, could decrease HIV transmission to the child. Final results from PACTG 076 showed that 22.6% of infants in the placebo group became infected, compared to only 7.6% of infants in the ZDV group, for a 66% reduction in transmission risk (Outers for Disease Control and Prevention, 1998a). PACTG 185 investigated this effect in women with low CD4 counts who were already taking antiretroviral therapy. Interim results showed a transmission rate of only 4.8%, suggesting that ZDV was also effective for preventing HIV transmission to infants of women with advanced HIV disease, CD4 counts below 200 cells/jlL, and previous ZDV therapy (Centers for Disease Control and Prevention, 1998a). The mechanism by which ZDV reduces HIV transmission to the fetus has not been fully defined. ZDV metabolism in the placenta may significantly contribute to its protective effect, even beyond its antiretroviral effect in the mother. It is still unknown whether other antiretrovirals will perform as well (Centers for Disease Control and Prevention, 1998a). Because there is a possibility of transplacental carcinogenicity due to ZDV, long-term follow-up of children is necessary. The results of PACTG 076 strongly support encouraging all pregnant women to be tested for HIV (The Institute of Medicine [1998]

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has recommended routine HIV testing for all pregnant women). HIV treatment for the woman and prevention of HIV transmission to the infant are separate but related issues to consider in deciding on appropriate therapy for the pregnant woman with HIV and can raise a number of ethical questions. Ultimately, the decision about drug therapy to prevent HIV transmission should be made by the woman after full, noncoercive discussion with her provider about the known and unknown possible effects on both herself and the fetus (Centers for Disease Control and Prevention, 1998a).

Occupational Exposure to HIV In general, people's greatest risk for HIV infection tends to come from behaviors in their personal lives, not from professional activities. Nonetheless, exposures on the job can occur, especially to health care workers such as nurses and laboratory technicians. To prevent occupational exposure to HIV and other blood-borne pathogens, the Centers for Disease Control and Prevention (1998b) have developed standard precautions (formerly called universal precautions). Standard precautions call for health care workers to use gloves, safety glasses, masks, gowns, and other barriers to keep themselves from coming in contact with the blood or other body fluids of all patients, regardless of whether the patient appears to be at risk for having HIV. Standard precautions require health care workers to exercise judgment about which procedures are likely to result in exposure to blood or body fluids. Engineering changes in devices such as syringes and operating room equipment have also been developed to further minimize the likelihood of injury. When a worker is exposed to HIV, the risk of transmission depends on the type of exposure: 0.3% (3 transmissions per 1,000 injuries) with percutaneous injury, 0.1% with mucocutaneous exposure (eyes, nose, or mouth), and less than 0.1% with skin exposure (Centers for Disease Control and Prevention, 1996d). HIV transmission from percutaneous exposure is more likely when injuries are deep or involve visibly bloody equipment, or when the source patient dies of AIDS within 2 months of the exposure (Cardo et al., 1997). If skin has been exposed to HIV-infected fluid, transmission is more likely with prolonged contact over a large area of disrupted integrity

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(Centers for Disease Control, 1996d). There is, of course, no risk of HIV transmission via any of these routes if the source patient is not infected with HIV. Postexposure Prophylaxis for Occupational and Other Types of HIV Exposure. Treatment with antiretrovirals may decrease the risk of seroconversion following occupational exposure to HIV by as much as 80%, although the magnitude of the decrease has been questioned (Cardo et al., 1997). For massive exposure to blood with a high HIV titer, prompt initiation of antiretroviral therapy with ZDV, lamivudirie, and indinavir is recommended (Rachlis & Zarowny, 1998). ZDV and lamivudine may be offered for moderate exposures as well. The timeframe within which PEP must begin to be effective is not clear. Seroconversion has been known to occur despite ZDV monotherapy initiated within 30 minutes of the exposure (Jochimsen, 1997), so, if antiretroviral therapy is warranted, it should begin promptly. Although treatment may be initiated as long as 48 to 72 hours after exposure, administering the first dose within 1 hour of the exposure is strongly encouraged (Henderson, 1999). Some institutions have developed rapid response programs to achieve this goal, including on-call teams to evaluate the exposure and initiate therapy quickly (e.g., Zeh et al., 1998). The treatment period is generally 4 weeks, with HIV testing continuing for at least 6 months and preferably 1 year (Henderson). The exposed worker will need explicit counseling regarding the use of safer sex practices and other risk reduction measures to prevent possible transmission to others until lack of HIV transmission is confirmed. The National Clinicians Post-Exposure Prophylaxis Hotline (1-888-448-4911) is available 24 hours a day, every day, to help clinicians counsel and treat health care workers who have been exposed to HIV or hepatitis viruses. Recommending postexposure prophylaxis following occupational exposures raises the question of prophylaxis for other types of exposure to HIV. The per-episode risk of HIV infection from unprotected sex has been estimated to range from approximately 3% for receptive anal intercourse to 0.03% for insertive vaginal intercourse (Katz & Gerberding, 1998). Because these figures are similar to the risks related to occupational exposure and because prophylactic antiretroviral therapy is associated with decreased rates of transmission in those cases, similar antiretroviral therapy has been suggested follow-

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ing known sexual exposure to HIV (Lurie, Miller, Hecht, Chesney, & Lo, 1998). Victims of rape are candidates for antiretroviral therapy even when the serostatus of the rapist is unknown, because the physical trauma often associated with rape increases the risk of transmission (Lurie et al.). Prophylaxis may also be recommended after isolated incidents of sharing injection equipment with a person known to be infected with HIV (Katz & Gerberding, 1997), or with a person of unknown serostatus in an area with HIV prevalence of 30% or more (Lurie et al.)- For individuals who intend to continue high-risk sexual or injection behavior, postexposure prophylaxis is not recommended, since in effect they would need to be on continuous antiretroviral therapy to address their on-going exposures. However, such individuals should receive explicit risk reduction counseling. Further information on postexposure prophylaxis following nonoccupational exposure is presented in Appendices 1 and 2. Antiretroviral therapy following sexual or IDU exposure remains controversial for a number of reasons (Desmond & Coker, 1998; Evans, Darbyshire, & Cartledge, 1998). Health care providers may be concerned that easy availability of postexposure prophylaxis for sexual or injection exposure will make people less vigilant in avoiding risky behaviors. Timely access to the medications is also much more difficult to arrange in the context of a nonoccupational exposure, diminishing the potential effectiveness of the therapy. Finally, widespread use of such therapy can be quite expensive, with cost estimates ranging from $136,500 to $2 million per case of HIV prevented (Lurie et al., 1998). Further evidence regarding the efficacy of postexposure prophylaxis for nonoccupational exposures and clarification of the costs, benefits, and ethical aspects of access to such therapies are needed to answer this question. Sports-related Exposure The risk of contracting HIV during athletic activities has been estimated to be less that 1 per 85 million game contacts (Mast, Goodman, Bond, Favero, & Drotman, 1995). Again, as with health care workers, the vast majority of the athlete's risk of HIV lies in activities not related to sports, including unprotected sex and sharing equipment

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used to inject performance-enhancing drugs (Centers for Disease Control and Prevention, 1996b). For sports with significant body contact, basic precautions are appropriate, including covering any open wounds to prevent leakage of blood or other fluids during play. Fresh wounds leaking blood or other fluid should be washed with soap and water and covered completely before the athlete returns to play. Anyone else exposed to the fluid should promptly wash it off with soap and water as well. Trainers or medical personnel working with injuries should wear disposable exam gloves when contact with blood or body fluids is anticipated. Strict enforcement of regulations prohibiting unsportsmanlike conduct such as biting and scratching will also minimize potential exposure to blood.

PREVENTION PROGRAMS HIV prevention efforts can take many forms, and may be most effective when using a coordinated strategy that includes a variety of approaches. Formats may include mass media campaigns, counseling and testing services, individual and community outreach programs, and school prevention programs. Mass media campaigns are appropriate for reaching a wide audience with informational messages that encourage condom use and sexual responsibility and discourage drug use. HIV counseling and testing programs can be useful in higher prevalence populations. There is evidence that seropositive individuals who know they are infected are more likely to use risk reduction techniques, although people who test negative do not appear to alter their risk behaviors (Corby &; Jamner, 1996). Outreach programs have come to form the cornerstone of HIV prevention efforts among at-risk populations who may be difficult to access through conventional means. Outreach to individuals aims to help individuals identify those behaviors that place them at risk for HIV infection and implement risk-reduction strategies. This type of outreach is often performed by peer educators who may have experience with the lifestyle of the individuals they contact. In addition to educating individuals about risk reduction, this type of outreach can help them connect with services already available in the communitv. By contrast, community outreach works with social

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groups to shift social norms toward safer practices (Stimson, Eaton, Rhodes, & Power, 1994). School-based HIV prevention programs have been controversial because of fears that they would encourage early sexual activity among teenagers. Kirby and colleagues (1994) reviewed 23 studies of HIV prevention programs in schools, looking for evidence of adverse outcomes and effectiveness. Concerns that explicit HIV prevention messages would result in increased sexual activity were not borne out. All of the programs either delayed the onset of sex or had no effect. No program resulted in increased frequency of sexual activity, and some programs may have resulted in increased condom use. The programs that demonstrated the desired outcomes of increasing condom use, delaying the onset of sexual intercourse, and reducing other risk behaviors such as number of partners had several characteristics in common. First, these programs were grounded in theories of social learning and social influence. They also had a narrow focus, concentrating on reducing specific sexual risk behaviors. Successful programs relied heavily on experiential activities rather than lecture to convey their information and incorporated skills-building activities such as role playing. These programs also included discussion of how to manage social pressures toward having sex and reinforced age- and experience-appropriate values and norms against unprotected sex. School-based condom programs have not been shown to increase sexual activity, although there are indications that they may result in modest but significant increases in condom use (Guttmacher et al., 1997). A number of reviews of HIV prevention programs are available (Centers for Disease Control and Prevention, 1996e; Coates et al., 1996; Corby & Jamner, 1996; Des Jarlais, Padian, & Winkelstein, 1994; Holtgrave et al., 1995; National Institutes of Health, 1997), and their conclusions are highly consistent. HIV prevention programs can bring about behavior change that will prevent transmission of HIV, but not all prevention efforts are equally effective. Several major principles for developing effective HIV prevention programs have emerged: 1. HIV prevention programs should be targeted to well-defined audiences and should have clear objectives and interventions.

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3.

4.

5.

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Defining the audience may require a considerable investment prior to initiating the program itself. Ethnographic studies and inclusion of community informants during development will enhance the program's cultural competence and increase its impact on risk behaviors within the community. Prevention messages should be sensitive to the audience's culture, developmentally appropriate, and linguistically specific (Holtgrave et al., 1995). HIV prevention programs should be grounded in the behavioral and social sciences, incorporating theories of behavioral change and self-efficacy. Concepts from these theories have proven to be empirically important in predicting changes in risk behavior. Information, motivation, and skills building, including condom use, accessing supplies such as condoms, negotiation skills, anticipating the need for protection, and critical thinking skills, are key elements of HIV prevention programs. The intervention should be designed with an appropriate "dosage," in terms of number, duration, and intensity, to have sufficient impact to bring about lasting behavior change. Sustained interventions appear to produce long-term behavioral changes, and more intense interventions may lead to greater risk reduction (Coates et al., 1996). The program should address community myths, such as concerns that NEPs will increase drug use or that AIDS education in schools will increase adolescents' sexual activity. In fact, the demonstrated outcomes of such programs are generally quite congruent with community values. Being prepared to address these questions with clear presentation of the research findings will make it easier for community leaders to support the program. Ongoing evaluation of the program and its impact are important in allowing modifications of the intervention that meet the community's changing needs. Recruiting people from the community to convey prevention information helps keep the message culturally appropriate, and also demonstrates that peers do support behavior changes to protect against HIV.

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Vaccines The spread of HIV infection around the world provides evidence that knowledge alone is inadequate in preventing the transmission of the virus. For often complex reasons discussed earlier in this chapter, individuals may engage in behaviors that place them at risk of HIV infection. As the number of persons infected .with HIV has increased dramatically over the past two decades, scientists have searched diligently for effective treatments for HIV infection and for a safe, effective vaccine. Scientists have sought a vaccine that will either prevent infection by HIV-1 or boost the immune systems of infected individuals. Clinical trials in humans began in the United States as early as 1987 with "simple subunit vaccines" (Frey, 1999, p. 95). Over time scientific knowledge has led to the understanding that an HIV-1 vaccine needs to stimulate both cell-mediated and antibody responses. Proposed vaccines have included live viruses genetically altered to attenuate their pathogenic potential, inactivated whole viruses with various adjuvants, live vector-based (e.g., pox viruses) vaccines, DNA vaccines, HIV peptides and pseudovirions (Fauci, 1998; Letvin, 1998). Some recent vaccines have been recombinantly engineered to include the genome of multiple proteins for HIV (Frey, 1999). Because HIV-1 mutates frequently, scientists have experienced difficulty in developing one or a combination of vaccines that will overcome the generation of viruses capable of escaping immune recognition. A few vaccines have advanced to phase 3 clinical trials, but most have not advanced beyond phase I. While several vaccines have been at least partially successful in preventing HIV infection in nonhuman primates, this partial success has not been replicated in human subjects (Letvin, 1998). In a 1998 speech Fauci summarized impediments to developing an HIV vaccine to include "geographic variability of HIV subtypes, lack of a clear understanding of the correlates of protective immunity in HIV infection, the limitations of available animal models of HIV infection, and challenges of inducing mucosal immunity to prevent sexual transmission of HIV." In addition to the scientific challenges of developing a safe and effective vaccine, several other factors make developing and testing an HIV vaccine difficult. These include difficulty in finding an ade-

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quate number of volunteers for testing; concerns about the safety of those enrolled in clinical trials; social risks of testing HIV antibody positive after receiving a vaccine, depending upon the type of vaccine; concerns that volunteers in clinical trials of vaccines may be more inclined to engage in activities that place them at risk of infection because of an unwarranted belief that they are protected by their participation in the clinical trial; the enormous costs associated with development and testing of potential vaccines; and controversies related to clinical trials in underdeveloped nations (Angell, 1997; Bloom, 1998; Fauci, 1998). While a vaccine for HIV is a\op priority of the federal Office of AIDS Research (a part of the National Institutes of Health), the federal government has been criticized for inadequately funding vaccine research aimed at achieving President Clinton's goal of HIV vaccine by 2007, a goal that some scientists believe cannot be achieved (Wheeler, 1999). Until such time as a safe and effective vaccine and/or a curative treatment is available, efforts to combat the spread of HIV will feature preventive strategies discussed earlier in this chapter. This chapter has provided basic information on sources of risk for HIV infection and factors that modify that risk. After more than a decade of experience with HIV, and with no immediate prospects for an effective vaccine or cure, prevention remains the best solution to stemming the spread of HIV. WThile prevention of HIV transmission is straightfonvard in its basic requirements, the complexities of human motivation and behavior complicate the simplest HIV prevention messages. Efforts to provide the information, motivation, and equipment needed to prevent HIV must continue. Closely involving the community in these prevention efforts will enhance their acceptabilitv and effectiveness. REFERENCES Airhihenbuwa, C. O., DiClemente, R. J., Wingood, G. M., & Lowe, A. (1992). HIV/ AIDS education and prevention among African-Americans: A focus on culture. AIDS Education and Prevention, 4, 267-276. Albert, A. E., Warner, D. L., Hatcher, R. A., Trussell, ]., & Bennett, C. (1995). Condom use among female commercial sex workers in Nevada's legal brothels. America?!. Journal of Public Health, 85, 1514-1520. Alcabes, P., & Friedland, G. (1995). Injection drug use and human immunodeficiency virus infection. Clinical Infectious Diseases, 20, 1467-1479.

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Coates, T. J., Aggleton, P., Gutzwiller, F., Des Jarlais, D., Kihara, M., Kippax, S., Schechter, M., & van den Hoek, J. A. R. (1996). HIV prevention in developed countries. Lancet, 348, 1143-1148. Corby, N. H., & Jamner, M. S. (1996). HIV prevention interventions: What works and what doesn't? [online]. [http://hivinsite.ucsf.edu/prevention/ evaluating_programs/2098.33 14.html] de Vincenzi, I., for the European Study Group on Heterosexual Transmission of HIV. (1994). A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. New England Journal of Medicine, 331, 341-346. Des Jarlais, D. C., Friedman, S. R., & Ward, T. P. (1993). Harm reduction: A public health response to the AIDS epidemic among injecting drug users. Annual Review of Public Health, 14, 413-450. Des Jarlais, D. C., Padian, N. S., & Winkelstein, W. (1994). Targeted HIV-prevention programs. New England Journal of Medicine, 331, 1451-1453. Deschamps, M.-M., Pape, J. W., Hafner, A., & Johnson, W. D. (1996). Heterosexual transmission of HIV in Haiti. Annals of Internal Medicine, 125, 324-330. Desenclos, J.-C., Papaevangelou, G., & Ancelle-Park, R., for the European Community Study Group on HIV in Injecting Drug Users. (1993). Knowledge of HIV serostatus and preventive behaviour among European injecting drug users. AIDS, 7, 1371-1377. Desmond, N. M., & Coker, R. J. (1998). Should preventive an tire tro viral treatment be offered following sexual exposure to HIV? The case for. Sexually Transmitted Infections, 74, 144-145. Dwyer, R., Richardson, D., Ross, M. W., Wodak, A., Miller, M. E., & Gold, J. (1994). A comparison of HIV risk between women and men who inject drugs. AIDS Education and Prevention, 6, 379-389. Edlin, B. R., Irwin, K. L., Faruque, S., McCoy, C. B., Word, C., Serrano, Y., Inciardi, J. A., Bowser, B. P., Schilling, R. F., Holmber, S. D., & Multicenter Crack Cocaine and HIV Infection Study Team. (1994). Intersecting epidemics—Crack cocaine use and HIV infection among inner-city young adults. New England Journal of Medicine, 331, 1422-1427. Edwards, S., & Carne, C. (1998). Oral sex and the transmission of viral STIs. Sexually Transmitted Infections, 74, 6-10. El-Bassel, N., Krishnan, S. P., Schilling, R. F., Witte, S., & Gilbert, L. (1998). Acceptability of the female condom among STD clinic patients. AIDS Education and Prevention, 10, 465-480. European Study Group on Heterosexual Transmission of HIV. (1992). Comparison of female to male and male to female transmission of HIV in 563 stable couples. EM], 304, 809-813. Evans, B., Darbyshire, J., & Cartledge, J. (1998). Should preventive antiretroviral treatment be offered following sexual exposure to HIV? Not yet! Sexually Transmitted Infections, 74, 146-148. Farr, G., Gabelnick, H., Sturgen, K., & Dorflinger, L. (1994). Contraceptive efficacy and acceptability of the female condom. American Journal of Public Health, 84, 1960-1964.

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Fauci, A. (1998, July 22). HIV vaccine research: Considerations for the new millennium. 32nd National Immunization Conference, Atlanta, Georgia. Flynn, N., Jain, S., Keddie, E. M., Carlson, }. R., Jennings, M. B., Haverkos, H. W., Nassar, N., Anderson, R., Cohen, S., & Goldberg, D. (1994). In vitro activity of readily available household materials against HIV-1: Is bleach enough? Journal of Acquired Immune Deficiency Syndromes, 7, 747-753. Frey, S. (1999). HIV vaccines. Infectious Disease Clinics of North America, 13(1), 95-112. Frezieres, R. G., Walsh, T. L., Nelson, A. L., Clark, V. A., & Coulson, A. H. (1998). Breakage and acceptability of a polyurethane condom: A randomized, controlled study. Family Planning Perspectives, 30, 73-78. Fullilove, M. T.. Fullilove III, R. E., Haynes, K., & Gross, S. (1990). Black women and AIDS prevention: A view towards understanding the gender rules. Journal of Sex Research, 27, 47-64. Gibson, S., McFarland, W., Wohlfeiler, D., Scheer, K., & Katz, M. H. (1999). Experiences of 100 men who have sex with men using the Reality condom for anal sex. AIDS Education and Prevention, 11, 65-71. Gleghorn, A. A., Doherty, M. C., Vlahov, D., Celentano, D. D., & Jones, T. S. (1994). Inadequate bleach contact times during syringe cleaning among injection drug users. Journal of Acquired Immune Deficiency Syndromes, 7, 767-772. Gold, M., Gafni, A., Nelligan, P., & Millson, P. (1997). Needle exchange programs: An economic evaluation of a local experience. Canadian Medical Association Journal, 157, 255-262. Goldbaum, G., Perdue, T., & Higgins, D. (1996). Non-gay-identifying men who have sex with men: Formative research results from Seattle, Washington. Public Health Reports, / / / ( S u p p l . 1), 36-40. Gollub, E. L., & Stein, Z. (1993). Commentary: The new female condom—Item 1 on a women's AIDS prevention agenda. American Journal of Public Health, 83, 498-500. Gollub, E. L.. Stein, Z., & El-Sadr, W. (1995). Short-term acceptability of the female condom among staff and patients at a New York City hospital. Family Planning Perspectives, 27, 155-158. Gostin, I.. O., Lazzarini, Z., Jones, T. S., & Flaherty, K. (1997). Prevention of HIV/ AIDS and other blood-borne diseases among injection drug users: A national survey on the regulation of syringes and needles. Journal of the American Medical Association, 277, 53-62. Greenfield, L.. Bigelow, G. E., & Brooner, R. K. (1992). HIV risk behavior in drug users: Increased blood "booting" during cocaine injection. AIDS Education and Prevention, 4, 95-107. Grinstead, O. A., Peterson, J. L., Faigeles, B., & Catania, J. A. (1997). Antibody testing and condom use among heterosexual African Americans at risk for HIV infection: The National AIDS Behavioral Surveys. AmericanJournal of Public Health, 87, 857-859. Grund, J.-P. ( ., Kaplan, C. D., & Adriaans, N. F. P. (1991). Needle sharing in the Netherlands: An ethnographic analysis. American Journal of Public Health, 81, 1602-1607.

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Grund,J.-P. C., Kaplan, C. D., Adriaans, N. F. P., Blanken, P., & HuismanJ. (1990). The limitations of the concept of needle sharing: The practice of frontloading. AIDS, 4, 819-821. Guttmacher, S., Lieberman, L., Ward, D., Freudenberg, N., Radosh, A., & Des Jarlais, D. (1997). Condom availability in New York City public high schools: Relationships of condom use and sexual behavior. American Journal of Public Health, 87, 1427-1433. Heckman, T. G., Sikkema, K. J., Kelly, J. A., Fuqua, R. W., Mercer, M. B., Hoffmann, R. G., Winett, R. A., Anderson, E. S., Perry, M. J., Roffman, R. A., Solomon, L. J., Wagstaff, D. A., Cargill, V., Norman, A. D., & Crumble, D. (1996). Predictors of condom use and human immunodeficiency virus test seeking among women living in inner-city public housing developments. Sexually Transmitted Diseases, 23, 357-365. Henderson, D. K. (1999). Postexposure chemoprophylaxis for occupational exposures to the human immunodeficiency virus. Journal of the American Medical Association, 281, 931-936. Hillier, L., Harrison, L., & Warr, D. (1998). "When you carry condoms all the boys think you want it": Negotiating competing discourses about safe sex. Journal of Adolescence, 21, 15-29. Hingson, R. W., Strunin, L., Berlin, B. M., & Heeren, T. (1990). Beliefs about AIDS, use of alcohol and drugs, and unprotected sex among Massachusetts adolescents. American Journal of Public Health, 80, 295-299. Holtgrave, D. R., Quails, N. L., Curran, J. W.( Valdiserri, R. O., Guinan, M. E., & Parra, W. C. (1995). An overview of the effectiveness and efficiency of HIV prevention programs. Public Health Reports, 110, 134-146. Hook, E. W., Cannon, R. O., Nahmias, A. J., Lee, F. F., Campbell, C. H., Glasser, D., & Quinn, T. C. (1992). Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. Journal of Infectious Diseases, 165, 251-255. Howe, J. E., Minkoff, H. L., & Duerr, A. C. (1994). Contraceptives and HIV. AIDS, 8, 861-871. Jochimsen, E. M. (1997). Failures of zidovudine postexposure prophylaxis. American Journal of Medicine, 102(5S), 52-55. Joffe, A. (1993). Adolescents and condom use. American Journal of Diseases of Children, 147, 746-754. Kane, S. (1991). HIV, heroin and heterosexual relations. Social Science and Medicine, 32, 1037-1050. Katz, M. H., & Gerberding, J. L. (1997). Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection-drug use. New England Journal of Medicine, 336, 1097-1100. . (1998). The care of persons with recent sexual exposure to HIV. Annals of Internal Medicine, 128, 306-312. Kegeles, S. M., Adler, N. E., & Irwin, C. E. (1988). Sexually active adolescents and condoms: Changes over one year in knowledge, attitudes and use. American Journal of Public Health, 78, 460-461.

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Kelly, J. A., Sikkema, K. J., Winett, R. A., Solomon, L. J., Roffman, R. A., Heckman, T. G., Stevenson, L. Y, Perry, M. J., Norman, A. D., & Desiderate, L. J. (1995). Factors predicting continued high-risk behavior among gay men in small cities: Psychological, behavioral, and demographic characteristics related to unsafe sex. Journal of Consulting and Clinical Psychology, 63, 101-107. Kirby, D., Short, L., Collins, J., Rugg, D., Kolbe, L., Howard, M., Miller, B., Sonenstein. F., & Zabin, L. S. (1994). School-based programs to reduce sexual risk behaviors: A review of effectiveness. Public Health Reports, 109, 339-360. Lackritz, E. M., Satten, G. A., Aberle-Grasse, J., Dodd, R. Y., Raimondi, V. P.Janssen, R. S., Lewis, W. F., Notari, E. P., & Petersen, L. R. (1995). Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. New England Journal of Medicine, 333, 1721-1725. Laga, M., Manoka, A., Kivuvu, M., Malele, B., Tuliza, M., Nzila, N., Goeman, J., Behets, F., Batter, V,, Alary, M., Heyward, W. L., Ryder, R. W., & Piot, P. (1993). Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: Results from a cohort study. AIDS, 7, 95-102. Latkin, G., Mandell, W., Vlahov, D., Oziemkowska, M., & Celentano, D. (1996). People and places: Behavioral settings and personal network characteristics as correlates of needle sharing. Journal of Acquired Immune Deficiency Syndromes and Human Retnnnrology, 13, 273-280. Laumann, E. ()., Gagnon, J. H., Michael, R. T., & Michaels, S. (1994). The social organization of sexuality. Chicago: University of Chicago Press. Lazzarin, A., Saracco, A., Musicco, M., Nicolosi, A., & Italian Study Group on HIV Heterosexual Transmission. (1991). Man-to-woman sexual transmission of the human immunodeficiency virus. Archives of Internal Medicine, 151, 2411-2416. Leigh, B. C., Temple, M. T., & Trocki, K. F. (1993). The sexual behavior of US adults: Results from a national survey. American Journal of Public Health, 83, 1400-1408. Lemp, G. F., Hirozawa, A. M., Givertz, D., Nieri, G. N., Anderson, L., Lindegren, M. L., Janssen, R. S., & Katz, M. (1994). Seroprevalence of HIV and risk behaviors among young homosexual and bisexual men: The San Francisco/Berkeley Young Men's Survey. Journal of the American Medical Association, 272, 449-454. Leonard, T. L. (1990). Males clients of female street prostitutes: Unseen partners in sexual disease transmission. Medical Anthropology Quarterly, 4, 41-55. Letvin, N. (1998). Progress in the development of an HIV-1 vaccine. Science, 250(5371). 1875-1880. Levine, W. C., Pope, V., Bhoomkar, A., Tambe, P., Lewis, J. S., Zaidi, A. A., Farshy, C. E., Mitchell, S., & Talkington, D. F. (1998). Increase in endocervical CD4 lymphocytes among women with nonulcerative sexually transmitted disease. Journal of Infectious Diseases, 177, 167-174. Longshore, D., Hsieh, S. C., & Anglin, M. D. (1994). Reducing HIV risk behavior among injection drug users: Effect of methadone maintenance treatment on number of sex partners. International Journal of the Addictions, 29, 741-757. Lurie, P. (1995). When science and politics collide: The federal response to needleexchange programs. Bulletin of the New York Academy of Medicine, 72, 380-396. Lurie, P., Miller, S., Hecht, F., Chesney, M., & Lo, B. (1998). Postexposure prophylaxis after nonoccupational HIV exposure: Clinical, ethical, and policy considerations. Journal of the American Medical Association, 280, 1769-1773.

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Marin, B. V., Marin, G., & Juarez, R. (1988, August). Prevention of AIDS in the Latino Community: Cultural Issues. Paper presented at the Annual Convention of the American Psychological Association, Atlanta. Marks, G., Richardson, J. L., & Maldonado, N. (1991). Self-disclosure of HIV infection to sexual partners. American Journal of Public Health, 81, 1321-1323. Marzili, T. J. (1989). The biologic possibility of HIV transmission during passionate kissing [Letter to the editor ].Journalof the American Medical Association, 262, 22302231. Mast, E. E., Goodman, R. A., Bond, W. W., Favero, M. S., & Drotman, D. P. (1995). Transmission of blood-borne pathogens during sports: Risk and prevention. Annals of Internal Medicine, 122, 283-285. Mays, V. M., & Cochran, S. D. (1988). Issues in the perception of AIDS risk and risk reduction activities by Black and Hispanic/Latina women. American Psychologist, 43, 949-957. McCoy, C. B., Rivers,]. E., McCoy, H. V., Shapshak, P., Weatherby, N. L., Chitwood, D. D., PageJ. B., Inciardi,J. A., & McBride, D. C. (1994). Compliance to bleach disinfection protocols among injecting drug users in Miami, journal of Acquired Immune Deficiency Syndromes, 7, 773-776. McKeganey, N. P. (1994). Prostitution and HIV: What do we know and where might research be targeted in the future? AIDS, 8, 1215-1226. National Commission on AIDS. (1994). Preventing HIV/AIDS in adolescents. Journal of School Health, 64(1), 39-51. National Institutes of Health. (1997). NIH Consensus Statement: Interventions to prevent HIV risk behaviors [online], [http://odp.od.nih.gov/consensus/ cons/104/ 104_intro.htm] Neaigus, A., Friedman, S. R., Curtis, R., Des Jarlais, D. C., Furst, R. T., Jose, B., Mota, P., Stepherson, B., Sufian, M., Ward, T., & Wright, J. W. (1994). The relevance of drug injectors' social and risk networks for understanding and preventing HFV infection. Social Science and Medicine, 38, 67-78. Nelson, K. E., Vlahov, D., Cohn, S., Lindsay, A., Solomon, L., & Anthony, J. C. (1991). Human immunodeficiency virus infection in diabetic intravenous drug users. Journal of the American Medical Association, 266, 2259-2261. Padian, N. S., Shiboski, S. C., & Jewell, N. P. (1990). The effect of number of exposures on the risk of heterosexual HIV transmission. Journal of Infectious Diseases, 161, 883-887. Paone, D., Des Jarlais, D. C., Gangloff, R., Milliken, J., & Friedman, S. R. (1995). Syringe exchange: HIV prevention, key findings, and future directions. International Journal of the Addictions, 30, 1647-1683. Plummer, F. A., Simonsen, J. N., Cameron, D. W., Ndinya-Achola, J. O., Kreiss, J. K., Gakinya, M. N., Waiyaki, P., Cheang, M., Piot, P., Ronald, A. R., & Ngugi, E. N. (1991). Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. Journal of Infectious Diseases, 163, 233-239. Polonsky, S., Kerr, S., Harris, B., Gaiter, J., Fichtner, R. R., & Kennedy, M. G. (1994). HIV prevention in prisons and jails: Obstacles and opportunities. Public Health Reports, 109, 615-625. Rachlis, A. R., & Zarowny, D. P. (1998). Guidelines for antiretroviral therapy for HIV infection. Canadian Medical Association Journal, 158, 105-114.

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Remafedi, G. (1994). Predictors of unprotected intercourse among gay and bisexual youth: Knowledge, beliefs, and behavior. Pediatrics, 94, 163-168. Rhodes, T., Stirnson, G. V., & Quirk, A. (1996). Sex, drugs, intervention, and research: From the individual to the social, Substance Use and Misuse, 31, 375-407. Romer, D., Black, M., Ricard, I., Feigelman, S., Kaljee, L., Galbraither, J., Nesbit, R., Hornik, R. C., & Stan ton, B. (1994). Social influences on the sexual behavior of youth at risk for HIV exposure. American Journal of Public Health, 84, 977-985. Rotheram-Bonis, M. J., & Koopman, C. (1991). Sexual risk behaviors, AIDS knowledge, and beliefs about AIDS among runaways. American Journal of Public Health, 81 206-208. Ruiz, J., Facer, M., & Sun, R. K. (1998). Risk factors for human immunodeficiency virus infection and unprotected anal intercourse among young men who have sex with men. Sexually Transmitted Diseases, 25, 100-107. Sacco, W. P., Rickman, R. L., Thompson, K., Levine, B., & Reed, D. L. (1993). Gender differences in AIDS-relevant condom attitudes and condom use. AIDS Education and Prevention, 5, 311-326. Seal, D. W., £ Ehrhardt, A. A. (1999). Heterosexual men's attitudes toward the female condom. AIDS Education and Prevention, 11, 93-106. Seidlin, M., Vogler, M, Lee, E., Lee, Y. S., & Dubin, N. (1993). Heterosexual transmission of HIV in a cohort of couples in New York City. AIDS, 7, 1247-1254. Seidman, S. N., & Rieder, R. O. (1994). A review of sexual behavior in the United States. American Journal of Psychiatry, 151, 330-341. Shapshak, P., McCoy, C. B., Shah, S. M., Page,]. B., Rivers, J. E., Weatherby, N. L., Chitwood, D. D., & Mash, D. C. (1994). Preliminary laboratory studies of inactivation of HIV-1 in needles and syringes containing infected blood using undiluted household bleach. Journal of Acquired Immune Deficiency Syndromes, 7, 754-759. Singer, M. (1991). Confronting the AIDS epidemic among IV drug users: Does ethnic culture matter? AIDS Education and Prevention, 3, 258-283. St. Lawrence,}. S. (1993). African-American adolescents' knowledge, health-related attitudes, sexual behavior, and contraceptive decisions: Implications for the prevention of adolescent HIV infection. Journal of Consulting and Clinical Psychology^, 61, 104-112. Stein, M. D., Freedberg, K. A., Sullivan, L. M., Savetsky,J., Levenson, S. M., Hingson, R., & Samet, ]. H. (1998). Sexual ethics: Disclosure of HIV-positive status to partners. Archives of Internal Medicine, 158, 253-257. Stein, Z. A. (1995). Editorial: more on women and the prevention of HIV infection. American Journal of Public Health, 85, 1485-1488. Stiffman, A. R., Earls, F., Dore, P., & Cunningham, R. (1992). Changes in acquired immunodeficiency syndrome-related risk behavior after adolescence: Relationships to knowledge and experience concerning human immunodeficiency virus infection. Pediatrics, 89, 950-956. Stimson, G. V., Eaton. G., Rhodes, T., & Power, R. (1994). Potential development of community oriented HIV outreach among drug injectors in the UK. Addiction, 89, 1601-1611. Stryker, }., Coates, T. J., DeCarlo, P., Haynes-Sanstad, K., Shriver, M., & Makadon, H. J. (1995). Prevention of HIV infection: Looking back, looking ahead. Journal of the Amen can Medical Association, 273, 1143-1148.

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Trocki, K. F. , & Leigh, B. C. (1991). Alcohol consumption and unsafe sex: A comparison of heterosexuals and homosexual men. Journal of Acquired Immune Deficiency Syndromes, 4, 981-986. Van Ameijden, E. J. C., van den Hoek, J. A. R., van Haastrecht, H. J. A., & Coutinho, R. A. (1992). The harm reduction approach and risk factors for human immunodeficiency virus (HIV) seroconversion in injecting drug users, Amsterdam. American Journal of Epidemiology, 136, 236-243. Voeller, B. (1991). AIDS and heterosexual anal intercourse. Archives of Sexual Behavior, 20, 233-276. Warner, D. L., Boles, J., & Goldsmith, J. (1997). Disclosure of condom breakage to sexual partners [Letter to the editor]. Journal of the American Medical Association, 278, 291-292. Walters, J. K. (1989). Observations on the importance of social context in HIV transmission among intravenous drug users. Journal of Drug Issues, 19, 9-26. Wheeler, D. (1999, March 26). As AIDS continues to spread, some scientists are pessimistic about developing a vaccine. The Chronicle of Higher Education, A21. Wiebel, W. W., Jimenez, A., Johnson, W., Ouellet, L., Jovanovic, B., Lampinen, T., Murray, J., & O'Brien, M. U. (1996). Risk behavior and HIV seroincidence among out-of-treatment injection drug users: A four-year prospective study. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 12, 282-289. Wight, D. (1992). Impediments to safer heterosexual sex: A review of research with young people. AIDS Care, 4, 11-23. Wilson, T. E., Minkoff, H., DeHovitz, J. Feldman, J., Landesman, S. (1998). The relationship of cocaine use and human immunodeficiency virus serostatus to incident sexually transmitted diseases among women. Sexually Transmitted Diseases, 25(2), 70-75. Wingood, G. M., & DiClemente, R. J. (1997). The effects of an abusive primary partner on the condom use and sexual negotiation practices of African-American women. American Journal of Public Health, 87, 1016-1018. Witte, S., El-Bassel, N., Wada, T., Gray, O., & Wallace, J. (1999). Acceptability of female condom use among women exchanging street sex in New York City. International Journal of STD & AIDS, 10, 162-168. Wittkowski, K., Susser, E., & Dietz, K (1999). The protective effect of condoms and nonoxynol-9 against HIV infection. American Journal of Public Health, 89, 109-110. Wold, C., Seage III, G. R., Lenderking, W. R., Mayer, K. H., Cai, B., Heeren, T., & Goldstein, R. (1998). Unsafe sex in men who have sex with both men and women. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 17, 361-367. Woolley, R. J. (1989). The biologic possibility of HIV transmission during passionate kissing [letter]. Journal of the American Medical Association, 262, 2230. Zeh, J., Wong, M. T., Torterella, F. J., Kaatz, J. S., Allen, P., Kaplowitz, L. G., & Weiir-Wiggins, C. (1998). The PEP team: A multidisciplinary team approach to provide continuous coverage for post-exposure prophylaxis in an urban university hospital setting (abstractno. 60200). International Conference on AIDS, 12,1035. Zekeng, L., Feldblum, P.J., Oliver, R. M., & Kaptue, L. (1993). Barrier contraceptive use and HIV infection among high-risk women in Cameroon. AIDS, 7, 725-731.

4

Promoting Wellness in Persons with HIV Infection Susan L. Keller

nfection with the human immunodeficiency virus (HIV) results in the progressive deterioration of the human immune system. The immunopathogenesis of HIV results from the gradual loss of CD4+ T lymphocytes in untreated persons infected with the virus. CD4+ T lymphocytes are crucial to maintaining appropriate immunological responses to a wide array of pathogens as well as malignant neoplasms. Deterioration of the human immune system results in severe immunosuppression with the subsequent development of opportunistic infections and neoplasms (Fauci & Rosenberg, 1994; Glaser, Rabin, Chesney, Cohen, & Natelson, 1999). Although, scientific understanding of the behavior of HIV has advanced substantially since the initial reports of AIDS nearly 20 years ago, the precise mechanism whereby HIV causes the depletion of these lymphocytes has yet to be fully understood. The specific clinical course of HIV disease is difficult to predict. Expression of the continuum of HIV disease is dependent on both host and viral factors, as described in chapters 1, 2, and 5. The progression of the immune system deterioration as a result of HIV infection varies considerably from person to person and is not con-

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stant throughout the course of HIV disease (Feinberg, 1996). Factors such as host genetic immunity (Kaslow et al., 1996), age (Darby, Ewart, Giangrande, Spooner, & Rizza, 1996), exposure to environmental antigens or common infections (Stanley et al., 1996; Staprans et al., 1995), and ongoing viral replication and mutation (BarreSinoussi, 1996; Ho et al., 1995; Wei, et al., 1995) may affect the rate of progression of HIV disease. In the absence of effective antiviral therapy, a common pattern of the course of HIV infection has been recognized progressing along a continuum from asymptomatic illness to episodes of severe morbidity (Pantaleo & Fauci, 1997). HIV infection typically advances through stages of acute HIV infection and clinical latency to clinically apparent disease. The result of infection with HIV is most often acquired immunodeficiency syndrome (AIDS), the final stage of HIV disease (Ho et al., 1995; Wei et al., 1995). Progression of HIV is not necessarily linear in nature. Persons living with HIV disease often experience periods of well-being interspersed with episodes of severe morbidity. Advancements in understanding modes of transmission, clinical manifestations, and treatment approaches have successfully led to prolonged life through slowed disease progression and reduced risk of opportunistic illness in many persons infected with HIV. Most specifically, recent development and short-term success of highly active antiretroviral therapy (HAART) agents have contributed to the hope of transforming a once definitively fatal illness into a chronic condition that can remain stable with therapy for many years (Feinberg, 1996). However, despite these advancements, knowledge of the long-term benefits of HAART on HIV disease progression is still not known, and HIV disease must still be considered an eventually fatal illness. Persons with HIV disease continue to experience morbidity that may affect the progression of their disease and/or diminish their quality of life. In addition, development of opportunistic disease is associated with a risk of mortality independent of CD4+ count (Chaisson, Gallant, Keruly, & Moore, 1998). Therefore, efforts to reduce morbid episodes through a "wellness" or a health-promoting self-care approach to living with HIV should be recommended throughout the course of the disease.

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HIV DISEASE AS CHRONIC ILLNESS AND HEALTH PROMOTION Chronic illness as defined in Donnelly (1993, p. 3) is "a condition not cured by medical intervention and requiring periodic monitoring and supportive care to reduce the degree of illness and to maximize the person's functioning and responsibility for self-care." Bennett (1988) defined chronic disease as one with silent pathology progression and variable asymptomatic periods, as well as a lack of symptoms not reflecting the severity of pathology. Based on these definitions. HIV disease could be considered a chronic illness. Health can be measured by an individual's "sense of well-being," resulting from "reducing unnecessary suffering, illness and disability" and "an improved quality of life" (U.S. Department of Health and Human Services [HHS], 1992, p. 6). Therefore, if health and illness are defined as two interrelated but distinct concepts, it is reasonable to consider health maintenance and health promotion for individuals who are living with HIV disease (Irish, 1989). Health promotion activities are "efforts to enhance positive health and prevent ill-health, through the overlapping spheres of health education, prevention, and health protection" (Downie, Fife, & Tannahill, 1990, p. 59). By utilizing social and personal resources individuals develop skills to effect change in their lives. Persons must be "empowered to define, seek, and find conditions, resources and processes to be an effective agent in meeting the significant needs" (Jones & Meleis, 1993, p. 12). Cognitive perceptions of health, personal characteristics (who they are), coping responses (what they do in certain situations), and availability of resources (personal and social) directly influence individuals' health promotion behaviors, health care seeking, and acceptance of health interventions (Jones & Meleis, 1993). Persons living with HIV experience physical and psychosocial manifestations associated with their disease. Issues including alterations in self-concept, social support, self-efficacy, coping mechanisms, hope, uncertainty, symptom distress, and access to resources mav all be related to participation in health-promoting behaviors. Persons with HIV disease should be encouraged to adopt practices minimizing the effects of "cofactors" that may, although unproven, enhance the progression to clinical disease (Bartlett 8c Finkbeiner,

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1993; Lang, 1993). These purported cofactors include malnutrition, repeated exposure to HIV or other pathogens through exposureprone sexual practices or injecting drug use, chronic infections, stress, and recreational drug and alcohol use (Flaskerud, 1992). Participation in health-promoting self-care activities are recommended for persons living with HIV disease (Bartlett & Finkbeiner, 1993; Maclntyre, Holzemer, & Philippek, 1997). These activities include regular medical care and adherence to recommended therapy, proper nutrition, exercise, adequate rest, smoking and other recreational drug cessation, stress management, sobriety, and safer sexual practices (Bartlett & Finkbeiner, 1993; Flaskerud, 1992; Irish, 1989; Jewett & Hecht, 1993; Lang, 1993; Maclntyre & Holzemer, 1997). Persons with HIV disease may not extend their lives by practicing health promoting self-care. No proven cause-and-effect relationship exists between health-promoting self-care activities and prolonged life with HIV infection. It has been suggested, however, that these strategies pose few risks and may restore a measure of self-control for persons infected with HIV (Lang, 1993). These interventions may improve an HIV-infected person's quality of life by enhancing overall health and immunity, thus reducing the risk of opportunistic disease or minimizing the effects of illness when they occur (Jewett & Hecht, 1993). Adopting a wellness approach to HIV disease, in conjunction with appropriate medical management, may have an effect on the morbidity experienced by these persons. Fries (1983, 1988, 1989a, 1989b) described a "compression of morbidity hypothesis," stating: If the morbid period may be defined as that period from the onset of chronic infirmity until death, and if the time of occurrence of such morbid events can be postponed, and if life expectancy is relatively constant, then morbidity will be compressed into a shorter period of time. (1989a, p. 208)

Compressing morbidity may enhance a person's quality of life by reducing the number of morbid episodes experienced before death. Fries (1989b) envisioned that health promotion interventions offer the dividend of reduction in the population illness burden on society. Health promotion strategies may also reduce medical utilization and thus expenditures. Health promotion interventions for persons with HIV disease attempt to aid in the reduction of illness episodes, thereby potentially reducing health service utilization, as well as

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enhancing the quality, although not necessarily the quantity, of their lives. Participation in certain self-care behaviors (i.e., safer sexual practices) may also reduce the transmission of HIV to uninfected persons. Self-care behaviors may also include use of alternative (or complementary) therapies such as vitamin supplements, traditional Chinese herbs, and massage, even though the benefits of some of these treatments remain unproven (Freeman 8c Maclntyre, 1999). COFACTORS OF HIV DISEASE As stated previously, persons with HIV disease should be encouraged to adopt practices minimizing the effects of "cofactors" that may, although unproven, enhance the progression to clinical disease (Bartlett & Finkbeiner, 1993). The effects of specific behaviors, including nutrition, exercise, smoking, alcohol use, and unsafe sexual behavior, on HFV disease have been examined in the literature. Nutrition Nutrition has an influence on susceptibility to infection and immune response (Gorman, 1993). Infection with HIV may affect an individual's metabolism by increasing resting energy expenditure and caloric requirements. This impact reportedly often begins in the early, asymptomatic stages of HIV disease (Grunfeld et al., 1992; Hommes, Romijn, Endert, & Sauerwein, 1991; Niyongabo et al., 1997). Malnutrition often significantly contributes to HIV morbidity and mortality (Babameto & Kotler, 1997), occurs frequently, and has been shown to predict patient survival independent of CD4+ count (Ott et al., 1995; Suttman et al., 1995). A loss of just 10% of baseline weight in the year prior to developing AIDS may result in reduced survival (Palenicek et al., 1995). HIV-related wasting (Chlebowski, Grosvenor, & Lillington, 1995) and low serum albumin levels (Guenter, Muurahainen, & Simons, 1993) have been shown to be more significantly related to mortality than CD4+ count. Specific micronutrient deficiencies, such as vitamins A, E, and B12, may accelerate progression to AIDS (Liang, Chung, Araghiniknam, Lane, & Watson, 1996; Tang, Graham, Chandra, 8c Saah, 1997). Higher dietary nutrient

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intake may be related to higher CD4+ T lymphocytes, which is inversely related to AIDS risk even when adjusted for health status (low CD4+ counts and symptoms) at baseline (Abrams, Duncan, & Hertz-Picciotto, 1993). Persons with HIV disease should be assessed thoroughly, including medical and diet history, physical assessment with anthropometric measures, and laboratory studies, to fully understand their nutritional status (Casey, 1997; Walsek, Zafonte, & Bowers, 1997). Effective dietary counseling leading to increased nutrient intake may improve quality of life, reduce the incidence of nutritional deficiencies, and aid in maintaining satisfactory weight during hypermetabolic states (Dowling, Mulcahy, & Gibney, 1990). Nutritional assessment and counseling should start early and continue throughout the course of HIV disease to detect early signs of malnutrition. Nutritional counseling should include information on healthy eating principles (what nutrients are important and frequency of eating), a healthy eating plan (what and how much to eat), managing nutrition-related symptoms (dealing with poor appetite, nausea, vomiting, diarrhea, stomatitis), foodborne disease prevention (storage, preparation, dining out), and alternate nutritional methods when necessary (nutritional supplements, enteral or parental support) (American Dietetic Association/Canadian Dietetic Association, 1997; Casey, 1997; Walsek et al., 1997). Early intervention to limit nutritional deficiencies may improve survival and quality of life in persons with HIV (Niyongabo et al., 1997).

Smoking Suggestions that cigarette smoking may alter immune response or modify host response to HIV infection have led to scientific studies yielding conflicting results. Cigarette smoking has been reported as increasingly prevalent in HlV-infected gay men and possibly associated with high-risk sexual behavior (Burns et al., 1991; Penkower et al., 1991; Royce & Winkelstein, 1990). Most early studies examining the effect of cigarette smoking on lymphocyte profiles in HIV-infected persons determined no direct correlation between cigarette smoking and a fall in CD4+ lymphocytes or progression of HIV

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disease (Burns et al., 1991; Park et al, 1992; Royce 8c Winkelstein, 1990). Nieman, Fleming, Coker, Harris, and Mitchell (1993) challenged these findings. Their study consisted of a retrospective, case series analysis of HIV-seropositive persons without an AIDS diagnosis whom the researchers initially saw for an asymptomatic respiratory assessment but then subsequently developed AIDS. The study concluded that progression to AIDS and the incidence of Pneumocystis carinii pneumonia was significantly related to smoking habit. These findings may have been due to the detrimental effect of smoking on the local pulmonary defense rather than on systemic immunocompromise. Unfortunately, this study has been criticized for its lack of betweengroup control for individuals' CD4+ count and duration of HIV infection upon entry to the study (Park, Margolick, & Munoz, 1993). More recent findings concur with earlier findings in revealing no correlation between cigarette smoking and HIV disease progression (Conley et al., 1996; Galai et al., 1997). Despite conflicting arguments surrounding cigarette smoking and progression of HIV disease, agreement does exist regarding the detrimental effect of cigarette smoking on a person's health. Cigarette smoking reduces the number of alveolar macrophages necessary for initiating cellular immune response against invading pathogens in the lung (Twigg, Soliman, & Spain, 1994). Cigarette smoking is associated with the incidence of malignancies and increased respirator)' tract bacterial infections, including influenza and varicella pneumonia (Burnsetal., 1991). In persons with HIV disease, smoking cigarettes may lead to an increased risk of oral lesions (including mucosal ulceration, oral candidiasis, and hairy leukoplakia) and bacterial pneumonia (Burns et al., 1996; Conley et al., 1996; Galai et al., 1997; Palacio, Hilton, Canchola, & Greenspan, 1997; Palmer et al., 1996; Rogers, 1997; Tumbarello et al., 1998). Smoking cigarettes may also act as an exogenous factor stimulating the activitation of HIV in the local lung tissue, thereby having a direct negative impact on lung function (Rich, 1998). HIV-positive smokers have reduced carbon monoxide diffusing capacity than HIV-positive nonsmokers even when free of other HFV-related lung disease (McCabe et al., 1997). Women smokers may have five times the risk of developing human papilloma virus (HPV)-related genital warts compared to nonsmokers (Feldman, Chirgwin, Dehovitz, & Minkoff, 1997).

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Presence of HPV-related genital warts may increase the risk of cervical carcinoma in HIV-infected women. Finally, cigarette smoking by HIV-infected pregnant women may result in an increased risk for perinatal HIV transmission (Burns et al., 1994; Turner, Hauck, Fanning, & Markson, 1997). Based on these findings, efforts to assist persons with HIV disease in smoking cessation behavior change are warranted.

Alcohol Similar to smoking, alcohol use and its resultant effect on HIV progression is unclear. Overall, heavy alcohol consumption has been associated with altered lymphocyte production and function (Dunne, 1989). Moderate to heavy alcohol use has been reported to suppress cellular immune function and response. Skin testing in a homogeneous sample of moderate to heavy drinkers revealed depressed response to seven delayed hypersensitivity antigens. This depression was noted to be reversible within 8 to 10 weeks of abstinence from alcohol (Tonnesen, Kaiser, Nielsen, & Pedersen, 1992). Alcohol intake has been shown to have an impact on immune functioning in general population samples and has been duplicated in persons known to be infected with HIV (Avins et al., 1994; Bagasra et al., 1996; Fong, Read, Wainberg, Chia, & Major, 1994). More recent evidence shows that chronic alcohol consumption leads to a significant decrease in CD4+ count (Pol, Artru, Thepot, Berthelot, & Nalpas, 1996) and increased viral replication (Bagasra et al., 1996) in persons with HIV disease. Decreases in CD4+ count were reversible with alcohol cessation (Pol et al., 1996). Despite this evidence, the role of alcohol consumption in HIV disease progression continues to be disputed (Dingle Be Oei, 1997). There may be a relationship between alcohol consumption and sexual practice. Using alcohol may make an individual more susceptible to unsafe sexual practices (Bagasara et al., 1996; Boscarino et al., 1995; Clark, Kissinger, Bedimo, Dunn, & Albertin, 1997; Dermen, Cooper, & Agocha, 1998; Malow, McMahon, Cremer, Lewis, & Alferi, 1997; Seage et al., 1998; Shillington, Cottier, Compton, & Spitznagel, 1995; Woods et al., 1996); however, this assertion has been refuted (McManus & Weatherburn, 1994). Messiah, Bloch, and Blin (1998)

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reported that alcohol consumption may help identify individuals in at-risk situations but does not predict that these individuals will participate in unsafe sexual practices while using alcohol (see also chapter 3). Alcohol consumption can also complicate HIV disease management. Alcohol abuse may delay entry to primary care for some HIVinfected individuals (Samet et al., 1998). Alcohol may directly interact with certain antiretrovirals, leading to an increased risk of pancreatitis and liver dysfunction. Reducing alcohol consumption reduces the risk of these complications (Whitfield, Bechtel, & Starich, 1997). Other complications related to alcohol include nutritional deficiencies, enhanced malabsorption, gastritis, and esophagitis (McManus & Weatherburn, 1994). Exercise Exercise has a direct impact on immune responsiveness; however, this response is dependent on many factors including intensity, duration, and mode of exercise, body temperature, and hydration status (Eichner 8c Calabrese, 1994; Nieman, 1997). Although in many studies regular exercise has not been shown to significantly enhance or reduce CD4+ lymphocytes in persons living with HIV disease (LaPerriere etal., 1997; Nieman, 1997), in at least one study exercise was shown to increase concentrations of circulating CDS cells in persons with HIV (Phillips et al., 1997). Loss of muscle mass early in the progression of HIV disease may be a result of decreased physical activity (Evans, Roubenoff, & Shevitz, 1998). The physical benefits of regular exercise such as increased cardiopulmonary fitness, improved muscle function, and weight gain have been demonstrated in HIV-positive individuals. Physical exercise may improve mood states, reduce psychological stress, and increase active coping behaviors (LaPerriere et al., 1997). In addition, prescribed exercise regimens can significantly increase neuromuscular strength and cardiorespiratory fitness in persons with HIV disease, including symptomatic individuals, without negative effects on immune status (MacArthur, Levine, & Birk, 1993; Rigsby, Dishman, Jackson, Maclean, &: Raven, 1992; Stringer, Berezovskaya, O'Brien, Beck, & Casaburi, 1998). When combined with appropriate protein intake,

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resistance exercise may increase energy intake, nitrogen balance, and functional capacity in persons with HIV/AIDS (Evans et al., 1998). Finally, all of the above mentioned benefits of physical exercise may have a dramatic effect on the feelings of negative body image, stress, anxiety, and depression many HIV-positive individuals experience. It should be noted, however, that HIV-seropositive individuals, without AIDS, have exhibited exercise dysfunction as demonstrated by exercising to a significantly lower workload and lower ventilatory anaerobic threshold when compared to an otherwise similar group of HFV-seronegative individuals (Johnson et al., 1990). In addition, persons with HIV disease with a history of bronchopulmonary complications exhibit reduced exercise capacity when compared to those without a history of such complications (Pothoff, Wasserman, & Ostmann, 1994). Sexual Behavior Informing sexual partners of one's seropositive status and practicing protective sexual behaviors are recommended and in some states mandated for persons with HIV disease. The benefits of these behaviors include both reducing transmission of HIV to others and reducing acquisition of virologically different HIV by those already infected. Encouraging clients to protect themselves from different strains of virion is increasingly important with recent evidence supporting sexual transmission of multidrug-resistant virus, including protease inhibitor (Hecht et al., 1998). Health providers are challenged to consider this evidence as not simply anecdotal but instead utilize it as an opportunity for education with their clients (Cohen & Fauci, 1998). Despite the recommendations, knowledge of HIV-seropositive status in conjunction with knowing the benefits of practicing risk-reduction behaviors may not lead to reductions in risky sexual behavior (DiScenza, Nies, & Jordan, 1996). Persons with HIV disease may not alter their sexual practices or may do so inconsistently (Posner & Marks, 1996). Forty percent of individuals receiving HIV care in an urban center asked about whether they had disclosed their HIV status to sexual partners reported they had not disclosed. More than half of these individuals

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also reported using condoms inconsistently. Participants with greater numbers of sexual partners disclosed less frequently (Stein et al., 1998). Changing sexual behavior presumably for one's lifetime is difficult. Unprotected sexual behavior may be related to sexual impulsivity, substance use, sexual enjoyment, communication difficulties, or low individual intentions to change risk behavior (Hays et al., 1997; Kalichman, Kelly, & Rompa, 1997). Sexual behavior is most often viewed as pleasurable, and changing this behavior may lead to feelings of loss of pleasure or desirability and obviously requires the ability to negotiate with others. Nursing interventions must assist individuals with HIV disease to acquire not only the information required to change sexual behavior but also the support and skills to do so (Cole, 1997). Encouraging clients to consistently disclose their HIV seropositivity and implement safer sex practices with sexual partners may require multiple intervention episodes in order to produce the desired outcome (DeRosa 8c Marks, 1998). (See also chapter 3.) HEALTH-PROMOTING BEHAVIOR AND PERSONS WITH HIV DISEASE While documentation exists on the effects of specific behaviors on HIV disease, there is continued debate regarding the effect of these behaviors on HIV disease progression. Despite differences in opinion and results of scientific study, persons infected with HIV should be encouraged to participate in a wellness-oriented approach to their disease (Maclntyre, Holzemer, & Philippek, 1997). It is possible to be well and to maintain a healthy approach to the disease experience (Ardell, 1984; Fender, 1987). A few studies have reported the adoption of health-promoting behaviors by HIV-infected persons. See Table 4.1 for a summary of the literature on this approach to living with HIV. Many persons living with HFV disease are working to promote or maintain their health through self-care behaviors. Self-care behaviors reported by people with HIV include focusing on proper nutrition, hygiene, stress reduction, nontraditional medicine, and symptom surveillance, reduction in alcohol consumption, and an increase in

TABLE 4.1

Living with HIV Disease: A Summary of Research on Health Promotion

Citation

Purpose

Sample

Design

Findings

Allan, 1990

Describe self-care activities used by HIV+ men

11 gay, HIV+ men

Qualitative, naturalistic

5 clusters of self-care: diet, exercise, stress reduce, lifestyle change, attitude adjust; accounted for most help-seeking, mainly health maintenance/ disease prevention; reduced uncertainty, increased control

Barroso, 1995

Describe self-care activities of long-term survivors of AIDS

14 men, 6 women with AIDS for at least 3 years

Qualitative, naturalistic

Self-care activities reported: discontinuing negative health habits, undertaking health-promoting activities, being responsible for one's health, decreasing stress

Carson, 1993

Determine behaviors related to hardiness among persons with HIV

100 persons, HIV+, ARC, AIDS

Comparative, descriptive

Increased hardiness related to increased perception of physical, emotional, spiritual health; > 50% of sample report health-promoting behaviors (HPB); increased HPB related to increased hardiness

Gloersen et al., 1993

Identify processes that enhanced AIDS patients states of well-being

16 PWAs (persons with AIDS)

Qualitative, grounded theory

Grimes & Cole, 1996

Examine factors contributing to life quality in persons with HIV disease

83 persons with HIV/AIDS

Descriptive

Self-help is influenced negatively by dependency and positively by enabling skill; enabling skill mediates negative effects of dependency on self-help

TABLE 4.1

(continued)

Citation

Purpose

Sample

Design

Findings

Kelly, 1991

Evaluate specific situational/social context factors and coping methods r/t sexual risk taking

470 gay men

Descriptive

Increased risk taking related to exclusive relation with partner, known HIV status, difficulty w/safe sex, younger age, less education, increased # partners; resisters coping related to self-guidance, fear/worry, benefits of safety/health

Kendall, 1996

Identify meaning of wellness in men with HIV/ AIDS

29 gay men

Qualitative, grounded theory

Need for intimacy and sense of community; feeling connected to others promoted sense of being well

Kendall et al., 1989

Identify factors enhancing well-being in persons with AIDS

3 men "doing well" with AIDS

Qualitative, naturalistic

"Doing well" themes: autonomy or mastery over disease, existential, spiritual journey toward understanding, self-acceptance, staying active and involved, positive thinking

Lovejoy & Moran, 1988

Describe select behaviors, beliefs, and info needs of gay/bisexual men with ARC/AIDS

30 gay/bisexual men w/ ARC/AIDS

Descriptive

Beliefs: sexual behavior hazardous, use sex to relieve tension, use unsafe sex under influence ETOH/drugs; HPB: used more often in recent years, stress reduce, nutrition, sleep, less ETOH, safer sex; info needs: immune building (continued)

TABLE 4.1

(continued)

Citation

Purpose

Sample

Design

Findings

Lovejoy, Moran, & Paul, 1988

Describe self-care behaviors and info needs of HIV+ men w/wo AIDS

178 gay/bisexual men, HIV+; self-selected convenience sampling

Descriptive

SC (self-care) = nutrition, hygiene, stress reduce, nontraditional medicine, surveillance; increased use of SC after diagnosis; most frequent: less drugs/stimulants; want ways to build immune/ health

Lovejoy, Morgenroth, Paul, Freeman, & Christianson, 1992

Describe potential predictors/patterns of info seeking after diagnosis w/ HIV; describe info seeking networks

60 HIV+ gay men attending outpatient clinic; self-selected convenience sampling

Descriptive

High use of 39/81 SC behaviors; info sources = friends, MD, media; use of SC before/after diagnosis + r/t info seeking; those performing before most likely to perform after

Lovejoy, Paul, Freeman, & Christianson, 1991

Identify patterns of selfcare/symptom distress; potential correlates of frequent use of self-care

162 gay/bisexual men receiving outpatient services

Descriptive

Increased frequency of self-care behaviors after diagnosis w/HIV; self-care related to use prior to HIV diagnosis, AIDS diagnosis, feeling "connected," feeling close to friends; self-care negatively related to lack of control

TABLE 4.1

(continued)

Citation

Purpose

Sample

Design

Findings

Siegel & Krauss, 1991

Identify challenges of living daily with HIV infection before AIDS and adaptive tasks

55 HIV+ gay men

Secondary analysis of qualitative study

3 challenges: dealing with shortened life span, reactions to stigmatizing illness, developing strategies to maintain health; adaptation: assume responsibility, influence course of infection, follow healthy lifestyle, maintain vigilance

Sowell et al., 1997

Describe self-care activities of women with HIV

27 women with HIV/AIDS from urban and rural settings

Qualitative

Seven categories of self-care identified: special dietary and nutrition practices, choosing not to use medically prescribed therapies, spiritual reliance and rituals, staying active, cognitive strategies, self-education, and healthy lifestyles

Valente, Saunders, & Uman, 1993

Examine relationships among perceived impact of HIV status, psychological distress, and changes in self-care

220 men, 20 women with known HIV or at risk for HIV

Comparative descriptive

Symptoms related to depression related to unhealthy behaviors; hopelessness related to unhealthy behaviors

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the use of safer sexual practices (Allan, 1990; Lovejoy, Moran, & Paul, 1988; Lovejoy & Moran, 1988; Sowell et al., 1997). These persons, in particular gay men, also identified sexual behavior as a means of tension relief and confessed to a failure in safer sexual practices when under the influence of alcohol (Lovejoy & Moran, 1988). Health-promoting activities may be used to reduce uncertainty toward the future and/or to enhance a sense of control in one's life (Allan, 1990). Persons with HIV disease may believe they can affect the course of their disease by taking responsibility for their wellbeing (Siegel & Krauss, 1991), and such "self-help" may improve their quality of life (Grimes & Cole, 1996). Health-promoting and protective activities may enhance a sense of well-being among persons with HIV and provide them with the ability to further accept and positively face their illness by relating mind and body (Gloerson et al., 1993). Enhancing psychological well-being may reduce the risk of mortality associated with a depressive affect (Mayne, Vittinghoff, Chesney, Barrett, & Coates, 1996). Persons living with AIDS for more than 2 years have reported using health-promoting activities as a means by which they "reconstructured his or her own life within the context of HIV disease" (Barroso, 1995, p. 49) and actually contributed to why they thought they had survived longer than expected (Remien, Rabkin, & Williams, 1992). A wellness-oriented approach to living with HIV may lead to a sense of psychological and spiritual growth (Dunbar, Mueller, Medina, & Wolf, 1998). Some individuals with HIV believe their positive attitude and healthy approach to living with their disease is as influential on their lack of disease progression as biological factors or use of pharmaceutical therapy (Troop et al., 1997). These beliefs highlight the importance of developing partnerships with patients in their treatment plan in order to serve them in the most holistic manner possible. Approaching persons with HIV as individuals with their own set of beliefs and values will convey a sense of respect for their life experience, an experience that is truly their own and that the nurse cannot fully feel or understand. Unfortunately, individuals adopting this approach to living with their disease may encounter negative attitudes from traditional Western medicine health providers regarding the benefits of "complementary medicine." Some health providers have deemed such an approach as unproven and questionable regarding its benefit on HFV disease

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outcomes. These attitudes were in direct contrast to their patients' beliefs regarding their nonconventional treatment approaches (MacIntyre et al., 1997). Negative attitudes or a lack of understanding toward an individual's approach to his or her disease experience potentially broadens the gap of acceptance in the patient-provider relationship. PREDICTORS OF HEALTH-PROMOTING BEHAVIORS IN PERSONS WITH HIV INFECTION Less is known about what motivates persons with HIV disease to practice health-promoting behaviors. Simply knowing you are living with a serious illness does not necessarily lead to changing or adopting new behaviors. Health providers should not be naive to this fact. The factors influencing a wellness-oriented approach to living with HIV disease are often individualized, diverse and complex. Lovejoy and colleagues (1991) described the self-care behaviors and the relationship between self-care and symptom distress of homosexual/bisexual men. Their study examined patterns of symptom distress, mood states, individual characteristics, and their relationship to self-care. Previous participation in -self-care behaviors was reported as significantly related to continued participation in these behaviors after diagnosis with HIV. Other identified potential correlates to self-care included becoming aware of an AIDS diagnosis, feeling connected to the environment, and feeling close to friends. Increased frequency of certain self-care behaviors was related to being informed of an HIV-seropositive status. Behaviors that showed significant increases following an HIV diagnosis were stress reduction, information seeking, and symptom surveillance. However, certain positive health behaviors remained unchanged or decreased after learning of HIV status such as smoking cessation, refraining from going to bathhouses, reducing alcohol use, and exercise. Persons participating in positive health behaviors prior to their HIV diagnosis have been shown to continue these behaviors after learning their seropositive status (Lovejoy et al., 1992). Positive perceptions of hope and social support may influence a person with HIV to adopt health-promoting behaviors (Keller, 1995). Presence of HIV-related symptoms, feelings of depression, and a sense of

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hopelessness may result in participation in unhealthy behaviors (Valente et al., 1993). Feelings of intimacy with others, a sense of community, and feeling connected to others in an era of uncertainty may influence feelings of well-being (Kendall, 1996). Such social interaction and relationships may offer a protective influence on health outcomes. Finally, providing health-promotion education sessions through structured wellness programs may result in positive behavior change (Gifford, Laurent, Gonzales, Chesney, & Lorig, 1998; RotheramBorus & Miller, 1998). Wellness programs have demonstrated increased self-efficacy and reduced health service utilization among participants (Watt, Verma, & Flynn, 1998). RECOMMENDATIONS FOR NURSING PRACTICE Persons are living longer with HIV infection than ever before. Encouraging these individuals to stay well and reduce their risk for morbid episodes is increasingly important. Although participation in positive self-care may not impact longevity in persons with HIV/ AIDS, it may enhance quality of life, reduce illness episodes (thus reducing health resource utilization), and reduce the transmission of HIV to others. Nurses must act as facilitators of their clients' realization of health potential. However, influencing behavior change is extremely complex. By understanding the factors influencing their clients' health behavior, nurses can develop health-promotion interventions based on identified antecedents to a specific health outcome. Health-promotion interventions must be appropriate and acceptable to those to whom the intervention is directed. By giving patients the opportunity to be active participants in their own care, nurses can help to foster a sense of personal responsibility in those patients. Nurses are challenged to enhance their knowledge of factors influencing participation in positive health behaviors by their clients in order to assist in the development of appropriate health-promotion interventions. Understanding who their clients are, what they do in certain situations, and the availability of their personal and social resources can assist nurses in serving clients "where they are." Simply instructing someone to "take care of yourself is usually insufficient

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in producing a desired outcome. Nurses must understand the array of factors influencing health behavior and direct health-promotion interventions toward those factors. Such understanding can lead to the development of interventions aimed at enhancing clients' beliefs and perceptions of living with HIV disease, which may empower them to take care of themselves. The challenge to nurses is to discern methods of fostering positive perceptions of living with HIV among their clients. Nursing interventions must focus on the factors influencing the decision to adopt strategies to promote, maintain, and restore health among persons with HIV disease. Serving clients in a holistic manner may help them to develop strategies that will facilitate integration of positive health behaviors into their daily lifestyle. Due to the increasing recognition of asymptomatic HIV infections as a result of widespread HIV testing and because persons are living longer with HIV disease, greater numbers of persons with HFVrelated disease are seeking health care. In an era of limited health care resources, care of persons with HIV disease must emphasize health maintenance, health enhancement, and prevention of hospitalization (Agency for Health Care Policy and Research, 1994). Individuals with HIV disease must be empowered to participate in healthpromoting self-care activities that may promote and enhance their health or quality of life. The challenge nurses face in facilitating this approach to living with HIV disease is enormous. Yet trying to empower clients to stay well is important not only from a resource standpoint but also from the hope that one day there will be successful development of longevity-producing treatments or even a cure and that they will live to reap the benefits. REFERENCES Abrams, B., Duncan, D., & Hertz-Picciotto, I. (1993). A prospective study of dietary intake and acquired immune deficiency syndrome in HlV-seropositive men. Journal of Acquired Immune Deficiency Syndromes, 6, 949-958. Agency for Health Care Policy and Research. (1994). Evaluation and Management of Early HW Infection. U.S. Department of Health and Human Services, Publication No. 94-0572. Allan, J. (1990). Focusing on living, not dying: A naturalistic study of self-care among seropositive gay men. Holistic Nursing Practice, 4, 56-63.

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5

The Clinical Spectrum of HIV Infection and Its Treatment Felissa R. Lashley

he effects of HIV on the immune system (as discussed in chapters 1 and 2) render the affected individual susceptible to a variety of opportunistic conditions, including infections and neoplasms, many of which were rarely seen before 1980, as well as more vulnerable to common pathogens. HIV-infected persons can show a broad continuum of effects ranging from acute infection through an asymptomatic state through full-blown AIDS. The exact nature of the opportunistic conditions (OIs) that occur and the organ systems that are affected in each person vary and can result in unique, complicated presentations. The clinical presentations seen most commonly in developed countries are often different than those that are most common in developing countries. This is in part due to differences in the infections that are prevalent and endemic, socioeconomic conditions, and access to medical care of varying levels, among other reasons. The signs and symptoms seen in patients with HIV infection depend upon the nature of the underlying opportunistic infection or neoplasm and the organ systems directly or indirectly affected. These signs and symptoms may result not only from one condition but can

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be due to a combined variety of infections and neoplasms, such as Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma (KS). The onset of signs and symptoms may be abrupt or gradual. Some patients with full-blown AIDS may present with a combination of dermatologic, gastrointestinal, pulmonary, neurologic, ophthalmologic, and/or musculoskeletal conditions. As knowledge of the effects of HIV infection has evolved, clinicians have become much more experienced in anticipating and applying prophylaxis and preventive measures to delay or avoid opportunistic conditions resulting from immunosuppression. Early treatment that takes into account and monitors viral load and CD4+ cell counts is aimed at maintaining immune function and possibly eliminating HIV. Immune function is a major determinant of whether specific infections and neoplasms develop and the stage of the illness when they develop. The combination of protease inhibitors and other drugs in a regimen known as highly active antiretroviral therapy (HAART), as discussed in chapter 7, has positively affected the natural history of many HIV-related opportunistic infections, particularly cryptosporidiosis, microsporidiosis, Kaposi's sarcoma, progressive multifocal leukoencephalopathy, those caused by Molluscum contagiosum, Mycobacterium avium complex, and cytomegalovirus (CMV) infections and provided benefits even without other measures (Sepkowitz, 1998). Both host and environmental factors play a role in which OIs tend to be more frequently observed in persons with HIV infection. Behaviors associated with the epidemiologic groups of men who have sex with men and injecting drug use may increase to vulnerability to certain types of OIs and other conditions in HIV infection. For example, HIV-infected persons who inject drugs are more likely to develop bacterial endocarditis than men who have sex with men (MSM) because malnutrition and exposure play roles in disease development. On the other hand, MSM are more likely to develop KS due to human herpes virus 8 (HHV-8), a sexually transmitted agent (Jones, Hanson, Dworkin, Kaplan, & Ward, 1998). It must be remembered that HIV-infected persons may engage in overlapping, multiple behaviors and therefore may be at risk for developing opportunistic conditions for a variety of reasons, including socioeconomic status, living conditions, the geographic region of residence, and access to health care.

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One way the clinician may be able to detect a particular OI or HlV-related condition early is to monitor the CD4+ T-cell count. The degree of immune depression as reflected by the CD4+ Tcell count can be used to assess the HFV-infected person for those conditions observed to occur more frequently at those levels. For example, CMV retinitis is most frequently observed when the CD4+ count is < 50 cells/mm3. Therefore, although a general ophthalmologic examination is called for at higher levels of CD4+ cell counts, the clinician should be especially alert for CMV retinitis when a given patient has a CD4+ cell count approaching 50 cells/mm3. A listing of conditions noted to be particularly prevalent at various CD4+ cell counts are listed in Table 5.1. These are not meant to be absolute and do not preclude an HIV-infected person from developing a given condition at any CD4+ cell count level but can be used as a guide. Prophylaxis is a major force in the total management of HIV infection. The Centers for Disease Control and Prevention (CDC) strongly recommend strategies to prevent first episodes of diseases for the following: Toxoplasma gondii, Mycobacterium tuberculosis (MTB), Mycobaclerium avium complex (MAC), Streptococcus pneumoniae and varicella zoster virus (VZV) infections, and Pneumocystis carinii pneumonia (PCP), and generally recommends prophylaxis for hepatitis A and B, Streptococcus pneumoniae, and influenza (Centers for Disease Control and Prevention, 1997; USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). Prophylaxis for recurrence in adults is recommended as a standard of care for PCP, toxoplasmosis, MAC, CMV, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Salmonella. If frequent or severe, prophylaxis is indicated for Candida and herpes simplex virus. These are discussed later in this chapter. Major therapeutic efforts have centered on therapy aimed at the HIV itself, and these treatments are discussed in chapter 7. Therapeutic approaches depend, to a large extent, on what infections and/ or neoplasms are manifested. Many of the signs and symptoms of various manifestations require complex and exhausting nursing care often taking place in long-term care settings or the home, as discussed in chapters 6 and 10. Current approaches to treatment can be conceptualized as follows:

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TABLE 5.1 Selected Opportunistic Infections and Conditions Frequently Associated with CD4+ Cell Count Categories* CD4+ Cell Count Range

Condition

> 500 cells/mm3

Bronchitis Sinusitis HIV-associated myositis

200 to 500 cells/mm3

Oral candidiasis Oral hairy leukoplakia Bacterial pneumonia Anemia Autoimmune thrombocytopenic purpura Herpes zoster Pulmonary TB Kaposi's sarcoma

> 100 to < 200 cells/mm3

Pneumocystis carinii pneumonia HIV-associated nephropathy Progressive multifocal leukoencephalopathy Peripheral neuropathy Microsporidiosis Molluscum contagiosum

50 to 100 cells/mm3

Pseudomonas pneumonia Cytomegalovirus CMV retinitis Disseminated histoplasmosis Aspergillosis Primary CMS lymphoma Toxoplasmosis Bacillary angiomatosis Disseminated coccidioidosis Esophageal candidiasis HIV-associated wasting Disseminated Mycobacterium avium complex

*These are meant only as a guide. Conditions may appear at other CD4+ cell counts. Sources: Carmichael, 1997; Jung & Paauw, 1998; Reiter, 1998.

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1. Prophylactic therapy aimed at the prevention of opportunistic infections (OIs) and their reoccurrence 2. Therapy aimed at the treatment of OIs 3. Therapy aimed at the treatment of neoplasms 4. Therapy aimed at combating HIV itself by eliminating it or by preventing reactivation or progression 5. Strengthening the person's own immunocompetence 6. Therapy aimed at combating the side effects of treatment modalities 7. Combinations of these approaches In order to fully understand the clinical consequences of HIV infection on the body, this chapter will present information in the following ways. First, information about the major infecting organisms and malignancies will be presented. Then, each organ system will be considered for the effects that are manifested. The usual current therapies will be discussed, generally in conjunction with the clinical condition for which they are most commonly used. In general, information on clinical conditions presented in this chapter and the usual therapies relates to adults in developed countries. CLASSIFICATION SYSTEMS On May 23, 1986, the CDC published a classification system for HIV infection. This system delineated inclusive definitions and classifications that were used for patient care, health planning, public health strategies, prevention and control activities, and epidemiologic studies (Centers for Disease Control, 1986). This classification was revised, and the 1993 version classifies HIV-infected persons on the basis of CD4+ T cell count or percent in three ranges and three clinical categories resulting in a matrix of nine mutually exclusive categories (Centers for Disease Control and Prevention, 1992). These are shown in Table 1.1 (see chapter 1). The CD4+ T-cell categories are Category I Category 2 Category 3

> 500 cells/jlL or mm3 200-499 cells/jiL or mm3 < 200 cells/|lL or mm 3

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The clinical categories for adults or adolescents are A, B, and C. Clinical categories are divided into A, B, and C (see Table 1.2, chapter 1). Category A consists of one or more of the following Asymptomatic HIV infection Persistent generalized lymphadenopathy (PGL) Acute or primary HIV infection with accompanying illness or history of acute HIV infection (Centers for Disease Control and Prevention, 1992) Category B consists of "symptomatic conditions" not included in category C (Centers for Disease Control and Prevention, 1992). Examples of conditions in clinical category B are listed in Table 1.2 (see chapter 1). Category C includes the clinical conditions listed in the AIDS surveillance case definition as shown in Table 1.3 (see chapter 1). Once a person has had a category C condition, the person remains in category C.

PRIMARY HIV INFECTION Symptomatology of primary HIV infection or acute retroviral syndrome was first described in 1985 (Cooper et al., 1985; Ho et al., 1985). Early in the epidemic, this syndrome was often diagnosed as some type of nonspecific flulike or mononucleosislike illness and its significance in relation to HIV was not appreciated. From 50% to 95% of HFV-infected persons show at least one symptom or sign during this time while the others remain asymptomatic. However, if symptoms are mild, they may not be recognized. The time period from HIV infection to the onset of acute illness has been reported to range from 5 days to 30 days or longer, with the typical period being about 14 days (Quinn, 1997; Schacker, 1997; Vanhems & Beaulieu, 1997). The clinical signs and symptoms may typically include fever, fatigue, pharyngitis, weight loss, myalgias, headache, arthralgias, mucosal ulcerations, rash, and lymphadenopathy, although others may occur. Lymphadenopathy often develops in the second week of the illness and may be limited to axillary, occipital, and cervical nodes or may be generalized. The rash that may be seen is usually erythema-

THE CLINICAL SPECTRUM OF HIV INFECTION AND ITS TREATMENT 173

tons and maculopapular, most commonly affecting the face or trunk. Headaches can occur that are often retro-orbital, and acute encephalopathy or aseptic meningitis may be seen. Depression, irritability, photophobia, and cognitive changes may be seen. These probably represent the initial involvement of the central nervous system. Those who are symptomatic appear to have a more rapid progression to AIDS (Cohen, Sande, & Volberding, 1998; Perrin & Yerly, 1998; Schacker, 1997; Schacker, Hughes, Shea, Coombs, & Corey, 1998; Vanhems & Beaulieu, 1997). During primary HIV infection patients may be very infectious with high viral levels (Quinn, 1997). The time of primary HIV infection now is viewed as an opportunity to influence the rate of disease progression or to possibly "abort" HIV infection. Early, aggressive antiviral therapy may affect host response and influence the long-term outcomes (Schacker et al., 1998), although studies spanning a 3-year period have not yet yielded definitive results on this treatment approach. It is also thought that during this acute time the person's immune system is relatively intact, and the infecting virus tends to be relatively homogenous, meaning the infected individual may be more susceptible to antiretroviral therapy (Cohen et al., 1998). Thus, early recognition of the syndrome and diagnosis are important. In addition, postexposure prophylaxis for persons having nonoccupational exposures to HIV has been recommended by the CDC and is outlined in Appendix 1 (Centers for Disease Control and Prevention, 1998). Diagnosis may be confirmed by detection of HIV RNA or p24 antigen, because tests looking for HIV antibodies will usually be negative or indeterminate as seroconversion progresses during this period (Quinn, 1997). Reasons to intervene early in acute/primary HIV infection are: to suppress the initial burst of viral replication and decrease the magnitude of viral dissemination throughout the body to decrease the severity of acute disease to potentially alter the initial viral "set point," which may ultimately affect the rate of disease progression to possibly reduce the rate of viral mutation due to the suppression of viral replication (Centers for Disease Control and Prevention, 1998, p. 56), thereby reducing the problem of the virus developing resistant forms to prevent the virus from establishing sequestered reservoirs

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Potential disadvantages have also been identified. These include expense, issues of adherence to therapy and diminution of perceived risk, early emergence of resistant strains, and unpleasant side effects of the medications used (Burman, Reves, & Cohn, 1998). Thus, how early to begin therapy in HIV infection and how aggressive that therapy should be are not subjects of uniform agreement (Burman et al., 1998; Corey & Schacker, 1999; Walker & Basgoz, 1998). If diagnosis of primary HIV infection is made, the patient should be examined for sexually transmitted diseases and hepatitis A and B; if the latter are not evident, vaccination may be considered. Additionally, baseline CD4+ T-cell counts should be taken, HIV viral loads should be assessed regularly, and the person should be monitored for the occurrence of HIV seroconversion. The goal of therapy early in the infection is to suppress plasma HIV RNA levels to below detectable levels with a combination of two nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine, ddl, ddC, stavudine, or lamivudine, and one protease inhibitor (see chapter 7) (Cohen et al., 1998; Centers for Disease Control and Prevention, 1998). In one report, after beginning treatment for primary HIV infection before seroconversion, a patient voluntarily discontinued treatment and evidenced a later second acute syndrome with rebound viremia (Daar et al., 1998). At this time of early diagnosis, the long-term treatment plan as known should be discussed with the HIV-infected person, and preventive aspects such as maintaining wellness and avoiding transmission should be emphasized. Aspects of adherence should be discussed (see chapter 7). Adverse prognostic signs at primary infection include persistent symptoms (especially if lasting more than 14 days), neurologic involvement, acquisition of infection from a person with late-stage HIV disease, infection with a virulent viral strain such as SI, persistent p24 antiginemia, higher HIV RNA viremia following seroconversion, persistently low CD4+ T cell count, and other immunological parameters (Sande & Volberding, 1997). THE COURSE OF HIV INFECTION AND THE PROGRESSION TO AIDS Following initial infection, the most usual clinical course for the HIV-infected person is to enter an essentially asymptomatic phase as

THE CLINICAL SPECTRUM OF HIV INFECTION AND ITS TREATMENT 175

described above. Some, however, do develop persistent generalized lymphadenopathy (PGL) before other symptoms or disorders develop. Over time, the individual's chances for developing symptoms increases, particularly as the immune system is compromised, but the appearance of symptoms is influenced by many factors, including those related to the HIV, other organisms to which the person is exposed and their characteristics, host characteristics (including genetic factors, relative state of immunity, nutritional status), and environmental factors governing exposure and other parameters. After transmission of HIV, the organism establishes infection, initially replicating in CD4+ T lymphocytes, macrophages, and probably dendritic cells. HIV is transported to lymphoid tissue, where it replicates. An immune response is mounted. As HIV replicates, it may also mutate, making the population of HIV more genetically diverse. HIV RNA appears, followed by HIV antigens, and eventually antibodies appear and may be detected. During the immune response to HIV, some specific CD4+ cells and possibly CD8+ cell clones are lost that might be effective in controlling HIV (Cohen etal, 1998). After transmission, establishment of infection, and an initial immune system response, a "set point" is established. This is defined as a relatively constant steady state level of plasma HIV RNA resulting from a rate of HIV replication approximately equal to the rate of viral destruction (Cohen etal., 1998). An acute syndrome, described earlier, may accompany this process and may be seen within weeks of the primary infection and immune response. HIV antigen falls from peak levels early in the infection to undetectable levels. The set point usually remains stable. CD4+ cell counts drop initially, then rise to the set point. When plasma virus levels fall to virtually undetectable levels after treatment, HIV may still persist in resting memory CD4+ T cells forming a latent reservoir (Finzi, Blankson, Siciliano, et al., 1999). HIV may have a period where it is replicating rapidly and being destroyed in lymphoid tissue and is not really latent. PGL may reflect some of this activity (Cohen et al., 1998). The CDC definition of PGL includes patients with lymph node enlargement of 1 cm or greater at two or more extrainguinal sites that persist for more than 3 months in the absence of a concurrent illness other than HIV that explains these findings (Centers for Disease Control, 1986). PGL

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began to be described in the literature in the early 1980s when it was seen in homosexual males. The nodes most frequently affected, in decreasing order of frequency, are cervical, axillary, inguinal, supraclavicular, infraclavicular, and popliteal. PGL may persist for several years, even in the absence of other symptoms. Discomfort may result from pressure caused by the enlargement. After primary HIV infection, the patient usually becomes asymptomatic and usually remains so through the early stage of HIV disease, which has been defined by Cohen and colleagues (1998) as the period from the establishment of the set point to a CD4+ T cell count < 500 cells/mm3. In this early stage, dermatological abnormalities such as seborrheic dermatitis or folliculitis or idiopathic aphthous ulcers may appear, particularly as CD4+ cell counts slowly decline over time (Cohen etal., 1998; DeVita, Hellman, & Rosenberg, 1997). During the middle or intermediate stage of disease, the CD4+ cell count is between 200 and 500 cells/mm3. While the person may still be relatively asymptomatic, intermittent conditions such as candidiasis of the mouth or herpes zoster infections may be seen. There may be episodes of recurrent herpes simplex virus (HSV) or the occurrence of diarrhea. Persons are also at higher risk for TB and bacterial infections such as sinusitis (Cohen, Sande, & Volberding, 1998; DeVita, Hellman, & Rosenberg, 1997). As disease advances to CD4+ cell counts below 200 mm3, the CDC's definition of AIDS is met (Centers for Disease Control and Prevention, 1992). DeVita and colleagues (1997) call the stage of 50 to 200 CD4+ cells/mm3 late stage disease, whereas Cohen and associates (1998) call it advanced HIV disease. At this stage there is substantial risk for PCP, esophageal candidiasis, T. gondii encephalitis, C. neoformans infections, cryptosporidiosis, isosporiasis, TB, KS, B cell lymphomas, and neurological disorders. Individuals with CD4+ cell counts below 50 cells/mm3 are said to have late stage (Cohen et al., 1998) or advanced stage disease (DeVita et al., 1997). The risk of MAC, CMV, cryptococcal meningitis, PML, and disseminated fungal diseases become more likely. DeVita and colleagues (1997) include a terminal stage in their progression. This stage represents an inability to successfully treat symptoms and comfort becomes a primary goal. Gates, Chesney, and Cohen (1997) simply separate phases of HIV infection into primary, which encompasses early and

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acute phases, and chronic, which is defined as occurring after the viral set point is established. Although development from initial infection to AIDS-defining illness can be 10 to 12 years or more, some persons (known as nonprogressors) have been symptom free for about 15 to 20 years, whereas others show symptoms relatively quickly (rapid progressors). Conditions usually associated with progression are oral candidiasis, oral hairy leukoplakia, and herpes zoster (Cohen et al., 1998; DeVita et al., 1997). Diseases commonly associated with various CD4+ cell count categories were shown in Table 5.1. Reduction of CD4+ cell counts below 200 mm3 results in the probability of developing OIs of 33% 1 year later and 56% 2 years later (Klepser & Klepser, 1997). The stages described above are influenced by prophylaxis, treatment, and factors pertaining to the host, organism, and environment. INFECTIONS Opportunistic infections have been one of the hallmarks of AIDS. Many of these infections are ones that were rarely described in humans before the advent of the AIDS epidemic. Many of the infections seen represent the reactivation of previously acquired latent infections but can also represent primary infection, or infections with organisms that usually cause little or no pathogenicity in the immunocompetent host. The most frequent causes of infection in persons with AIDS are parasitic, viral, and fungal organisms, although bacteria, particularly the mycobacteria, are also problematic and becoming more so. The person with HIV infection is likely to have multiple infections that are either simultaneous or consecutive and are caused by different organisms. Fungal, parasitic, and viral infections are frequently not curable; rather, treatment is aimed at controlling acute episodes. Long-term suppressive therapy even over a lifetime may be needed, and response is often delayed. Treated individuals are prone to experience increased frequency and severity of side effects of medications. The frequency of specific fungal and parasitic infections in persons with AIDS in a specific geographic area depends on the endemicity of the organism in that area. Thus, more cases of coccidioidomycosis will be seen in persons with HIV infection in the Southwest because more cases occur in non-HIV-

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infected persons in that region. In persons with HIV infection/AIDS, infections may show a different disease presentation, have atypical locations, have more rapid progression, be more severe, be more likely to be disseminated, and have a high density of organisms than in those without HIV infection, although this is not always the case in early stages when CD4+ cell counts are relatively high. There are differences in the patterns and prevalence of infections seen in developed and developing countries. In comparison to developed countries, the spectrum of opportunistic infection in developing countries may differ. For example, Pneumocystis carinii pneumonia, cytomegalovirus, and disseminated MAC are seen far less frequently than in Western populations, while skin diseases, intestinal complications (including severe diarrhea), tuberculosis, Toxoplasma gondii encephalitis, and cryptococcal meningitis occur more frequently (Karp & Neva, 1999). "Slim disease," a type of wasting syndrome, was recognized in Africa before its significance in relation to HIV infection was understood (Serwadda et al., 1985). Ideal treatment of OIs in persons with HIV infection includes prevention of infections, treatment of active infections, and prevention of recurrences (secondary prophylaxis). When prophylaxis should be used depends on several factors, including the incidence of the disease in the patient's community, how severe the disease is, efficacy of the regimen, simplicity of regimen, frequency and type of side effects, cost, potential adherence of the patient, and risk of emergence of drug-resistant pathogens (Carmichael, 1997). In 1995 an extensive document on prophylaxis of infections in persons with HIV infection was published (Centers for Disease Control and Prevention, 1995), and these were updated in 1997 and 1999 (Centers for Disease Control and Prevention, 1997; USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). Recommendations for prophylactic medication for initial occurrences and for recurrences of OFs in adults and adolescents are given in Appendices 2 and 3, respectively. Nonpharmacological preventive measures are given in Appendix 4 and in the USPHS/IDSA document. These appendices should be consulted for specific information related to each infection discussed below. The major parasitic, fungal, viral, and bacterial infections seen in HIV infection are described below and their therapy briefly discussed.

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PARASITIC INFESTIONS The appearance of pneumonia caused by what was then considered a protozoan, Pneumocystis carinii, in previously healthy male homosexuals was one of the events that initially drew attention to what was later recognized as AIDS (Centers for Disease Control, 1981a, 1981b). In the immunocompetent person, opportunistic parasitic infections are generally self-limiting. In HFV-infected individuals, the relative prevalence of various parasitic infections depends upon geographic factors and upon the prevalence of the organism in the population. Significant morbidity and mortality for HIV-infected persons have resulted from opportunistic parasitic infections, especially from Toxoplasma gondii (central nervous system lesions), Cryptosporidiumparvum, and hospora belli (diarrhea and malabsorption), Enterocytozoon bienuesi and Encephalitowon intestinalis (microsporidiosis resulting in diarrhea), and Strongyloides stercoralis (strongyloidosis). Other parasitic illnesses causing a lesser incidence of morbidity in the United States include Cydospora cayetanensis (Ackers, 1997).

Cryptosporidiosis Cryptosporidiosis is caused by the protozoan parasite Cryptosporidium parvum (Lew, Poles, & Dieterich, 1997) and is now known to be one of the most common enteric infections (Griffiths, 1998). It is an enteric protozoan infection seen in animals since 1907 but not described in humans until the 1970s (Rose, 1997). Person-to-person contact is the most important mode of transmission, but other routes include fecal contamination of the environment, including water and food, and animal-human contact (Griffiths, 1998; Rose, 1997). In the United States, the groups at highest risk of infection are children in day care centers, animal handlers, foreign travelers, and immunocompromised persons, including those with malnutrition and HIV infection (Atkins, Caceres, & Cleary, 1998; Rose, 1997). This infection has also been spread nosocomially from health care workers. Differences exist in prevalence rates for cryptosporidial enteritis for persons with AIDS in developed and developing countries. In the United States the organism can be found in up to 20% of persons with HIV, whereas in developing countries such as Africa

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and Haiti it is approximately 50% (Lew et al., 1997; Manabe et al., 1998). North American outbreaks have occurred from contamination of drinking water in cities such as Milwaukee (1993), Las Vegas (1994), and Gainesville, Florida (1995), and associated with swimming pools in Vancouver (1990) and Los Angeles County (1988). The mortality rates in Milwaukee and Las Vegas for patients with AIDS were 68% and 52.6%, respectively (Perz, Ennever, & LeBlancq, 1998; Rose, 1997). Cryptosporidiosis affects immunocompromised and immunocompetent persons differently. The latter have a self-limited illness with varying degrees of watery diarrhea, cramping abdominal pain, malaise, anorexia, and weight loss. Nausea, vomiting, and low-grade fever may be present. Symptoms commonly resolve within 5 to 14 days (Kartalija & Sande, 1999; Lew et al., 1997). In persons with AIDS, however, cryptosporidiosis manifests with choleralike diarrhea with bowel movements of up to 20 or more per day. The volume of watery stool lost is often as much as 10 to 20 liters per day but is more usually 3 to 6 liters per day. The exact mechanism of the diarrhea is unclear. In persons with AIDS the symptoms mentioned above are more severe and wasting may be life threatening (Atkins et al., 1998). Involvement of the gall bladder and biliary tree has also been recognized. Effects may include cholecystitis, biliary stenosis, and obstruction. There have been reports of cryptosporidial colonization of the lungs and stomach (Ventura et al., 1998). Diagnosis is based on the identification of parasitic oocysts in fecal specimens using various stains and microscopy, or monoclonal immunofluorescent stain and enzyme-linked immunosorbent assays (ELISA) for detection of antibodies in the stool. Intestinal biopsy is rarely used due to cost, invasiveness, and false negative results (Atkins et al., 1998). There is still no effective specific treatment for cryptosporidiosis but HAART decreases symptoms (Kartalija & Sande, 1999). Limited therapeutic success has been reported with diclazuril and letrazuril, and paromomycin may be used. There have been mixed reports on the effectiveness of antidiarrheal agents, including morphine sulfate, in reducing stool volumes and for antisecretary therapy with somatostatin analogues such as octreotide. Some reports have indicated usefulness of hyperimmune bovine colostrum. Immunomodulators such as interleukin-2 may improve symptoms (Atkins et al., 1998; Carr, Marriott, Field, Vasak, & Cooper, 1998; Lew et al.,

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1997). Preventive and prophylactic measures are listed in Appendices 2, 3, and 4. Especially important is avoiding contact with feces, handwashing after handling pets, gardening, or before eating, and avoiding ingesting river, lake, or swimming pool water or unpasteurized juices. Isosporiasis Isosporiasis is caused by the protozoan Isospora belli. This parasite is ubiquitous in animals and has been the cause of several outbreaks of diarrhea in institutions in the United States. It is endemic in parts of South America, Africa, and Asia. It has been found in approximately 0.2% of U.S. patients with AIDS in developed countries, as opposed to 15% to 18% of AIDS patients in developing countries such as Haiti and Africa (Atkins et al., 1998; Kartalija & Sande, 1999). Clinically, the immunocompetent person generally demonstrates a self-limited enteritis, whereas those who are immunocompromised as in AIDS show chronic intermittent disease. Symptoms are very similar to those of cryptosporidiosis. Diagnosis is based on identification of I. belli oocysts from stools or more rarely by intestinal biopsy (Atkins et al., 1998). Isosporiasis responds to treatment with oral trimethoprim-sulfa-methoxazole (TMP-SMZ) or pyramethamine-sulfadiazine, and other therapies may also be successful. The use of antiretroviral therapy including a protease inhibitor may result in improvement due to improved immunity (Atkins et al., 1998; Carr et al., 1998; Kartalija & Sande, 1999). Recurrences are common, and ongoing drug regimens may be needed for prophylaxis (Lew et al., 1997; Kartalija & Sande, 1999). Preventive and prophylactic measures are listed in Appendices 2, 3, and 4. Toxoplasmosis Toxoplasmosis is caused by the protozoan Toxoplasma gondii and is a common infection in both animals and humans. It is an obligate intracellular parasite. The route of transmission is believed to be oral-fecal from contamination by feline feces or from eating food infected with the organism, such as unwashed vegetables or un-

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dercooked or raw meat. HIV-infected persons should avoid contact with cat litter, cleaning horse stables, or sandboxes to reduce exposure to T. gondii. T. gondii infection is the m<-v common cause of focal encephalitis in persons with AIDS (Boyer, Remington, & McLeod, 1998; Lynfield & Guerina, 1997; Walker, 1998). It also crosses the placenta and can infect the fetus, causing various manifestations including microcephaly, mental retardation, and chorioretinitis in infected infants (Feigen & Cherry, 1998; Lashley, 1998). Toxoplasmosis in HIV-infected persons most often results from reactivation of previously acquired latent infection; therefore, those countries and geographic locations with higher general population prevalence can be expected to see a higher prevalence of toxoplasmic encephalitis in persons with AIDS. Thus, HIV-infected persons who have antibodies to T. gondii should be considered at risk for the development of toxoplasmic encephalitis. In countries where seroprevalence of T. gondii is high, toxoplasmic encephalitis is often a presenting symptom of AIDS (Subauste, Wong, & Remington, 1997). Encephalitis due to T. gondii is one of the most common neurological diseases in AIDS. The major features in clinical presentation are fever, headache, and focal neurologic deficits, including hemiparesis, seizures, and altered mental status. The latter may include confusion, lethargy, psychosis, global cognitive impairment, delusions, or coma. In addition to hemiparesis, other focal neurologic deficits may include ataxia, aphasia, movement disorders, and visual field loss (Blumenthal et al., 1999; Subauste et al., 1997). Noninvasive tests currently available lack specificity; thus, definitive diagnosis can only be made by detection of the organism from brain tissue obtained at either an open or a closed brain biopsy. Such lesions, however, are often inaccessible. While biopsy is the only method currently available to definitively distinguish toxoplasmosis from other causes, the high morbidity and mortality rates, coupled with the possibility of false negative results, often means that in practice clinicians initiate therapy based on positive serologic findings, clinical picture, and/or magnetic resonance imaging (MRI) or CT scan data. PCR and molecular testing using cerebrospinal fluid (CSF) are being increasingly used in diagnosis (Cohen, 1997). T. gondii may also infect the lung after dissemination. Typical symptoms include fever, cough, hypoxemia, lymphadenopathy, and skin rash, and it may resemble PCP. The lungs may be involved even

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when neurologic disease is not evident. The eye is another major site of infection. Other affected sites involved after dissemination are the heart, adrenal glands, liver, stomach, colon, pancreas, and testes, with necrosis occurring in these organs (Subauste et al., 1997). It is considered that the presence of extraneural toxoplasmosis means concurrent central nervous system disease. Treatment of toxoplasmosis is accomplished with a combination ofpyrimethamine (a diaminopyrimidine antimicrobial) andsulfadiazine. Clindamycin may also be used (Goldschmidt & Dong, 1999). Improvement is often seen within 10 to 14 days, but there is a high rate of relapse and therapy is generally continued for 4 to 6 weeks. The side effects of pyrimethamine (leukopenia, thrombocytopenia, and anemia) are related to an altered metabolism of folate, so folinic acid (leucovorin) is given concomitantly or added when blood counts so indicate. There is also a high frequency of complications in about 40% to 45% of patients manifested by bone marrow suppression or rash necessitating discontinuation of therapy. Treatment often lasts 3 to 6 months, although the optimal duration is unknown. Therapy is often necessary for the lifetime of the patient. Some drugs that have shown promise against toxoplasmic encephalitis in animal experiments or early clinical trials include roxithromycin, clarithromycin, azithromycin (macrolide antibiotics with relatively long halflives), and the hydroxynapthoquinone atovaquone (Klepser 8c Klepser, 1997; Lynfield & Guerina, 1997). Prophylaxis against toxoplasmosis is indicated, especially when the CD4+ count is < 100 cells/ mm' or if a prior episode has occurred (see Appendices 2 and 3). Nonpharmacological preventive measures have also been described (see Appendix 4 and Lashley, 1998; USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). Especially important are good handwashing, avoiding raw or undercooked meat, and avoiding cat litter. Microsporidiosis Microsporidiosis is caused by a unicellular spore-producing protozoan, and disease in humans appears most commonly due to Enterocytozoon bieneusi, with a smaller number resulting from Encephalitozoon intestinalis (Carr et al., 1998; Sobottka et al., 1998). Prior to the

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emergence of AIDS, microsporidiosis was rarely described in humans, although it was well known in both invertebrate and vertebrate animals (Carr et al., 1998). In the United States, especially, microsporidiosis is almost never seen in immunocompetent persons. In humans, transmission is believed to occur by the fecal-oral or urinary-oral route and may be food or waterborne (Kartalija & Sande, 1999). The prevalence in persons with AIDS ranges from 7% to 50% (Didier, 1998). Disease effects in clinical cases of AIDS in the United States include reports of myositis, intestinal infections, cholecystitis, peritonitis, and hepatitis. Keratoconjunctivitis (suggesting direct inoculation) and disseminated disease have also been reported (Didier, 1998). Microsporidia are regarded as one of the leading causes of diarrhea in HIV-infected persons (Sobottka et al., 1998). Symptoms depend on the site of infection. In persons with small intestine infection, symptoms include the occurrence of persistent watery diarrhea, weight loss, and abdominal pain. Malabsorption results (Kotler & Orenstein, 1998). Albendazole (a microtubule inhibitor) is used in treatment but is not as effective against E. bieneusi as other species of microsporidia. Fumagillin (an antibiotic) is used especially to treat keratoconjunctivitis topically. TNP-470 (a fumagillin analogue) holds promise (Didier, 1998). For prevention, see Appendices 2, 3, and 4. Strongyloides stercoralis Strongyloides stercoralis is an intestinal worm or a nematode with a worldwide distribution that is endemic in many tropical and subtropical regions, including the southeastern United States (Karp & Neva, 1999; Wehner & Kirsch, 1997). Usually larvae penetrate the skin, then migrate to the lungs, where they ascend the trachea and are swallowed. They mature in the gut. Larvae migrate from bowel to lung, where they can cause pneumonia. The migration of the larvae can cause gram negative bacteremia and shock. Infections may be acute or chronic, and they may be localized to a specific system or become disseminated. In persons without AIDS, infections tend to be either asymptomatic or mild after causing self-limited vomiting and diarrhea. In heavy abdominal infection, abdominal pain, weight loss, and diarrhea may be seen. Eosinophilia and symptoms specific

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to the respiratory tract may also be seen, and 5. stercoralis may cause adult respiratory distress syndrome (Wehner & Kirsch, 1997). Diagnosis is by detection of larvae in stool or tissues. S. stercoralis is considered potentially lethal in persons with AIDS because it can cause a hyperinfection syndrome. Dissemination to the lung and brain is also possible. Pruritus, urticaria, and a rash may also occur transiently. S. stercoralis can live in the heart with only occasional symptoms. Unexplained enterobacteremia or meningitis may indicate disseminated disease; therefore, strongyloidiasis should be considered in patients from endemic areas with nonspecific skin, pulmonary, and gastrointestinal symptoms, particularly with eosinophilia (Karp & Neva, 1999; Schneider & Rogers, 1997). Thiabendazole is used for treatment, and it is important to completely eradicate the parasite (Wehner & Kirsch, 1997). Cyclospora cayetanensis Cyclospora cayetanensis came to attention in the United States after an outbreak caused by imported raspberries in 1996 (Centers for Disease Control and Prevention, 1996a). Prior to this occurrence, the first major human outbreak causing diarrhea and cramping was noted in Chicago in a medical residence (Huang et al., 1995). The organism is a spore-forming, round to ovoid protozoa and may be waterborne (Brown & Rotschafer, 1999; Ortega, Sterling, & Gilman, 1998). These protoza may cause self-limiting diarrhea in immunocompetent persons and severe protracted diarrhea in those who are immunocompromised. Symptoms include watery diarrhea, malaise, myalgia, anorexia, weight loss and vomiting and fever in some. Asymptomatic carriage has been reported (Atkins et al., 1998). Diagnosis is made after finding the organism in the stool. Prophylaxis for HlV-infected persons with TMP-SMZ appears to prevent recurrences (Atkins et al., 1998; see Appendices 2 and 3). Treatment is also with trimethoprim-sulfamthoxazole (TMP-SMZ) (Brown & Rotschafer, 1999; Ortega et al.,1998; Soave, Herwaldt, & Relrnan, 1998).

Other Parasitic Diseases In addition to the parasites listed above, other parasitic diseases are being increasingly identified in persons with AIDS. Some, such as

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Giardia lamblia, are more commonly seen in homosexual males and children in day care than in the general population, but they are not particularly associated with HIV infection and therefore are not discussed here. Disorders such as leishmaniasis are relatively uncommon in developed countries, although they may be encountered in persons with AIDS who were born in a developing country often causing visceral leishmaniasis. Trypanosoma cruzi or Chagas' disease may be responsible for some AIDS-related brain disease (Karp &Neva, 1999). FUNGAL DISEASES Fungal diseases are important OIs in persons with HIV infection, and their frequency of occurrence can vary greatly with geography since many are endemic whereas others (e.g., Candida) are ubiquitous. Fungal infections such as cryptococcosis and infection with Penicillium marneffei are particularly prevalent in Southeast Asia (Kaplan et al., 1996; Karp & Neva, 1999), a region where specific disease associations with HIV infection are still being newly recognized. The major fungal infections are discussed here. The most important, Pneumocystis carinii, was previously considered a parasite. Pneumocystis carinii Pneumocystis cariniiis a unicellular organism, having some characteristics of a protozoan parasite and others of a fungus. Based on recent nucleotide sequence analysis, it appears most closely related to fungi but with some differences (Deresinski, 1997; Kaneshiro, 1998; Santamauro & Stover, 1997). It is almost exclusively seen in persons who are immunosuppressed (e.g., those receiving chemotherapy or immunosuppressive therapy or in HIV infection). Most normal children demonstrate antibody to P. carinii by 4 years of age, probably due to subclinical infection. Clinical illness from P. carinii was not described until the early 1950s (Hughes & Anderson, 1998). Before extensive prophylactic efforts, it was the most common life-threatening opportunistic infection seen in patients with AIDS and often resulted from reactivation of earlier latent infection (Cavert, 1997a).

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Before vigilant prophylaxis, PCP was the presenting opportunistic infection seen in about 60% to 65% of persons with AIDS. Earlier in the epidemic about 75% to 85% of persons with AIDS eventually developed PCP (Santamauro & Stover, 1997). Far fewer cases are now seen but PCP is still the most common AIDS-defining illness to occur first in the United States (Centers for Disease Control and Prevention, 1999). The most common expression of P. carinii is as pneumonia (PCP). Extrapulmonary pneumocystis is relatively rare. Sites of extrapulrnonary infection when they occur most often include lymph nodes, adrenal glands, liver, choroid of the eye, external and middle ear, thyroid, kidney, spleen, skin, gastrointestinal sites, and mediastinum and disseminated disease (Kaplan et al., 1995; Kroe, Kirsch, & Jensen, 1997; Santamauro & Stover, 1997). In one series Telzak, Cote, and Gold (1990) found an incidence of 2.5% of extrapulrnonary pneumocystis at autopsy. The most frequent presenting symptoms of PCP are relatively nonspecific—fever, nonproductive dry cough, tachypnea, and shortness of breath, which may be seen initially only on exertion (Cavert, 1997a). Persons who smoke or have complicating bacterial infection may have sputum production. Spontaneous pneumothorax may occur, and any patient with AIDS and pneumothorax should be investigated for PCP (Santamauro & Stover, 1997). Chest x-rays may show diffuse alveolar or interstitial infiltration distributed throughout the lung, but other changes such as patchy asymmetric infiltrates or discrete areas of pneumonia have been noted, especially when disease is more severe (Santamauro & Stover, 1997; Walsh, Rolfe, & Rumbak, 1999). Hopewell (1988) reported that 5% to 10% of patients with AIDS and later shown to have PCP have normal chest x-rays. Some radiologic patterns have changed over time (Boiselle et al., 1999). Pulmonary function testing results show nonspecific changes that may typically include reduced vital capacity, total lung capacity, and single breath diffusing capacity for carbon monoxide. Definitive diagnosis of PCP is based on finding the organism in pulmonary secretions or lung tissue. In experienced hands, sputum induction using hypertonic saline mist inhalation is a noninvasive, inexpensive method of diagnosis, but a negative result does not exclude PCP. Indirect immunofluorescent staining using monoclonal antibodies on induced sputum has improved the technique.

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A direct fluorescence test using monoclonal antibodies performed on sputum is widely available, and molecular and PCR testing has potential to also be so. Bronchoalveolar lavage (BAL) may also be sufficient for diagnosis before attempting more invasive procedures such as fiberoptic bronchoscopy with or without bronchoalveolar lavage and transbronchial biopsy. Open lung biopsies are rarely necessary for diagnosis (Hughes & Anderson, 1998; Kroe et al., 1997; Santamouro & Stover, 1998; Walsh, Rolfe, & Rumbak, 1999). Once HIV infection is diagnosed, chemoprophylaxis against PCP is indicated if the person has a history of orophayngeal candidiasis, PCP, a fever above 37.7° C > 2 weeks, and/or a CD4+ lymphocyte count < 200/|LiL (Centers for Disease Control and Prevention, 1997; Kaplan, Masur, Holmes, Wilfert, Sperling, & Baker, 1995). Standard prophylactic therapy for persons with HIV infection includes TMPSMZ (Bactrim or Septra) given orally. TMP-SMZ is a combination of antimicrobials resulting in a synergistic effect. SMZ inhibits the incorporation of PABAinto folic acid, while TMP (a diaminopyrimidine) prevents the reduction of dihydrofolate to tetrahydrofolate, thus acting on sequential steps in the pathway of a bacterial enzymatic reaction. TMP-SMZ also may confer cross-protection against some bacterial infections and toxoplasmosis (Centers for Disease Control and Prevention, 1997; USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). Unfortunately, there is a high frequency (up to 65%) of adverse reactions to TMP-SMZ in AIDS patients that may include anemia, neutropenia, dermatitis, thrombocytopenia, altered sense of taste, nausea, pruritis, stomatitis, headache, depression, and renal disease. Folate deficiency can occur, particularly in the chronically ill. For those who cannot tolerate TMP-SMZ, alternative recommended prophylaxis includes dapsone alone, dapsone and pyrimethamine, and leucovorin, atovaquone, or aerosolized pentamidine administered by the Respirgard nebulizer (Centers for Disease Control and Prevention, 1997; El-Sadret et al., 1999; Goldschmidt & Dong, 1999). (See also Appendices 2, 3, and 4.) Aerosol pentamidine is not effective against extrapulmonary P. carinii. Children with a history of PCP may require lifelong chemoprophylaxis to prevent recurrence. Before starting dapsone and certain other sulfa-based drugs, persons should be tested for glucose6-phosphate-dehydrogenase deficiency to prevent hemolysis (Cohen

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et al., 1998; Lashley, 1998). A detailed discussion may be found in Lashley (1998). Regimens for treatment of acute infection may include oral or intravenous preparations of TMP-SMZ, depending on disease severity. Dapsone alone has been shown to be nearly as effective as TMPSMZ. Other drug combinations include dapsone-trimethoprim, clindamycin-primaquirie, and atovaquone. Corticosteroids may be used as an adjunct in the absence of contraindications and with certain other criteria (Deresinski, 1997; Hughes, 1998). Adverse reactions to pentamidine isethionate, particularly when given parenterally, have included hypoglycemia followed by hyperglycemia, leukopenia, anorexia, altered taste, pancreatitis, orthostatic hypertension, elevated creatinine, and renal failure. Too rapid intravenous administration can be followed by severe reactions such as dizziness, breathlessness, vomiting, facial flushing, headache, prolongation of the QT interval, tachycardia, and even sudden death (Cohen et al., 1998). The finding of some studies have indicated that especially when treated with HAART, PCP prophylaxis may not need to be lifelong (Furrer et al., 1999; Masur & Kaplan, 1999; Weverling et al., 1999). Candidiasis Candidiasis (also called candidosis) is caused by members of the genus Candida, most often Candida albicans. In HFV-infected persons, non-albicans strains accounted for 3.4% of oropharyngeal isolates in the late 1980s, but by 1990 they accounted for 16.8% (Darouiche, 1998). More recently other species such as C. krusei and S. tropicalis are responsible for infection in a small percent of cases (Cartledge, Midgley, & Gazzard, 1999; Burden & Elewski, 1997). Candida is considered to be part of the normal flora of the gastrointestinal tract, including the oral cavity, and mucocutaneous regions. In immunocompetent persons, the organism is prevented from proliferating by other microorganisms in the normal flora and by immunoregulatory mechanisms. In the normal vagina of nonpregnant women, the incidence of C. albicans is about 5%; in pregnant women or those taking oral contraceptives, the incidence can be as high as 30% (Rippon, 1988). Up to 60% of healthy persons may

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harbor C. albicans'm the mouth (Sweet, 1997). Although C. albicans is not considered to be part of the normal flora of the skin, it is often isolated from folds, especially in moist areas such as between the fingers or under the breasts (Rippon, 1988). A number of factors have been identified in which the equilibrium between the human host and C. albicans is altered and opportunistic infection can occur. These include age, physiologic alterations, metabolic alterations, antibiotic administration, decreased immunocompetence, steroid administration, and invasive techniques that break natural barriers such as indwelling catheters and central lines or chronic injections (Hughes & Flynn, 1998; Rippon, 1988). Candidiasis of the oral cavity and esophagus is found in up to 90% of the HIV-infected persons, making it the most common fungal infection (Darouiche, 1998). Less frequently, vulvo-vaginal (in women) or anal infection is seen. Oral candidiasis may be first seen when the CD4+ T-cell count falls to 200 to 500 cells/mm3 and is an indicator of progression to AIDS. Esophageal candidiasis meets criteria for an AIDS diagnosis. Persons with AIDS do not commonly have systemic candidiasis, because granulocytes are the major defense against it as opposed to mucosal surfaces, where T cells are the major defense; however, it may be nosocomially acquired and cause severe illness in late-stage AIDS (Launay et al., 1998). Oropharyngeal candidiasis occurs in up to 90% of persons with HIV infection in the United States at some point in their illness (Darouiche, 1998). Oropharyngeal candidiasis maybe seen in several forms primarily of three major types: (1) pseudomembranous (usually synonymous with thrush), (2) erythematosus (atrophic), and (3) angular cheilitis (Phelan, 1997). The most common is pseudomembranous candidiasis. In this form, white curdlike removable plaques can be seen on the oral mucosa. These can be removed, leaving behind an erythematous or bleeding surface. The erythematous form manifests as smooth red areas in the oral cavity or the dorsal surface of the tongue, where patchy depapillation may be seen, and are easy to miss on inspection. Candida infection also can produce redness and cracking at the edges of the mouth (angular cheilitis) (Greenspan & Greenspan, 1997; Phelan, 1997). Diagnosis is by potassium hydroxide (KOH) preparation of a smear from the oral lesion or other staining techniques. Treatment for oral candidiasis can vary. Topical therapy includes nystatin sus-

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pension or oral pastilles or clotrimazole troches. Oral fluconazole, itraconazole, and ketoconazole can also be used. The angular cheilitis usually responds to topical antifungal agents such as nystatin and clotrimazole creams. Oral candidiasis usually responds well to therapy, especially early in HIV infection (Phelan, 1997). Esophageal candidiasis is accompanied by dysphagia, painful swallowing (odynophagia), and retrosternal pain without swallowing, although the latter may be due to lesions from other organisms (Minamoto & Rosenberg, 1997). Occasionally patients initially show esophageal perforation or upper gastrointestinal bleeding. Yellowishwhite plaques may be seen in the esophagus. The practical approach to HFV-infected patients with oral candidiasis and esophageal symptoms is to initiate empiric treatment for esophageal candidiasis and not perform endoscopy, although it may be done in order to confirm a potential AIDS diagnosis by biopsy. Treatment usually involves administration of fluconazole or ketoconazole and may require amphotericin B (a systemic antifungal agent with potentially severe toxicity that is not effective orally) in refractory cases (Goldschmidt & Dong, 1999; Minamoto & Rosenberg, 1997). Definitions of what is refractory may vary (Fictenbaum & Powderly, 1998). Despite therapy, esophageal lesions may persist and make obtaining adequate nutrition by normal methods difficult and painful, thereby resulting in inadequate nutrition and loss of weight. Routine primary prophylaxis against candidiasis is not currently recommended because treatment remains generally effective despite some reports of fluconazole-resistant strains. For recurrence, particularly for esophageal candidiasis, fluconazole or itraonazole may be considered for suppression (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999; Greenspan & Shirlaw, 1997). Vaginal candidiasis may occur frequently in those women who do not have HIV infection, as well as those who do. It is the second most common vaginal infection in those who are non-HIV-infected (Sobel et al., 1998). Thus, clinicians may miss this indication of underlying immunodeficiency, which is often a presenting manifestation of HIV disease in women. Common symptoms include vulvovaginal pruritus, burning, and a white or sometimes yellow, thick vaginal discharge usually without odor. Suspicion of HIV infection should be aroused in women who have vaginal candidiasis that is recurrent or refractory to treatment (Cohen & Durham, 1993; Minkoff et

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al., 1999; Wright & Johnson, 1997). Sobel (1992) defines recurrent vaginal candidiasis as "the occurrence of at least four mycologically proven symptomatic episodes within 12 months, with the exclusion of other common vaginal pathogens" (p. S148), whereas others counsel that one should be suspicious of HIV infection in women who have more than two episodes within 6 months or persistence of candidiasis after two treatment courses. Severe vaginal candidiasis is an HIVassociated symptomatic disorder. See Appendixes 2, 3, and 4.

Cryptococcosis (Cryptococcus neoformans) C. neoformans, the cause of cryptococcosis, is a yeast that is encased in a capsule. Pigeons appear to be the chief vector, and the organism is found in pigeon dung and in the debris of pigeon roosts as well as soil contaminated with pigeon and chicken droppings (Buchanan & Murphy, 1998). In humans, inhalation of the organism can cause primary infection in the lung. Relatively recently it has been recognized that many healthy individuals experience mild or subclinical cryptococcal disease with the discovery of old healed lesions found on routine autopsies. In New York City alone there are an estimated 15,000 subclinical cases per year (Rippon, 1988). C. neoformans is considered to be the third most common life-threatening fungal infection in persons with AIDS, developing in an estimated 5% to 10% of patients in the United States and up to 30% in patients in Africa (Aberg & Powderly, 1998; Oursler et al., 1999). The prevalence in children with AIDS may be about 1% (Abadj et al., 1999). In HIV disease, the major clinical pictures are pulmonary, central nervous system, and skin lesions, and may result from dissemination. In HIVinfected persons, cryptococcosis may result from acute infection, reactivation of an earlier infection, or both (Hajjeh et al., 1999). Although the lung is the usual primary infection site, C. neoformans has a predilection for the central nervous system. It can also affect the skin, mucous membranes, bone marrow, blood, genitourinary tract, and viscera. Over 75% of cases of crypococcosis occur when the CD4+ count falls below 50 cells/mm3 (Aberg & Powderly, 1998). In persons with cryptococcosis complicating AIDS, disseminated disease can occur in up to 50% (Grant & Armstrong, 1988). C. neoformans is the third most common infectious agent (after HIV itself

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and T. gondii) causing neurological disease in patients with AIDS. Meningitis is the most common manifestation seen and may occur as either the initial opportunistic infection or as a later complication. Manifestation of cryptococcal meningitis may be either subtle or acute. Fever, headache, and altered sensorium, which may persist for weeks, are the most common symptoms. Papilledema may occur. Seizures, photophobia, meningismus, and focal neurologic defects are less common. Some patients only demonstrate fever and malaise, with or without headache; thus, it is suggested that persons who are at risk for AIDS or who are known to have HIV infection be evaluated for cryptococcal meningitis and other central nervous system diseases in the presence of persistent fever with or without headache (Minamoto & Rosenberg, 1997). While CT scanning or MRI may be used to detect space-occupying lesions in persons with HIV infection and central nervous system dysfunction, in cryptococcosis the CT scan is usually normal or nonspecifically abnormal. Studies of the cerebrospinal fluid obtained by lumbar puncture may show only mild non-specific abnormalities such as in the white blood cell count or protein and glucose levels, but usually specific tests for cryptococcal antigen are positive. Cryptococcal antigen in the serum may indicate systemic disease, or the organism may be detected in tissue or the cerebrospinal fluid (Minamoto & Rosenberg, 1997). The usual therapy is high-dose parenteral amphotericin B alone or with oral 5-flucytosine (an orally active antifungal agent with relatively low toxicity), with serum levels being monitored for optimum effectiveness. Fluconazole therapy may follow. Side effects of amphotericin B include fever, chills, nausea, vomiting, renal dysfunction, and necrosis, while flucytosine can cause rash, hepatitis, diarrhea, or bone marrow depression. Treatment failure and relapse are common, and long-term suppressive therapy is usually indicated often with fluconazole. Patients receiving it should be monitored for liver function abnormalities and disease. Despite treatment, mortality from cryptococcal meningitis is high in persons with AIDS (Cohen et al., 1998; Klepser & Klepser, 1997; Larsen, 1999). C. neoformans may cause pulmonary disease, and the lung is usually the portal of entry for the organism. Signs and symptoms may include cough, fever, malaise, tachypnea, shortness of breath, pleuritic pain, and focal or diffuse infiltrates on radiograph (Aberg & Powderly,

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1998). Cutaneous manifestations occur and vary greatly and is a sign of dissemination. When Cryptococcus attacks the adrenal glands, adrenal insufficiency may arise (Cohen et al., 1998). Primary prophylaxis is indicated only in unusual circumstances, and prophylaxis with fluconazole is recommended after an initial episode (USPHS/ IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2, 3, and 4.) Smoking and certain outdoor occupations have been associated with an increased risk of cryptococcosis (Hajjeh et al., 1999).

Histoplasmosis Disseminated histoplasmosis has been recognized recently as an important opportunistic infection in AIDS and is included in the case definition of AIDS. It is caused by Histoplasma capsulatum and is a major endemic mycosis in the Caribbean, Central America, and South America and in river valleys in the United States, especially in the central and eastern areas (Minamoto & Rosenberg, 1997; Walker, 1998). In the United States it is endemic in the Midwest, where 85% to 90% of the population has been infected by 20 years of age. In most cases infection is asymptomatic (Walker, 1998). H. capsulatum is widely distributed in the soil and grows in association with fecal material from birds (including chickens) and bats. In immunocompetent persons, primary infection occurs by inhalation of spores. Cells are then distributed by the blood to other organs. In the immunocompetent person the organisms are usually sequestered or destroyed by the immune system, and the lung lesions heal. Occasionally infection is associated with high fever and pneumonia. In persons with AIDS, histoplasmosis may be a primary infection or reactivation of a latent one. Persons may have acquired primary infection when residents in an endemic area or merely while traveling in one. Clinical manifestations of disseminated histoplasmosis typically include fever, lymphadenopathy, hepatosplenomegaly, weight loss, cough, and pulmonary infiltration. Occasionally neurological manifestations such as meningitis present (Sande & Volberding, 1997). In persons with AIDS, unusual manifestations may also be present, including endocarditis or central nervous system (CNS) involvement

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(Minamoto & Rosenberg, 1997). Diagnosis is made through culture of tissue, especially bone marrow. Antigen to H. capsulatum has been detected in blood and urine specimens by radioimmunoassay or ELISA (Minamoto & Rosenberg, 1997). Therapy is less successful in persons with AIDS than in other immunocompromised conditions. The mortality rate is very high, and relapses are quite common. At present, the therapy of choice is amphotericin B, followed by itraconazole or fluconazole. Lifelong maintenance therapy is necessary to prevent relapse (Cohen et al., 1998). Primary prophylaxis is not routinely indicated, but prophylaxis usually with itraconazole is indicated to prevent recurrence (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2, 3, and 4.) Coccidioidomycosis Coccidioidomycosis is caused by the fungus Coccidioides immitis. This organism is endemic in the southwestern United States, especially in Arizona, California, and New Mexico. It is also commonly found in Mexico and Central and South America. Disseminated Coccidioidomycosis is rare in immunocompetent persons. In persons with AIDS, it is usually the result of reactivation of latent infection, although primary infection is possible (Minamoto & Rosenberg, 1997). Infection is acquired by exposure to contaminated soil. Inanimate objects, such as packages from endemic areas, can also carry the infection (Galgiani, 1999; Meunier, 1988). In the immunocompetent person, most infection is asymptomatic or an upper respiratory infection may be noticed. However, as many as 35% to 40% will develop symptomatic pulmonary infections, and a small number will develop a pulmonary nodule or cavity or disseminated disease (Kirkland & Fierer, 1996). In one series of 170 patients with HIV infection living in Arizona, 25% developed Coccidioidomycosis (Ampel, Dols, & Galgiani, 1993). In persons with AIDS, diffuse and focal pulmonary disease, meningitis, cutaneous lesions, and/or disseminated disease may be seen. The clinical presentation includes fever, malaise, weight loss, and cough. Severe, disseminated Coccidioidomycosis is more common in persons with CD4+ T cells < 200 jl/L. Pulmonary involvement is usually present and is manifested

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on chest x-ray. Treatment with fluconazole or itraconazole can be effective in non-meningeal infections (Kirkland & Fierer, 1996). Meningeal infection is involved in about one third to one half of cases of disseminated coccidioidomycosis. Usually this meningitis is either subclinical or chronic, but it can present as an acute illness in the immunodeficient patient. Treatment with amphotericin B, either intravenously or intrathecally, is necessary in mehingeal infections (Kirkland & Fierer, 1996). Acute therapy is followed by longterm maintenance therapy usually with fluconazole, itraconazole, or, if necessary, amphotericin B (Lortholary, Denning, & Dupont, 1997). Prophylaxis against recurrence is recommended for life (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2, 3, and 4.) Other Fungi Penicillium marneffei, causing penicilliosis, is considered to be an emerging pathogen. It is most common in Southeast Asia, such as Thailand and Taiwan, and parts of China. In HIV-infected persons in those areas it is the third most common OI after extrapulmonary TB and cryptococcosis. It has been suggested by some to be an addition to the list of AIDS indicator diseases for HIV-infected persons who visit or live in these areas (Duong, 1996; Hung et al., 1998). Symptoms of P. marneffei infection may include nonspecific clinical manifestations such as fever, anemia, weight loss, hepatosplenomegaly, and lymph adenopathy. It has a predilection for the skin and lungs and may disseminate. Skin lesions include papules, a generalized papular rash, and abscesses or nodules. If the respiratory tract is involved then a nonproductive cough may be seen. Diagnosis is by culture, and PCR techniques are also available. Treatment for severe disease is amphotencin B usually followed by itraconazole for life (Cooper & McGinnis, 1997; Duong, 1996; Kantipong, Panich, Pongsurachet, & Watt, 1998; Karp & Neva, 1999). Aspergillosis may result from several organisms, but Aspergillus fumigatus is most common. Aspergillus fumigatus is an opportunistic mold that appears to be increasing in infection prevalence. It is ubiquitous, even being found in Antarctica. It is found in the soil,

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decaying vegetation, bird droppings, and air conditioning vent dust, as well as in pepper, spices, and marijuana. Clinical patterns vary with patient condition and organism source. In AIDS, it is most often seen in the late stages, and the lung is the most common site of infection. Symptoms include hemoptysis, arid it may be mistaken for TB (Denning, 1998; Walker, 1998). Mortality is high in immunosuppressed persons. Treatment typically is amphotericin B followed by itraconazole (Denning, 1998). Other fungal infections causing disease in HIV-infected persons less often include blastomycosis, the fusarium species Mucorales, Sporothrix schenckii, and even Saccharomyces cerevisae (Durden & Elewski, 1997; Minamoto & Rosenberg, 1997). Newer antifungal agents are being developed (Terrell, 1999).

VIRAL DISEASES The herpesvirus group of DNA viruses is ubiquitous and contains more than 70 identified members classified within three subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae (Walker, 1998). Those that are the most important in disease manifestation, especially in persons with HIV infection, are cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and human herpesvirus type 8, which is discussed under Kaposi's sarcoma. They share the property of persistence in latent form with the potential of reactivation after initial infection. Susceptibility of cells to primary herpesvirus infection depends on a variety of factors including, age, immune factors, and unique viral features. Reactivation of the latent virus may depend on imrnunocompetence and stress-related factors (Cavert, 1997b). Primary infection, the latent stage, and reactivation with the same virus can involve different cell types. Actual disease manifestations can therefore vary. The JC virus is a human polyomavirus associated with progressive multifocal leukoencephalopathy (PML), a demyelinating disease. It is considered an opportunistic pathogen in humans, as is parvovirus B19 and papillomavirus (Cavert, 1997b). The aforementioned viruses and others seen more rarely are discussed below in regard to their manifestations in persons with AIDS.

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Cytomegalovirus (CMV) CMV belongs to the Herpesviridae family of DNA viruses and the subfamily betaherpesvirus (Cohen et al., 1998; Demmler, 1998). CMV is ubiquitous, and most people are infected sometime in their life. Primary CMV infection in immunocompetent persons is usually benign and can be acquired at any age, although it occurs most frequently in childhood (Cavert, 1997b). In developed countries, by 50 years of age, about half of the population are seropositive for CMV. CMV seroprevalence in adults ranges between 50% and 80% (Belshe, 1991; Cohen et al., 1998). In developing countries, CMV infection occurs earlier, and about 90% of children are CMV-seropositive by school age (Belshe, 1991). Congenitally acquired CMV has severe effects and is a major problem in the United States and elsewhere. About 1 % of newborns are infected with CMV. Thousands of infants are born each year with symptomatic CMV disease (mental retardation, blindness, and/or deafness), many of whom die early. Of the additional asymptomatic infants born with CMV each year, about 15% later develop severe problems (e.g., deafness and neurological deficits), many of whom require major therapeutic interventions and/or custodial care. Prevention during pregnancy is important, including good handwashing, which helps reduce spread (Demmler, 1998; Lashley, 1998). CMV may be shed in oropharyngeal secretions such as saliva, cervical secretions, semen, urine, and breast milk for prolonged periods of time even if the person is asymptomatic (Belshe, 1991). Persons who are immunocompromised, especially due to defects in cellular immune response, either iatrogenically (e.g., chemotherapy, transplant recipients) or because of disease, can experience reactivation of latent CMV. Persons immunocompromised by HIV are no exception. Although severe primary CMV infection can occur in persons with HIV, the majority of infection results from reactivation of previously acquired CMV. As many as 90% or more of persons with AIDS develop active CMV infection, and, before the use of protease inhibitors, 20% to 40% of persons with AIDS developed CMV end-organ disease, particularly when CD4+ cell counts were below 50 cells/mm3 (Cheung & Teich, 1999; Jacobson, 1998). In persons with AIDS, CMV infection may be manifested in a variety of organs including the eye, esophagus, colon, lung, liver,

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brain, and adrenal glands. In addition, systemic CMV infection is often present, and multiple organs are often simultaneously involved (Cheung & Teich, 1999; Demmler, 1998); moreover, CMV may further contribute to imrnunosuppression caused by HIV. In HFV-infected persons suspected of having CMV infection, diagnosis is generally made by isolation of virus through tissue culture, detection of virus antigens by direct fluorescence or ELISA, or through molecular techniques and by use of CMV antibodies through serology (Belshe, 1991). Chorioretinitis is the most common opportunistic infection of the eye in persons with AIDS, often occurring when CD4+ T-lymphocyte counts fall below 50 cells/mm 3 (Cheung & Teich, 1999; Cohen et al., 1998; Cunningham & Margolis, 1998; Greenwood & Graham, 1997); therefore, persons with AIDS should have ophthalmologic examinations at regular intervals. Signs and symptoms of CMV retini tis depend on the location of the lesions. Often retinitis begins unilaterally but becomes bilateral because of the presence of CMV in the blood. Sometimes persons are initially asymptomatic but may complain of floaters, loss of peripheral vision, blurred vision, unilat eral visual field loss, or decreased visual acuity (Cohen et al., 1998; Greenwood & Graham, 1997). The ophthalmologic examination shows a perivascular whitish colored retinal infiltrate that may be accompanied by hemorrhage or a diffuse fluffy yellow white infiltrate with or without hemorrhage. These lesions have been described as "cottage cheese and ketchup" appearance and enlarge in a "brushfire" pattern (Demmler, 1998). Chemoprophylaxis against CMV disease in adults who are CMV seropositive and who have a CD4+ T lymphocyte count of < 50/mm3 is usually with oral ganciclovir. Trials attempting prophylaxis against CMV retinitis using ganciclovir have been reported (Jacobson, 1998). For treatment, ganciclovir, either orally or IV in combination with foscarnet (Foscavir), is usually the firstline choice. Maintenance therapy for the rest of the individual's life is necessary, as ganciclovir (Cytovene) is virostatic, not virocidal, and thus CMV is not eliminated. Reactivation is common. Cidofovir (Vistide) shows effectiveness when given IV (Jacobson, 1998). For CMV retinitis, ganciclovir may be administered through ocular injection or by means of intravitreal implant impregnated with ganciclovir and sometimes intravitreal foscarnet is used (Cavert, 1997b; Cheung & Teich, 1999; Greenwood & Graham, 1997; Martin et al.,

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1999). Oral ganciclovir may be given along with the implant (Martin etal., 1999). In persons with AIDS and pulmonary infection, CMV is detected alone quite infrequently and is associated with other pulmonary pathogens in many cases. Signs and symptoms resemble those of interstitial pneumonitis and include shortness of breath, dyspnea on exertion, hypoxemia, and a nonproductive cough (Demmler, 1998). Ganciclovir is less effective in treating CMV pneumonia than in treating CMV retinitis. In the gastrointestinal (GI) tract, CMV can cause colitis, gastritis, enteritis, ulceration, esophagitis, small bowel obstruction and perforation, and hepatitis. About one third of all persons with AIDS have CMV infection somewhere in the GI tract (Lew et al., 1997), typically resulting in diarrhea and cramping abdominal pain with as many as 20 liquid stools per day, weight loss, possible fever, anorexia, and malaise. Although most have a prolonged disease course, some show rapid disease progression, including perforation of the colon or hemorrhage. Diagnosis is often by biopsy, which shows intranuclear inclusions of CMV on histologic examination and other typical findings. Persons with esophagitis or gastritis due to CMV may present with dysphagia and substernal or epigastric pain. Ulcers may be demonstrated (Cohen et al., 1998). CMV may cause hepatitis and biliary disease, which may only become evident at autopsy (Cheung & Teich, 1999). Ganciclovir and foscarnet are used in treatment (Cheung & Teich, 1999). CMV also can infect the central nervous system, and in patients with AIDS, radiculop'athy may be found. Encephalitis, often in combinations with other pathogens, may occur. Symptoms of encephalitis may include altered mental state, headache, difficulty concentrating, personality changes, fever, and somnolence. Only brain biopsy gives confirmation of the diagnosis, but newer molecular biology techniques applied to CSF analysis are promising (Roullet, 1999). Radiculopathy symptoms include pain and weakness of the legs, spasticity, areflexia, urinary retention, and hypoesthesia (Cohen et al., 1998). CMV prophylaxis is often used for patients with CD4+ cell counts < 50mm3, usually with oral ganciclovir. (See Appendices 2, 3, and 4 for information on prevention and prophylaxis.) Herpes Simplex Virus Types 1 and 2 (HSV-1 and HSV-2) The herpes simplex virus (HSV) is classified within the alphaherpesvirus subfamily. There are two types, HIV-1 and HSV-2, that share

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approximately 50% of their DNA in common but which have some different biological properties and are antigenically distinct (Belshe, 1991; Walker, 1998). In general, HSV-1 is responsible for oral-facial lesions, visceral infections in the immunocompromised persons, and encephalitis, whereas HSV-2 is associated with genital tract infections and neonatal disease, although overlap exists (DeVita et al., 1997). Primary infection with HSV-1 is most likely acquired during the first decade of life, although as many as half of adults in upper socioeconomic classes of developed countries may lack HSV-1 antibodies. Primary HSV-2 infection is more likely to be acquired in the adolescent or adult years (Cavert, 1997b; Walker, 1998). About 25% of the general U.S. population is seropositive for HSV-2. Rates are higher for those who are more sexually active; in males with HIVinfection the rate for HSV-2 infection ranges from 50% to 80%, while for HIV-1 infection it is more than 90% (Cavert, 1997b). Primary infection of epithelial cells with HSV-1 is most often asymptomatic; however, in some, painful blisters and ulcerated lesions ("fever blisters," "cold sores") occur in the mucous membranes of the mouth and may involve the pharynx, lips, tongue, and palate. Fever, malaise, and regional lymphadenopathy may also occur. Symptoms generally last under 3 weeks, and the disease is self-limiting (DeVita et al., 1997). After primary infection, experts believe that HSV travels through sensory nerves to sensory nerve ganglia, such as sacral and trigeminal ganglia, where it becomes latent. Reactivation of HSV-1 can occur with asymptomatic shedding of the virus or with visible lesions, often on the lips and sometimes on the nose or eyes. Recurrent disease frequently follows stressful events that can include emotional stress, hormonal changes, fever, ultraviolet light exposure, and decreased cellular immunity, and may be related to decreased CD8+ cell surveillance. The HSV latency cycle consists of primary infection at a peripheral site where the virus replicates, travels via axons to neuronal cell bodies in sensory or autonomic ganglia where latency is established and maintained in neurons, and reactivation from latency with travel via the axon to the periphery, where replication and viral shedding may occur. HSV-1 can be responsible for genital herpes infection as well, although less commonly than HSV-2 (Cavert, 1997b; DeVita et al., 1997; Posavad, Koelle, & Corey, 1998; Sacks, 1999; Walker, 1998). Viral shedding of

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lesions can occur asymptommatically, and counseling should include information on prevention of transmission. Primary infection with HSV-2 most commonly is manifested as genital herpes, although HSV-2 has also been implicated in oral infections. Genital herpes has become one of the most prevalent sexually transmitted diseases in the United States. Signs and symptoms associated with primary infection include systemic symptoms such as malaise, fever and headache, dysuria, pain and tenderness in the affected area, lymphadenopathy, and vesicular lesions on the genitalia, which become ulcerated. In women, vaginal and cervical lesions may be present, while in homosexual men, perianal lesions and proctitis may occur. Lesions on the buttocks or thighs may also be present. Lesions may be present for 2 to 3 weeks. In some cases, primary infection may be asymptomatic (DeVita et al., 1997; Sacks, 1999). After primary infection, HSV-2 typically establishes latency in sacral ganglia, and recurrent infection may follow viral reactivation by the appropriate stimuli, as discussed above. Recurrent HSV-2 infection tends to be milder than primary infection, and tingling and burning sensations often precede lesions. HSV-2 infection of the fetus or the neonate may occur transplacentally, by passage through the birth canal or sometimes because of invasive fetal monitoring (Jackson & Soper, 1997). Asymptomatic shedding occurs especially around the time of a symptomatic episode (Sacks, 1999). Because most people have been infected with primary HSV before acquiring HIV infection, reactivation of the virus is usually responsible for clinical symptoms. Most frequently, mucocutaneous lesions are seen that originally may be local. Perianal HSV infection was one of the early reported opportunistic infections in persons with AIDS. Severe proctitis may also be present, the signs and symptoms of which include severe anorectal pain, perianal lesions that become ulcerated, constipation, itching, and neurological symptoms, which include impotence and neurogenic bladder (Sande & Volberding, 1997). HSV may also produce esophageal lesions and ulcerations that may be associated with difficult and painful swallowing; however, esophagitis in persons with AIDS is more commonly due to CMV and Candida (Sande & Volberding, 1997). HSV encephalitis may also occur but is infrequent and can be hard to distinguish from

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encephalitis caused by Cryptococcus neoformans and Toxoplasma gondii. The encephalitis may be acute or subacute (Sande & Volberding, 1997). HSV-1 is also associated with herpes simplex keratitis (a common cause of blindness). Oral lesions consisting of many palatal or gingival vesicles that ulcerate are common in HIV infection. Although healing usually occurs, recurrences are common (Cohen et al., 1998). Diagnosis is usually made on clinical grounds or on viral isolation from tissue. Treatment with acyclovir (Zovirax) is generally effective, although if recurrences are frequent and severe, long-term suppressive therapy may be necessary. In acyclovir-resistant HSV infections, foscarnet may be used but has a greater toxicity risk. Other drugs that may be used are valacyclovir and famciclovir (Balfour, 1999; Sacks, 1999). Newer approaches include nucleoside analogs and antisense compounds, as well as a HSV vaccine (Sacks, 1999).

Varicella-Zoster Virus (VZV) Varicella-zoster virus (VZV) is also an alphaherpesvirus. Primary infection with VZV usually occurs in childhood in the form of chicken pox, which is a worldwide illness. Recurrent VZV infection results in herpes zoster (shingles) and is most often seen in adults (Wright & Johnson, 1997). VZV probably is acquired by respiratory route, multiplies in the respiratory tract and local lymph nodes, is released into the blood, and is disseminated throughout the body. Varicella (chicken pox) usually begins with fever, headache, and malaise that precede a rash that develops sequentially into vesicles, pustules, and scabs that are widely distributed on the body. Ninety percent of chicken pox cases are in children under 10 years of age, and lesions heal without complications by the second week in most cases. In adults, varicella is often more severe and complicated, with varicella pneumonia, purpura, specific organ involvement (e.g., orchids, pancreatitis) , and neurologic (encephalitis, polyneuritis) complications seen (DeVita et al., 1997). Most persons with AIDS will have had primary infection with HZV in the form of chicken pox in childhood, and therefore primary varicella is not common. After initial infection, VZV invades the peripheral nerves and moves into the dorsal root ganglia, where it becomes latent. Under

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conditions of immunosuppression such as stress, aging, chemotherapy, and others listed above, the latent VZV reactivates as zoster (shingles). A nonimmune person who is exposed to VZV usually develops varicella (chicken pox), but the reverse is not usual. When VZV reactivates, the virus travels to the distal nerve branches and the skin, where lesions typically appear in the skin area supplied by the affected nerve. Before the rash is seen, persons may have malaise, fever, and increased sensation in the area of the subsequent rash. The rash is maculopapular with vesicle development and crusting. In herpes zoster, the rash is usually restricted to one to three dermatomes usually being local and segmented. In persons with AIDS, however, the rash is often more generalized. Neuralgia is often severe and persistent (DeVita et al., 1997; Sande & Volberding, 1997). Up to 15% of persons with HIV develop herpes zoster at some time (Geusau & Tshachler, 1997). If zoster remains localized, the dermatome site affected can determine the effects. The trunk is the most frequent site. Involvement of the ophthalmic branch of the trigeminal nerve can result in eye involvement, with effects on the cornea, eyelid, retina, conjunctiva, and uvea, leading to blindness (Cohen et al., 1998; DeVita et al., 1997; Sande & Volberding, 1997). Posttherpetic neuralgia can persist for months or even years. Treatment is usually with oral acyclovir, valcyclovir, or famciclovir. IV therapy may be necessary in severe central nervous system involvement, for example (Balfour, 1999; Cavert, 1997b). Analgesic agents and topical creams may prove helpful, but most have not been optimally effective. Primary prophylaxis against VZV is recommended as a standard of care in certain instances (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2, 3, and 4.) Epstein-Barr Virus (EBV) The Epstein-Barr virus belongs to the gammaherpesvirus subfamily. Members of this subfamily have a very narrow host range, grow in lymphocytes, and are capable of inducing transformation to malignancy (Walker, 1998). EBV is distributed widely throughout the world. In countries that are less developed and/or have a high population density, 80% to 100% of children demonstrate antibodies

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to EBV by 3 to 6 years of age. In more developed countries, such as the United States, infection may occur in later childhood in persons of lower socioeconomic status, while it may occur later (i.e., in adolescence or young adulthood) in persons of higher socioeconomic status. By 30 years of age, 80% to nearly 95% or more of persons worldwide show EBV seropositivity (Feigin & Cherry, 1998; Walker, 1998). There are two strains, type 1 and type 2. Type 2 is most commonly seen in Africa and has become endemic in HIVpositive homosexuals, whereas type 1 is most prevalent in developed countries among the general population (Yao et al., 1998). Primary infection that occurs early in childhood is usually asymptomatic. When primary infection occurs in later childhood, adolescence, or young adulthood, the most common outcome is infectious mononucleosis (Feigin & Cherry, 1998). EBV appears to initially infect B lymphocytes. EBV causes infection and replicates in the epithelial cells of the oropharynx, nasopharynx, and the salivary glands. EBV is disseminated by the blood and the lymphoreticular system and eventually usually becomes latent. EBV is known to cause infectious mononucleosis (Feigin & Cherry, 1998; Walker, 1998) and has been suspected of contributing to chronic fatigue syndrome. EBV was originally identified in tumor cells from a patient with Burkitt's lymphoma. It continues to be etiologically implicated in endemic Burkitt's lymphoma in Africa and some cases elsewhere, especially in immunocompromised persons, and in nasopharyngeal carcinoma, in which case it may require a genetic susceptibility factor as well (Rickinson, 1998; Walker, 1998), such as a chromosomal translocation. See Lashley (1998) for more details. EBV has been associated with oral hairy leukoplakia in adults with HIV and with lymphocytic interstitial pneumonitis in HlV-infected children, leiomyosai comas in children with AIDS, and, as mentioned above, lymphomas. Oral hair)' leukoplakia (HL) is characterized by whitish thickening or plaques seen on the oral mucosa, especially on the lateral surface of the tongue. In contrast to lesions caused by Candida they are difficult to remove. (The term "hairy" refers to projections that extend outward from the surface of the lesion and are evident on microscopic examination. It may not require treatment.) High doses of oral acyclovir or valciclovir may be used for treatment, and, if not successful, topical treatment such as podophyllin solution or retinoin may be used; however, hairy leukoplakia

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tends to return when treatment stops (Greenspan & Shirlaw, 1997). Because hairy leukoplakia is so frequently an indication of HIV infection or immunodeficiency, the underlying reason for its appearance should be investigated. HL is listed in the B category of the 1993 CDC criteria for AIDS and appears more frequently as the CD4+ cell count declines, being a harbinger of disease progression (Centers for Disease Control and Prevention, 1992; Cohen et al., 1998).

The JC Virus The JC virus (JCV) is a member of the genus polyomavirus, of the Papovavirus family. It was first isolated from the brain tissue of a person with progressive multifocal leukoencephalopathy and was first named in 1971 (Clifford et al., 1999; Richardson, 1988; Walker, 1998). This DNA virus has several types and subtypes (Agostini et al., 1998). Primary infection occurs in childhood, and JC antibody seroprevalence worldwide is between 60% and 80%. It appears that primary infection is subclinical or inapparent, and its nature and the mode of transmission remain unelucidated. It is suspected that viremia does occur, since JCV reaches the urinary tract, the brain, and other organs (Walker, 1998). It is not clear whether other factors are needed in addition to immunosuppression to allow JCV to cause progressive multifocal leukoencephalopathy (PML). PML is a demyelinating disease of the central nervous system that was first recognized in 1958. Lesions occur in both gray and white matter. Demyelination occurs as a result of infection of the oligodendrocytes (Sadler & Nelson, 1997b). It is ultimately reported in about 5% of patients with AIDS. Clinically the disease in persons with AIDS is similar to that in other immunocompromised patients. Common symptoms include mental status alterations, headaches, cognition difficulties, ataxia, focal neurologic signs, visual problems, and hemiparesis (Cavert, 1997b). Diagnosis is through detection of JCV DNA, especially in the cerebrospinal fluid, often by PCR (Lafon et al., 1998). The prognosis is poor, and survival after PML onset is often a matter of a few weeks or months. To date, specific therapy has been ineffective but HAART therapy that reduces viral load has

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resulted in longer survival periods (Clifford et al., 1999; Hall et al., 1998). Molluscum contagiosum Molluscum contagiosumis a member of the family Poxviridae (poxvirus) (Walker, 1998). Infection results in pearly or flesh-colored papules with a central white curdlike umbilicated core that may be located on the skin or mucous membranes. Lesions are often present on the trunk, extremities, genitalia, and the face, and spread by direct contact as well as possibly indirectly through fomites such as towels (Geusau & Tschachler, 1997; Walker, 1998). Lesions can cluster multiply, with secondary infection possible. In persons with AIDS, lesions often spread in sheets, especially across the face. It is thought that seeding may spread them. Because of their rapid multiplication in persons with AIDS, immediate treatment is desirable. Even in immunocompetent persons resolution of the lesions can take months to years. Sometimes physical methods such as cautery, curettage, and cryotherapy are used to remove the lesions. Lesions may be seen in up to 20% of HFV-infected persons (Geusau & Tschachler, 1997; Walker, 1998). Parvovirus Parvovirus B19 belongs to the family Paruoviridae. It is a nearly ubiquitous virus; infections are acquired in childhood (80% before age 15 years), and about half are asymptomatic. Infection results in various illnesses including erythema infectiosum in childhood (Walker, 1998). In HlV-infected persons, red cell aplasia can occur from parvovirus B19 infection. IV immunoglobulin has been used in treatment. Parvovirus infection should be considered in persons with HIV-infection who have severe anemia (Cavert, 1997b).

Human Papillomaviruses Human papillomaviruses (HPV) belong to the family Papovaridae. They are responsible for many kinds of warts, including common

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skin warts and those affecting anogenital, oral, and cervical areas such as condyloma acuminatum. Over 85 types are known (Walker, 1998; Wright & Johnson, 1997). Human papillomavirus infection may be the most common sexually transmitted disease (Cavert, 1997b). Certain HPV subtypes such as 16, 18, and 31 are associated with cervical intraepithelial neoplasia, which can lead to cervical cancer in women (Walker, 1998). Recognition of the risk that HIV infection and immunosuppression pose for cervical cancer in women eventually led to its being classified as an AIDS-defining condition in the 1993 definition (Centers for Disease Control and Prevention, 1992). Byrne, Taylor-Robinson, Munday, and Harris (1989) reported that 95% of HIV-infected women in their clinic showed clinical or subclinical evidence of HPV infection. While results from other studies vary, HIV-infected women are much more likely to have HPV infection than those who are HIV negative (Hankins et al., 1999). Younger women are more likely to have HPV (Palefsky et al., 1999). Cryotherapy is effective for common warts, and some respond to tretinoin. Topical podophyllin is effective for mucosal warts (Wright & Johnson, 1997). Orally, in addition to causing warts, HPV is sometimes found in conjunction with hairy leukoplakia (Noyer & Simon, 1997). Hepatitis Viruses Hepatitis may result from hepatitis virus types A through E, which are members of different classes. Hepatitis B and C may be particularly transmitted in similar ways to HIV (Alter, Mast, Moyer, & Margolis, 1998; Walker, 1998). The efficacy of transmission of hepatitis B and C appears increased in HIV infection, but other results of coinfection are unclear if present (Casey, Cohen, & Hughes, 1996; DeVita et al., 1997). Primary prophylaxis against both hepatitis A and B is generally recommended in susceptible persons (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). Hepatitis C was discovered in 1989 and is now considered a major cause of chronic liver disease, especially cirrhosis and liver failure (Younossi & Canute, 1999). (See Appendices 2, 3, and 4.) The various forms of hepatitis have similar symptoms but often no symptoms are present. Symptoms may include fatigue, fever,

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muscle aches, loss of appetite, nausea, vomiting, and vague abdominal pain. In some cases, jaundice, dark urine, and light colored stools may be seen. Hepatitis B and C have the potential to progress to chronic liver disease while this is not true of Hepatitis A (Focus on Hepatitis, 1999; Newell & Nelson, 1999).

BACTERIAL INFECTIONS Opportunistic bacterial infections were originally considered less important in complicating HIV infection than other microorganisms. However, this is no longer true, and they are now recognized for their true contribution to morbidity and mortality. CDC first listed recurrent bacterial pneumonias in the 1993 case definition of AIDS. The bacterial infections that are most important are those caused by mycobacteria such as Mycobacterium avium complex and Mycobacterium tuberculosis. Others discussed in this section are Nocardia, Bartonella, Salmonella, Haemophilus influenzae, Pseudomonas aeroginosa, and Rhodococcus equi. Certain other bacterial diseases cause pneumonia, bronchitis, and sinusitis in HIV-infected persons but are not actually considered opportunistic. Some of these are discussed briefly at the end of this section. Bacterial infections may also be secondary and follow other OIs such as after CMV infection of the lungs or GI tract or after perianal HSV ulcers (Kovacs, Leaf, & Simberkoff, 1997).

Mycobacterium Avium Complex (MAC) and Other Atypical Mycobacteria Mycobacteria other than M. tuberculosis are sometimes referred to as potentially pathogenic environmental mycobacteria (PPEM). Mycobacterium avium and Mycobacterium intracellulare are atypical mycobacteria that, although distinguishable from each other by DNA and certain other techniques, are very similar in many respects. Mycobacterium avium complex (MAC) is a complex of the two species. The PPEM include MAC and other mycobacteria such as M. kansaii and M. gordonae. MAC is ubiquitously distributed in soil and water (French, Benator, & Gordin, 1997). The laboratory often classifies

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the environmental mycobacteria according to growth rate and pigmentation according to the Runyon classification. MAC belongs to Runyon Group III, which is nonpigmented (Walker, 1998). Like many of the other infections now seen frequently in persons with HIV infection, few cases of disseminated MAC were reported before the early 1980s. Data from skin tests indicate that approximately 40 million persons in the United States have been infected by environmental mycobacteria, and MAC is virtually endemic in the southeastern United States. Before the AIDS epidemic, the typical patient was a middle-aged male who had slowly progressive pulmonary MAC disease in addition to previously existing pulmonary disease (Griffith, 1988), or one in which immunosuppression from predisposing causes such as hematologic malignancies allowed disseminated MAC to make an appearance. MAC appears to be the most frequent systemic bacterial infection seen in persons with AIDS, affecting 15% to 40% (French et al., 1997). There appears to be some type of interaction between HIV and MAC (Havlir etal., 1998). In persons without HIV infection, who develop MAC, pulmonary involvement is most common. Disseminated MAC is seen most often when CD4+ cell counts are below 50 cells/mm3. Clinically, the person with disseminated MAC and HIV infection demonstrates systemic symptoms that include high, swinging fever, weight loss, malaise, anorexia, weakness, myalgia, and night sweats. Cough and headache may be present. If MAC has invaded the colon and small intestine, then diarrhea and abdominal pain and malabsorption may also be seen, resulting in a "wasting" type of syndrome (French et al., 1997). MAC is frequently cultured from the sputum and may be present in pulmonary secretions and tissue. It is believed, however, that MAC alone rarely causes severe pulmonary disease in persons with AIDS. Diagnosis is made on the basis of blood culture, and, if necessary, cultures of sputum, bone marrow, or lymph nodes. Effective therapy may be difficult, and standard antituberculosis drugs when used alone are usually ineffective. Multidrug approaches include clarithromycin or azithromycin combined with ethambutol, often with rifabutin as well. Immunomodulators may also be used (Benson, 1998). Other atypical mycobacteria are now seen in conjunction with persons with AIDS. These include Mycobacterium kansasii, Mycobacterium gordonae, and Mycobacterium xenopi. The most frequently reported of these has been M. kansaii, causing both pulmonary and

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disseminated infection in persons with HIV. In general, the symptoms are similar to MAC (French et al., 1997). Prophylaxis for life as a standard of care is recommended after an initial infection with MAC or other atypical mycobacteria in all HIV-infected persons after disseminated disease and as primary prophylaxis for those with CD4+ cell counts < 50 mm3 (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2 and 3.) Mycobacterium Tuberculosis Beginning in 1984, the rate of decline of tuberculosis (TB) cases in the United States slowed. By 1986 the number of U.S. cases had increased. This trend continued to accelerate until 1993, when a decline began but that was not back to pre-AIDS rates (Centers for Disease Control, 1988; Centers for Disease Control and Prevention, 1994). This increase has been attributed to HIV-related defective cell-mediated immunity. Infectious diseases are the leading cause of death in the world, and among infectious diseases, TB is the major cause of death. TB is increasing worldwide, with about 8.8 million new cases each year and 3 million deaths per year. Worldwide nearly 6 million persons are infected with both HIV and TB, and 90% to 95% of them live in developing countries (Cohen & Durham, 1995; Daley, 1998; Schluger, 1999). Extrapulmonary and disseminated TB have been AIDS-defming illnesses, based on the 1987 CDC surveillance definition, but it was not until 1993 that pulmonary TB was added to the expanded surveillance definition (Centers for Disease Control and Prevention, 1987, 1992). This addition was because pulmonary TB is the most common type in HIV-infected persons and in recognition of the strong epidemiologic link between HIV infection and TB (Centers for Disease Control and Prevention, 1992). Many people acquire tuberculous infection, but in 90% of cases the immune system contains the tubercule bacilli. Active pulmonary TB results from uncontained primary infection, reactivation of a past, latent endogenous infection, or resurgence following a recent exogenous reinfection (Cohen & Durham, 1995). Like many other infections associated with AIDS, it was believed that most cases of AIDS-assodated tuberculosis were the result of reactivation of latent

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infection rather than from the progression of a primary recent infection. The use of recent molecular techniques have now indicated that in HIV-infected persons, primary infection may account for up to 40% of new cases in urban areas of developed countries (Schurmann, Nightingale, Bergmann, & Ruf, 1997). Some populations that have a higher background prevalence of tuberculosis even in the absence of HIV infection are injecting drug users, immigrants from countries with endemic tuberculosis, and economically disadvantaged inner city residents who often are members of racial/ethnic minorities. Thus, when persons from those populations are infected with HIV, they will also show a higher tuberculosis rate in contrast to White, middle-class homosexuals infected with HIV (Cohen & Durham, 1995). The increase in the tuberculosis case rate is particularly notable in areas in the United States that also have a high HIV infection prevalence. Tuberculosis has been reported in approximately 4% of patients with AIDS in California, 15% in New York City, and 8% in Florida, while in most states less than 3% of reported AIDS cases were associated with TB (Daley, 1998). A diagnosis of tuberculosis often precedes the diagnosis of AIDS. The affected site and manifestations of TB in HIV infection depend on the status of the person's immune system. Persons with HIV infection whose immune system is relatively intact present with clinical symptoms of HlV-associated tuberculosis that are similar to tuberculosis without HIV infection and include such constitutional symptoms as fever, night sweats, weight loss, anorexia, cough, and malaise (Telzak, 1997). Persons with pulmonary tuberculosis may have a cough with sputum production, dyspnea, and chest pain. As the CD4+ cell counts fall, TB may present in atypical ways and include extrapulmonary sites in 40% to 80% of cases (Telzak, 1997). Concomitant pulmonary disease may be present. Therefore, diagnosis of TB at an extrapulmonary site should prompt evaluation for pulmonary TB. Common indicators of extrapulmonary TB include lymphadenitis, disseminated disease and bacteremia, intra-abdominal disease, including the liver and urinary tract, and central nervous system disease, particularly meningitis (Cohen & Durham, 1995). The symptoms seen relate to the specific extrapulmonary sites involved. The frequency of drug-resistant and multidrug-resistant TB (MDR TB), which originally was thought to be due to the AIDS epidemic,

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has also increased and is particularly prevalent in certain geographic areas such as New York City. MDR-TB has been defined as "a case of tuberculosis caused by a strain of M. tuberculosis resistant to two or more antituberculosis drugs" (Riley, 1993, p. S442). However, geography and failed drug treatment due to incorrect therapy or nonadherence are more important in MDR-TB than AIDS. Nosocomial spread is a particular problem in MDR-TB, and the largest outbreaks have occurred in hospitals. Tuberculin skin testing for screening for TB is often a part of standard primary care for the HIV-infected person in the absence of TB-related symptoms. Interpretation of the Mantoux test is based on induration. Five or more millimeters induration is considered positive for persons with HIV disease. Because of the immunosuppression associated with HIV infection, anergy may be encountered; thus, a negative skin test may not accurately reflect actual status, and anergy testing may be recommended but is somewhat controversial. Therefore, it is important to maintain a high index of suspicion for tuberculosis in all persons with HIV infection. Preventive therapy may be considered for persons who are HIV infected and anergic who are from a group or region in which the prevalence of tuberculous infection is 10% or higher (Telzak, 1997). At the present time, persons with AIDS-associated tuberculosis respond well to standard antituberculosis chemotherapy. It is important that susceptibility testing precede treatment. Directly observed therapy is generally recommended, and ways to enhance adherence are an important component of treatment (Cohen, 1997; Cohen & Durham, 1995). Generally, the medication regimen for treatment consists of isoniazid, rifampin, pyrazinamide, and/or ethambutol for 2 months, followed by 4 months of rifampin and isoniazid. Sometimes streptomycin may be added as a supplement (Daley, 1998). Because of the increased risk of tuberculosis in HFV-seropositive persons, it is also important that health care workers protect themselves against transmission and instruct patients on appropriate precautions for household contacts. For those with tuberculosis infection, recommendations for preventive therapy with isoniazid (unless medically contraindicated) with pyridoxine for a minimum of 9 months in persons with HIV infection and a positive tuberculin test; however, a 2-month course of therapy of rifampin and pyrazinamide appears to be an effective alternative (Centers for Disease Control

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and Prevention, 1998). Rifampin is used less often because of interactions with protease inhibitors (Schluger, 1999) and newer recommendations reflect this. For a review of drugs used in TB and interactions with drugs used in HIV therapy, see Pozniak et al. (1999). Detailed information about TB may be found in the reference by Cohen and Durham (1995) and treatment information is in CDC, 1998 (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2 and 3 for other information on prevention and prophylaxis.)

Nocardiosis Nocardiosis is caused by the Nocardia species, especially Nocardia asteroides. This organism is partially acid fast and has gram-positive staining properties. These bacteria resemble fungi because of their branched, filamentous hyphaelike morphology (Walker, 1998). Distribution is worldwide. Nocardia's natural habitat is the soil, and the organism probably enters the body by inhalation of aerosolized organisms. It is also found in muddy water and rotting vegetables. Nocardiosis is generally considered an opportunistic infection because most infected persons have a serious underlying disease, although this is not essential for infection. Nocardiosis is estimated to occur in 0.3% of patients with AIDS (Kovacs et al., 1997). Most primary infections occur in the lung, with disseminated systemic disease possible. The clinical picture may vary from inapparent infection to severe pulmonary and disseminated disease. Ectopic foci may develop through blood-borne distribution after pulmonary infection (Walker, 1998). In the lung, solitary nodules, localized pneumonitis, or lung abscesses are possible. Clinical findings vary with the organ system involved and can include fever, chills, cough with sputum production, malaise, weakness, weight loss, and/or dyspnea. The most frequent sites of hematogenous spread are the central nervous system, causing brain abscess; the skin, causing infection of subcutaneous tissue; the bones; and the kidney. Other organs that may be affected are the heart, bones, spleen, liver, eyes, and lymph nodes. Prolonged therapy is necessary, sometimes for a year or more, and relapses are frequent. TMP-SMZ or a sulfonamide and/or a selected antibiotic such as

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ceftriaxone or amikacin are drugs of choice. Despite therapy, overall mortality is high, about 50% (Kovacs et al., 1997).

Bartonella (formerly Rochalimaea) Infections Bacillary angiomatosis and hepatic bacillary peliosis result from Bartonella henselae and B. quintana infection. These are gram-negative bacilli (Brouqui et al., 1999; Cohen et al., 1998). In immunocompetent hosts, B. henselae causes cat scratch disease, which is characterized by a lesion and lymphadenopathy that may be due to granuloma formation and be associated with fever. It typically resolves within 2 to 4 months (Walker, 1998). Bacillary angiomatosis (BA) is not usually seen in HIV infection until the CD4+ cell count is below 100 cells/mm3 (Spach & Koehler, 1998). A hallmark of BA is cutaneous or subcutaneous lesions. Subcutaneous lesions may appear as nodules with or without reddened overlying skin. They can erode through the surface. Cutaneous BA may appear as papular and red with a vascular appearance and bleed when traumatized. Other appearances are possible, and occasionally they appear as dry, scaly, hyperkeratotic or plaquelike and may be confused with Kaposi's sarcoma. Lymphadenopathy may be present, and lesions in the gastrointestinal tract, respiratory tract, central nervous system, larynx, oral areas, anal region, bones, endocardium, and perineum can occur, as can bacteremia (Cohen et al., 1998; Loutit, 1998; Spach & Koehler, 1998). Signs and symptoms depend on the site affected. Bacillary peliosis, or the formation of venous lakes within the liver or splenic parenchyma, has been associated with Bartonella (Spach & Koehler, 1998). Symptoms and signs include hepatosplenomegaly, thrombocytopenia, and/or pancytopenia. Diagnosis is by biopsy, and in some cases, an enzyme immunoassay or indirect fluorescence antibody test can detect Bartonella antibodies. PCR techniques are in use in certain situations. Treatment is usually erythromycin or doxycycline. If these are not possible, tetracycline, clarithromycin, azithromycin, and/or minocycline maybe used. Treatment needs to be long term (at least 2 months), and relapse is common. Prevention includes avoidance of interaction with cats that can lead to scratches, control of flea and louse infestation, and washing any scratches

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immediately (Cohen et al., 1998; Spach & Koehler, 1998). (See Appendices 2, 3, and 4 for other prevention information.) Rhodococcus equi Rhodococcus equi (formerly classified with the Corynebacterid) is a grampositive bacillus with many fungilike characteristics (Walker, 1998). The first case of R. equi infection in humans was reported in 1967 in a person who was immunocompromised due to steroid therapy for chronic hepatitis (Golub, Falk, & Spink, 1967), and in 1986, the first reported case in an HIV-infected person was described (Sarnies, Hathaway, & Echols, 1986). The most common resulting disease from infection is pneumonia, and fever, cough, chest pain, dyspnea, and later, hemoptysis and weight loss may be seen. Extrapulmonary infection may occur in about one quarter of cases and most commonly include subcutaneous, renal, pelvic, and brain abscesses as well as osteomyelitis. Dissemination may occur. Various combinations of antibiotics are used, and therapy should be long term, with at least two antibiotics used to which the organism is susceptible. Mortality in HIV-infected persons has been reported from 25% to 55% (Cohen et al., 1998; Hamrock et al., 1999). Haemophilus influenzae Haemophilus influenzae is one of the most common bacterial infections in HIV-infected persons (Cohen et al., 1998). It is a gram-negative rod with several biotypes. The main determinant of virulence is the capsule, and those with capsule type b (Hib) disseminate. H. influenzae carriage in the upper respiratory tract is common (seen in 35% to 85% of adults, and 60% to 90% of children); however, only about 0.4% of adults and 5% of all children carry Hib. In day care centers, up to 60% of children may carry Hib (Walker, 1998). In HIV-infected adults, pneumonia, sinusitis, and meningitis may be seen. Dissemination may occur. Symptoms in HIV-positive persons do not differ from those found in HIV-negative persons (Cohen et al., 1998; Walker, 1998). The treatment choices are second- or third-generation cephalosporins, doxycycline, or fluoroquinolones (Barrett, Brei-

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man, Mandell, & File, 1998). A vaccine is available for some types, and infants should be immunized as well as certain others at risk. Pseudomonas aeroginosa

Pseudomonas aeroginosa has been long known as an opportunistic and nosocomial pathogen. The annual incidence of these infections in HlV-infected persons, particularly in those in which the CD4+ cell counts are below 100 mm 3 , appears to be increasing (Cohen et al., 1998). P. aeroginosa is a ubiquitous gram-negative rod found in soil, water, and vegetation, primarily causing infections in those who are immunocompromised or who have indwelling catheters. It may be carried on the skin and in the GI tract or throat in about 3% of the general population (Walker, 1998). In persons with AIDS, the most frequent syndromes seen are pneumonia, characterized by fever and a productive cough, and bacteremia, although a malignant form of otitis externa has been seen. Diagnosis relies on organism detection. Treatment depends on susceptibility of the organism, and combination therapy with an antipseudomonal beta lactam with an aminoglycoside or fluoroquinolone is usual. Relapses are relatively frequent (Cohen et al., 1998). Staphylococciis aureus

StaphyLococcus aureus are pyogenic gram-positive cocci occurring in clusters (Lowy, 1998). It is a normal resident of the nose and bowel of 30% to 50% of the general population but is considered a top cause of nosocomial infection (Walker, 1998). It is considered one of the most common bacterial infections with patients with AIDS and causes local and invasive infections. Pyogenic skin infections, such as folliculitis, are a common manifestation (Kovacs et al., 1997). Bacteremia may be followed by endocarditis or other responses (Cohen et al., 1998; Lowy, 1998). Symptoms depend on the affected site, and treatment depends on susceptibility of the infecting organism. HIV-positive persons are similar to HIV-negative persons in relation to symptomatology, diagnosis, and treatment. The reduction of iatrogenic opportunities such as indwelling vascular catheters may decrease the opportunities for infection.

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Salmonella The Salmonella species is divided into seven subgroups, and there are nine serogroups based on cell surface antigens encompassing more than 2,000 serotypes (Cohen et al., 1998; Walker, 1998). Salmonella infections in persons with AIDS are usually due to the following serotypes: S, typhimurium, S. dublin, S. newport, and S. enteritidis. Common manifestations in persons with AIDS include diarrhea (seen in more than half of the cases of salmonellosis), fever, chills, and bacteremia (Cohen et al., 1998). Diagnosis depends on isolation of the organism. Antibacterial therapy is usually successful insofar as resolution of symptoms is concerned, but relapse upon discontinuation of therapy is common (Cohen et al., 1998). Salmonellosis frequently precedes the diagnosis of AIDS. Antibiotic treatment depends on organism susceptibility and classically includes chloramphenicol, ampicillin, amoxicillin, and TMP-SMZ. In AIDS, ceftriaxone and ciprofloxacin may be effective. Prevention includes not eating uncooked or partly cooked eggs, meat, poultry, and seafood, or using unpasteurized milk or dairy products. Handling animals such as reptiles and turtles has been associated with some cases of salmonellosis. Prophylaxis is recommended if previous bacteremia has occurred (USPHS/IDSA Prevention of Opportunistic Infections Working Group, 1999). (See Appendices 2 and 3 for more information.)

Other Bacteria Some of the bacterial organisms that have been described as causing increased problems in persons with AIDS include Listeria, Shigella, Campylobacter, Streptococcus pneumoniae, and Clostridium difficile. The proliferation of these organisms is associated with either T or B cell defects. Endocarditis due to a variety of bacterial pathogens has been described more frequently in injecting drug users who are HIVinfected than in those who are not HIV-infected. Other frequently encountered intestinal bacterial infections in HIV infection may be due to Shigella and Campylobacter. Manifestations include severe diarrhea, cramping, nausea, and fever. Colitis with bloody diarrhea

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may result from the toxin produced by Clostridium difficile. Treatment is with oral vancomycin or metronidazole. Bacteremia due to usually enteric pathogens is seen even more frequently than intestinal complications in conjunction with AIDS. Recurrences are common (Casey, Cohen, & Hughes, 1996). Campylobacterspp may cause bacteremia in patients with HIV infection with varying incidence (Pigrau, Almirante, Pahissa, & Bartolome, 1996). Bacterial pneumonias are seen in persons with HIV infection more commonly than in the general population and have become the most common pulmonary infection in AIDS (Afessa, Green, Chiao, & Frederick, 1998). The major implicated organisms include Haemophilus influenza?., Streptococcus pneuinoniae, P. aeroginosa, R. equi, and N. asteroides. The incidence of bacterial pneumonias appears higher among injecting drug abusers and in some foreign-born persons with AIDS than other groups. The signs and symptoms of pneumonia in HIV-infected persons is not usually different from persons without HIV infection. However, bacteremia is much more frequent. Treatment depends on the organism involved and its antimicrobial susceptibility (Kovacs et al., 1997).

MALIGNANCIES Malignancies are frequent in many immunodeficiency states, both congenital and acquired, as well as in HIV disease (Lashley, 1998; Sande & Volberding, 1997). The most frequent malignancies associated with HIV infection are Kaposi's sarcoma and non-Hodgkin's lymphomas, especially of the central nervous system. In the 1993 case definition of AIDS, the CDC added invasive cervical cancer to the list of AIDS-defming conditions that already included Kaposi's sarcoma and Burkitt's lymphoma, immunoblastic lymphoma, and primary lymphoma of the brain (Centers for Disease Control, 1992). Other malignancies described with increased frequency in AIDS vary and include Hodgkin's disease, multiple myeloma, seminoma, brain cancer, anorectal carcinoma, testictilar cancer, and small-cell carcinoma of the lung (Goedert et al., 1998; Katariya & Thurer, 1999; Sande & Volberding, 1997).

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Kaposi's Sarcoma In 1981 an unusual disseminated form of Kaposi's sarcoma (KS) was reported among young homosexual men (Centers for Disease Control, 1981b). Prior to this, KS in the United States was essentially considered a relatively indolent disease of older men or as a sequelae of immunosuppressant therapy (Friedman-Kien, 1988). A review of the literature has detected reported cases not encompassed in the preceding categories among American-born young single men as early as 1977 and in Europe in 1976 among travelers returning from endemic areas of KS in Africa, but not earlier (Biggar, Nasca, & Burnett, 1988; Schwartz, 1988). Speculation existed for some time that KS might be due to a transmissible agent, and at one time Epstein-Barr virus was among the leading candidates. Eventually, it was found that certain viral DNA fragments were present in KS lesions not only from KS associated with AIDS but the other types as well as such primary effusion lymphoma and HIV-associated Castleman's disease. This virus is called the Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8 (HHV-8) (Chang et al., 1994; Jaffe & Pellett, 1999; Kemeny, Gyulai, Kiss, Nagy, & Dobozy, 1997; Oksenhendler et al., 1998). HHV-8 is now used more frequently because sequences of this virus are found in other types of tumors as well.-Despite this, HIV may be a cofactor in KS (Cohen et al., 1998; Kemeny et al., 1997). Sexual transmission of HHV-8 appears likely, especially among homosexual men. In children, the risk of HHV-8 infection correlates with the HHV-8 status of their mothers, and it has been suggested that horizontal transmission such as that occurring in EBV infection may occur (Jaffe & Pellett, 1999). KS is the most frequently observed malignancy among persons with AIDS; however, there has been a recent decrease in incidence in the United States. In 1981 KS was seen in 44% of homosexual males with AIDS and continues to be most prevalent in that group (Friedman-Kien, 1988). KS is more frequent among homosexual and bisexual men with AIDS than among hemophiliacs. It appears likely that HHV8 is sexually transmitted (Boshoff & Moore, 1998). Types ofKS. In 1872, Moriz Kaposi, a Hungarian physician practicing in Vienna, first described the idiopathic multiple pigmented

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sarcomas on the lower extremities that became known as classic Kaposi's sarcoma (Iscovich et al., 1999). Today, four types are generally recognized: 1. Classic KS 2. Endemic African KS 3. latrogenic KS (also called KS in immimosuppressed non-AIDS patients or renal transplant associated KS) 4. AIDS-KS Each will be described below. Classic KS was the first type recognized. It is seen most frequently in males between the ages of 50 and 80 years who are of eastern and southern European extraction, particularly Ashkenazic Jews and Italians (Greenblatt, 1998; Sung, Louie, & Park, 1997). This concentration in ethnic groups, but not in families, led to the speculation of genetic susceptibility to KS. The ratio of males to females is 10:1 to 15:1. All forms of KS are more frequent in men than women. Women who develop KS may be estrogen deficient (Clayton & Clayton, 1997; Sung et al., 1997), and KS may be more aggressive when it does occur in women (Nasti et al., 1999). The most common presentation in classic KS is that of asymptomatic single or multiple lesions appearing usually on the lower extremities, especially the ankles or soles of the feet. These lesions may appear as a reddish, purple, or brown patch, placque, or nodule. Classic KS usually runs a rather indolent course over 10 to 15 years or more, with slow enlargement of the original lesions and the gradual appearance of additional ones. A multifocal origin is more common than true metastasis. Additional lesions tend to be close to the original ones but may appear on conjunctiva or oral mucosa, and, over a long period of time, visceral lesions can occur. Skin lesions may become hyperpigmented, and chronic venous stasis and lymphedema complicate the picture. While not common, local invasion of lymph nodes, tissue, and bone can occur. Up to one third of KS patients may develop second primary malignancies, usually lymphoproliferative disorders such as non-Hodgkin's lymphoma or Hodgkin's disease. Treatment of classic KS with radiation, surgical excision of lesions, or electrocauterization with curettage has generally been successful. Systemic chemotherapy has been used in more

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advanced cases. Most persons with classic KS have died from other causes (Sung et al., 1997). Endemic African KS began to receive attention in 1961 but had been noticed before, both in 1934 and.1950. In 1961 it was reported that KS accounted for about 9% of all cancers in black Ugandan males. In addition, the geographical distribution of KS in Africa appears to parallel that of Burkitt's lymphoma (Krigel & FriedmanKien, 1988). Within this type there have been several clinical subtypes identified. The first is similar to classic KS, although it tends to occur in a younger age group, usually 25 to 40 years of age. Lesions tend to be nodules and/or plaques. Death can occur within 5 to 8 years. The second pattern of endemic African KS includes florid and inflltrative types that are more aggressive. Rapid progression is seen, with lesions growing into tumors that invade the subcutaneous tissue and bone. This may be called infiltrative-aggressive KS. If not treated, death can occur in about a year. Another pattern of endemic KS occurs in children or occasionally in young adolescents with a male to female ratio of 3:1. This lymphadenopathic form is disseminated and aggressive and usually does not have cutaneous manifestations. Generalized lymphadenopathy and visceral organ involvement are prominent. The prognosis is very poor, with a reported fatality rate of 100% within 3 years of diagnosis (Sung et al., 1997). KS in immunosuppressed patients is usually due to iatrogenic immunosuppression and was first described in 1969 in association with a renal transplant. This is still the most frequent group in whom it is seen, but it also occurs in persons with lymphoma, myeloma, systemic lupus erythematosus, rheumatoid arthritis, hemolytic anemia, and other disorders in which therapy with immunosuppressive agents such as cyclosporine, azathioprine, prednisone, and cyclophosphamide is initiated. In these patients, KS may remain localized to the skin or show widespread mucocutaneous and visceral organ dissemination. The ratio of males to females is about 2.3:1. The average time for development of KS after transplant is about 16 months. Therapy is difficult because of already existing immunosuppression, and about 30% of transplant patients are reported to die with generalized KS. In some iatrogenically suppressed patients, reduction or discontinuation of immunosuppressants has resulted in regression of KS (Sung et al., 1997).

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AIDS-related or associated KS was reported in this country in association with what we now know to be AIDS as described above (Centers for Disease Control, 1981). Persons with KS may have systemic symptoms such as fatigue, weight loss, diarrhea, and/or intermittent fevers, or KS may be the first sign of AIDS in an otherwise asymptomatic individual, which occurs in about 15%. KS has steadily declined in the United States since the 1980s in connection with HIV infection (Tulpule & Matheney, 1998). Clinical Staging of KS. Various staging systems are used in KS. One staging system for AIDS-related KS has been developed and tested by the AIDS Cooperative Treatment Group, also known as TIS [ Junior (tumor extent), immune Function (measured by CD4+ cell count), and Systemic illness (the presence of associated systemic illnesses)]. In this system, a good prognosis is reflected by tumors confined to the skin and/or lymph nodes (and/or nonnodular sarcoma confined to the palate), CD4+ cell count > 150 mm3; a Karnofsky performance rating of > 70, no history of opportunistic infection or thrush, and no weight loss, fever, or night sweats. A poor prognosis is predicted by any of the following: tumor-associated edema or ulceration, extensive oral KS, gastrointestinal and/or pulmonary KS, and/or other visceral KS; CD4+ cell count < 150 mm3; the presence of opportunistic infection or thrush; symptoms of weight loss, fever, or night sweats; a Karnofsky performance rating of < 70; or the presence of another related illness, such as lymphoma or dementia (Kroll & Shandera, 1998; Krown, Testa, & Huang, 1997). Clinical Aspects ofKS in AIDS. Clinically, KS lesions can vary from flat macular patches to papules, plaques, and elevated nodules that range in color from faint pink to dark purple to bluish brown and are hyperpigmented in dark-skinned persons. Lesions that appear first are often faint, flat patches of discolored skin. In the absence of any clinical suspicion of HIV infection initial lesions may be overlooked or misdiagnosed, depending on their appearance, as such conditions as hemangiomas, insect bites, nevi, melanomas, or bruises. However, in contrast to classic KS, lesions grow in size and number very quickly and are widespread (Krown, 1997). While usually oval, sometimes cutaneous lesions follow a distribution pattern along skin cleavage lines (Langer's lines). A multicentric

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distribution pattern of multiple primary tumors may be seen. The most frequent skin sites affected include the face, especially the tip of the nose, the ears, the penis, and the chest, back, or abdomen, in contrast to the extremities, as seen in classic KS (Greenblatt, 1998). The size of the lesions vary from a few millimeters to several centimeters in diameter. They are generally painless and nonpruritic. As the disease progresses, KS lesions may progress from macule to plaque to nodule to fulminating lesion (Greenblatt, 1998; Kroll & Shandera, 1998; Krown, 1997). Because the skin lesions are often visible and difficult to conceal in AIDS-associated KS, the potential of social stigma is added to other problems. KS can also cause lymphatic obstruction leading to lymphedema especially of the face and legs that can cause considerable discomfort (Kroll & Shandera, 1998; Krown, 1997). AIDS-related KS also shows predilection for other sites such as the oral cavity, lymph nodes, gastrointestinal tract, and the lung. The liver, adrenal glands, and heart may also be affected, as well as many other organ systems. The nervous system is not often involved, but focal neurologic deficits may be seen. At autopsy, gastrointestinal involvement may be seen in as many as 80% of AIDS-related KS cases (Krown, 1997). In the oral cavity, KS lesions may present only as a discoloration and can be overlooked (Wiebe & Epstein, 1997). Recognition of KS lesions in the oral cavity should prompt an examination of the gastrointestinal tract for additional lesions. KS can cause obstructive lesions most often in the upper GI tract resulting in impaired swallowing, intussception, obstruction, perforation, disturbed motility, or even lymphatic blockade with exudative enteropathy. Hemorrhage may be a sequelae. Diarrhea is not generally caused by KS (Clayton & Clayton, 1997). In about 20% to 50% of cases, KS lesions occur in the respiratory tract. Dyspnea, shortness of breath, wheezing, hemoptsis, and pleural effusion may be seen (Tulpule & Matheney, 1998). The diagnosis may be accomplished by bronchoscopy since radiography may show nonspecific changes. Pulmonary involvement is ominous, with a median survival of 3 months after it occurs (Katariya & Thurer, 1999; Tulpule & Matheney, 1998). The spindle cells, considered to be the tumor cells, secrete large amounts of vascular endothelial growth factor, an angiogenic agent. Tumor progression is linked to its ability to develop new blood vessels (angiogenesis) (Boshoff, 1998). Definitive diagnosis of KS

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skin lesions is by biopsy, usually punch biopsy. Treatment may be local or systemic. Therapy must be considered in light of the already existing immunosuppression. For small lesions, intralesional injection of vinblastine or alpha interferon is sometimes used. Localized radiation therapy and surgical removal of skin lesions has been successful. Systemic chemotherapy is also used, especially for multiple lesions or extracutaneous disease. Taxol (given IV), liposomal daunorubicin and doxorubicin are used in chemotherapy (Tulpule & Matheney, 1998). Newer approaches are based on new understanding of the lesion and includes use of inhibitors of angiogenesis (e.g., fumagillin derivatives), inhibitors of basic fibroblast growth factor (e.g., pentosan polysulfate), inhibitors of tumor necrosis factor (e.g., thalidomide), inhibitors of interleukin 1 (IL-1 receptor antagonist), inhibitors of interleukin 6, inhibitors of invasion (e.g., tissue inhibitor of matrix rnetalloproteinase 2), (3 human chorionic gonado tropin, and inhibitors of HHV-8 such as cidofovir or foscarnet (Katariya & Thurer, 1999; Kroll & Shandera, 1998). Death is most often due to the acquisition of opportunistic infection. When death results directly from KS, it is most often due to gastrointestinal hemorrhage, perforation of the gut, cardiac tamponade, adrenal insufficiency, or bulky tumors obstructing the respiratory tract. HIV-asso elated Malignant Lymphomas Aggressive B-cell non-Hodgkin's lymphoma (NHL) is believed to occur in between 5% and 13% of all HFV-infected persons (Kaplan, 1998). The malignant lymphomas are relatively frequent in immunodeficiency and immunosuppression from various sources. Most of these are NHLs that are concentrated in extranodal locations, are of B cell origin, and are often polyclonal. Most are intermediate and high-grade small noncleaved. Histology includes diffuse large cell immunoblastic subtypes and other diffuse large cell lymphomas (Katariya & Thurer, 1999; Straus, 1997). EBV has been implicated in NHL but may not be essential for its development (Goedert et al., 1998). NHLs may be classified as systemic, those that affect the CNS and primary effusion types. Extranodal presentations occur in more than two thirds. The sites most affected are the bone marrow, meninges, and GI tract, while pleural, pericardial, and peritoneal effusions

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have been more recently described. Systemic presentation may include symptoms relating to the extranodal sites such as GI disease, which can be found from the oral cavity to the anorectal area, with the stomach being one of the more common sites (Kaplan, 1998; Straus, 1997). Beginning in 1980, a sizable increase in the occurrence of lymphomas in never-married males was noted. Primary lymphoma of the CNS has been considered a defining criteria for AIDS since the beginning of the epidemic. Patients often present with confusion, lethargy, memory loss, cranial nerve palsies, hemiparesis, headache, or seizures. Sometimes the initial symptoms are more subtle, with only personality changes evident. On radiology, lesions may resemble toxoplasmosis (Kaplan, 1998). There may be an initial response to radiation therapy, but results are not sustained. With systemic malignant lymphomas, patients frequently present with systemic symptoms such as persistent unexplained fever, night sweats, weight loss, and/or lymphadenopathy. Specific symptoms depend on the sites involved. For example, those with extranodal disease of the gastrointestinal tract often present with complaints of abdominal pain, an abdominal mass, or a recent history of gastrointestinal bleeding. The CNS is also a common extranodal site for systemic lymphomas (Kaplan, 1998). Treatment is difficult, but combination chemotherapy with or without radiation may be used and protocols with anti-IL-6 antibodies and IL-2 are being used (Kaplan, 1998; Katariya £ Thurer, 1999). Hodgkin's Disease Hodgkin's disease is also occasionally associated with HIV infection and is not an AIDS-defining illness. It may be slightly increased in frequency above the general population in persons with HIV disease and may have a different natural history (Kaplan, 1998; Straus, 1997). Invasive Cervical Cancer Invasive cervical cancer was added as an AIDS-defining diagnosis in the 1993 AIDS definition, and is more common in HIV-infected

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women than noninfected women. Cervical dysplasia and cervical cancer in situ were added to category B conditions (Centers for Disease Control and Prevention, 1992; Chin, Sidhu, Janssen, & Weber, 1998). Cervical intraepithelial neoplasia (CIN), therefore, is an HlV-associated condition and may precede cervical cancer. HPV is implicated in the etiology of both CIN and invasive cervical cancer, and HPV DNA is found in lesions. HPV types 16 and 18 are most commonly found in cervical cancer. More advanced CIN is associated with more advanced immunosuppression, especially below 200 cells/ mm 3 (Cohen et al., 1998; Goedert et al, 1998; Walker, 1998). In HlV-infected women, CIN may recur (Fruchter et al., 1996). The CDC has recommended that a complete gynecological examination be part of the baseline for HlV-infected women. If negative, the examination should be repeated in 6 months. If squamous epithelial lesions are seen, colposcopy may be indicated (Centers for Disease Control and Prevention, 1993). THE NERVOUS SYSTEM AND HIV INFECTION Neurological complications accompanying AIDS were noted early in the epidemic. However, it was not until reports were published in 1985 that the impact of HIV on the nervous system began to be appreciated (Black, 1985; Carne et al., 1985; Levy, Bredesen, & Rosenblum, 1985; Shaw et al., 1985). At autopsy, evidence of central nervous system disease in patients with AIDS were noted in 80% to 90% (Cohen, 1997). Astrocytes and microglia in the CNS are thought to be reservoirs for HIV (Allbright et al., 1999; Brack-Werner, 1999). It is generally accepted that neurologic signs and symptoms occur in 40% to 60% of HIV-infected persons at some time in the course of their illness and may be the presenting manifestation in 10% to 20% (Cohen, 1997). Symptomatology is probably underreported because some manifestations can be subtle. As HIV-infected persons survive longer, more minor cognitive motor disorders (MCMD) are seen. However, the functional mental and neurological status of persons who are asymptomatic and HIV seropositive, how they should be measured, and what testing and physical and laboratory abnormalities mean on a practical level are still the subject of discussion. It is now appreci-

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ated that HIV is neurotropic and can invade the nervous system early in infection, resulting in involvement of both the central and peripheral nervous systems. This involvement can be latent or overt. Among the earliest noticeable manifestations of central nervous system (CNS) involvement are those seen in acute primary HIV infec tion due to acute aseptic meningitis or encephalopathy. These include fever, headache, meningeal signs, and cranial nerve involvement (Cohen, 1997). Neurological dysfunction can result from any of the following alone or in combination: 1. 2. 3. 4. 5. 6. 7.

Direct infection with HIV Opportunistic infections Primary or metastatic neoplasms Cerebrovascular etiologies Metabolic encephalopathies Complications secondary to therapy Factors as yet unknown

These are shown in Table 5.2. Multiple neurological dysfunctions are common in persons with AIDS, thereby complicating diagnosis and treatment. Also complicating direct organic effects are those effects that are emotional or psychological, such as anxiety and depressive reactions to the diagnosis of HIV. AIDS Dementia Complex (ADC) AIDS dementia complex (ADC), also known as HIV-associated dementia and HFV-1-associated cognitive/motor complex, is the most common cause of neurological dysfunction in adults with HIV and is believed due to HIV itself rather than to another pathogen (Kolson, Lavi, & Gonzalez-Scarano, 1998). ADC is characterized by cognitive, motor, and behavioral disturbances and may be divided into late and early symptomatology (Cohen, 1997; Navia, 1997). Early symptoms are summarized in Table 5.3. Cognitive impairment may be noticed first (McArthur, 1997). Early cognitive impairment may be manifested by difficulty in concentration, slowed processing, and memory impairment, especially recall. Affected persons may forget

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TABLE 5.2

Selected HIV-related Central Nervous System Disorders

Primary infection with HIV AIDS dementia complex Aseptic meningitis Vacuolar myelopathy HIV encephalopathy of childhood Opportunistic infections Cerebral toxoplasmosis Progressive multifocal leukoencephalopathy Cytomegalovirus encephalitis Cryptococcal meningitis Herpes simplex encephalitis Varicella zoster encephalitis Coccidioidal meningitis Neoplasms Primary CMS lymphoma Other metastatic lymphomas Other Metabolic encephalopathies (e.g., secondary to hypoxia, sepsis) Cerebrovascular disorders (e.g., infarcts, thrombi, emboli) Secondary to therapy Sources: Dalakas, Wichman, and Sever (1989); Levy, Bredesen, and Rosenblum (1985); Navia and Price (1986); Blumenthal et al. (1999).

TABLE 5.3 Early Symptoms of AIDS Dementia Complex/HIV-associated Dementia Cognitive Difficulty in concentration Slowness in thinking and response Memory impairment and forgetfulness Easily distracted Behavioral Social withdrawal Apathy Personality changes Motor Clumsiness of gait Difficulty with fine motor movements Poor balance and coordination Sources: Navia and Price (1986); Price (1997).

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appointments, have difficulty in reading a book and remembering the theme, lose track of conversations or their train of thought, and exhibit verbal' and/or mental slowness that is noticed by others. Early behavioral dysfunction may include personality changes, social withdrawal, apathy, and occasionally depression. The apathy, plus mental slowing, may be mistaken for depression. Early motor function impairment may include clumsiness, fine tremors, lower extremity hypertonia, poor balance and coordination, and difficulty with fine motor movements. Affected persons may drop items, have difficulty with writing or eating, and have an increased tendency to trip and fall. Sensorium is usually intact (Cohen, 1997; Navia, 1997). These features worsen as the disease progresses. Later manifestations include worsening of the cognitive impairment that eventually can include mutism, global dementia, and vacant staring. The person may manifest organic psychosis and be unaware of the illness. Extremity weakness increases, with paraparesis, ataxia, tremors, and seizures becoming evident. Urinary and fecal incontinence complicate the picture. In the final stages, patients usually become vegetative, cannot leave their beds, stare vacantly, and are capable, at best, of only simple interactions. Patients may retain consciousness, and even those who exhibit hypersomnolence may be aroused easily unless metabolic or systemic disease complicates the picture (Cohen, 1997; Navia, 1997; Price & Brew, 1988b). Price and Brew (1988a) proposed a clinical staging system for AIDS dementia complex that is summarized in Table 5.4. Another proposed classification is that of the World Health Organization/ American Academy of Neurology, which has two categories: (1) HIV1-associated cognitive/motor complex with the subcategories of HIVassociated dementia for those with primarily cognitive presentations and HPv^-1-associated myelopathy for those with primarily myelpathic presentations, and (2) HIV-1-associated minor cognitive/motor disorder for those with minimal impairment. The former category corresponds to ADC stages 2 through 4, whereas the latter corresponds to ADC stage 1. There is no equivalent for ADC stages 0 and 0.5 (Price, 1997). Bedside mental status testing does not always reveal early abnormalities. Several groups have developed test batteries. A core battery of tests was assembled to assess neurocognitive performance by Sidtis, Gatsonis, and Price (1993). A composite score, the neuropsychologi-

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TABLE 5.4 Clinical Staging of the AIDS Dementia Complex Stage

Characteristics

Stage 0 (normal)

Normal mental and motor function.

Stage 0.5 (equivocal/ subclinical)

Absent, minimal, or equivocal symptoms without impairment of work or capacity to perform ADL. Mild signs (snout response, slowed ocular or extremity movements) may be present. Gait and strength are normal.

Stage 1 (mild)

Able to perform all but the more demanding aspects of work or ADL but with unequivocal evidence (signs or symptoms that may include performance on neuropsychological testing) or functional intellectual or motor impairment. Can walk without assistance.

Stage 2 (moderate)

Able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life. Ambulatory but may require a single prop.

Stage 3 (severe)

Major intellectual incapacity (cannot follow new or personal events, cannot sustain complex conversation, considerable slowing of all output) or motor disability (cannot walk unassisted, requiring walker or personal support, usually with slowing and clumsiness of arms).

Stage 4 (end stage)

Nearly vegetative. Intellectual and social comprehension and output are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic, with urinary and fecal incontinence.

ADL = activities of daily living Sources: Navia (1997); Price (1997); Price and Brew (1988a).

cal Z score (NPZ-8), is generated. Lower NPZ-8 scores correlate with a higher ADC stage (Navia, 1997; Navia et al., 1998). An HIVdementia scale developed at Johns Hopkins University has also been used as a rapid screening test (McArthur, 1997; Power, Seines, Grim, & McArthur, 1995). Development of cognitive impairment is in part related to the degree of immune suppression as reflected by the CD4+ cell count. The incidence rate of ADC reported in a Multicenter AIDS Cohort Study by Janssen, Nwanyanwu, Selik, and Stehr-Green (1992) indi-

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cated that in AIDS patients with a CD4+ cell count < 200/mm3 and < 100/mm3 the incidence of ADC increased threefold and sevenfold, respectively. Yet even patients with counts above 500 cells/mm3 could show cognitive impairment. It is believed that there are other contributing factors such as differences in strains of infecting HIV, genetic factors, and other disease processes (Navia, 1997). The issue of whether or not asymptomatic HIV-infected individuals develop neurologic impairment is somewhat unresolved, although subclinical infection of the nervous system may be found and CSF abnormalities may be seen even in the absence of symptoms (Navia, 1997; Price, 1997). McArthur (1997) believes that about 30% of HIV-seropositive patients fall in the latter category, which is insufficient to interfere with usual activities of daily living. Radiological findings using MRI show diffuse cerebral atrophy and abnormalities in the white matter. Single photon emission computed tomography (SPECT) measures regional blood flow in the brain and indicates that changes in cerebral blood flow occur early in persons with HIV infection. HIV may be recovered from macrophages. Other tests such as CSF analysis should be done to rule out other possible causes. Management is difficult, and strategies that improve immune function and decrease viral load such as use of antiretroviral agents and protease inhibitors have been used. Nimodipine (a calcium channel antagonist) and selegiline have shown promise in phase 1 clinical trials (McArthur, 1997). Vacuolar Myelopathy Myelopathies in HIV infection can be divided into segmental and diffuse types. Segmental types are rare. Vacuolar myelopathy, a diffuse form, mainly affects the lateral and dorsal columns of the thoracic spinal cord, affecting up to 30% of patients with AIDS. It may occur in conjunction with ADC or alone (Cohen, 1997; Price, 1997). It may result from neurotoxic effects of cytokines (Tyor et al, 1993). Vacuolar degeneration results in a loss of myelin from the spinal cord that chiefly affects the white matter. The vacuoles result from edema within the myelin sheath. Pathologically, vacuolar myopathy resembles degeneration caused by vitamin B12 deficiency (Cohen, 1997). Clinical features include leg weakness, gait ataxia, inconti-

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nence, upper motor neuron signs, and posterior column deficits that evolve over a period of weeks to months. Dementia is a very frequent association. Development of vacuolar myelopathy has occurred rarely as part of seroconversion when primary HIV infection occurs (Cohen, 1997). Miscellaneous Central Nervous System Disorders Other central nervous system disorders are also common with HIV infection. These are often due to opportunistic infections and/or neoplasms. The most frequent CNS complications due to infectious agents are toxoplasmic encephalitis, cryptococcal meningitis, and CMV or herpes simplex encephalitis. Others include progressive multifocal leukoencephalopathy caused by the JC virus, intracerebral candidiasis, abscesses, or meningoencephalitis due to C. immitis or M. tuberculosis, and herpes simplex encephalitis (Ammassari et al., 1998; Blumenthal etal., 1999; Cohen, 1997; Roos, 1998). These were discussed earlier. Neurosyphilis due to Treponema pallidum may cause neurological disease in HIV-positive patients as well (Cohen, 1997). Other opportunistic infections can affect the central nervous system, but do so infrequently. Among the neoplasms affecting the CNS, primary CNS lymphoma is most frequently seen in patients with AIDS. Systemic lymphomas, especially due to non-Hodgkin's lymphoma or Burkitt's lymphomas can invade the meninges and other parts of the nervous system. Spinal cord compression may also be seen. The 1993 CDC revised criteria for AIDS now allows for an AIDS diagnosis in HlV-seropositive patients with systemic lymphoma. Metastasis of Kaposi's sarcoma to the CNS in persons with AIDS occurs but is rare (Blumenthal et al., 1999; Centers for Disease Control and Prevention, 1992; Kaplan, 1998; Straus, 1997). Metabolic encephalopathies may affect the CNS either alone or in combination with another disorder. These can result from systemic illnesses experienced by persons with AIDS. Examples of these are generalized sepsis and hypoxia secondary to pneumonia. These may cause a decrease in alertness (Price & Brew, 1988b). Cerebrovascular complications can also affect the CNS. Most frequently described are infarcts, transient ischemic attacks, hemorrhage due to neoplasias that frequently occurred within the tumor,

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and cerebral vasculitis. In some cases, the cause can be identified, such as hemorrhage secondary to thrombocytopenia, but in others, the explanation is not evident. Lastly, CNS complications can arise as a result of therapy. These include both neurological and psychiatric side effects and may follow chemotherapy for neoplasms, antiviral therapy, or therapy for specific symptoms. The clinical presentations vary with the pharmacological agent.

Neuromuscular Manifestations of HIV Infection Although the CNS effects associated with HIV infection and AIDS have received more attention, awareness of the effects of HIV on the peripheral nervous system and of neuromuscular manifestations has increased. Neuromuscular disorders may be seen at any stage of HIV infection and may be the only indication of such infection. They may also coincide with acute illness and seroconversion, but this is less likely. The major neuromuscular disorders seen in HIV infection are the peripheral neuropathies (e.g., acute inflammatory demyelinating polyneuropathy or chronic inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, and sensory neuropathy) and inflammatory and noninflammatory myopathies such as polymyositis (Price, 1997). Neuropathies may also be due to viruses such as varicella zoster causing herpes zoster, as discussed earlier. Acute inflammatory demyelinating polyneuropathy (AIDP) in persons with HIV infection is very similar to theGuillain-Barre syndrome, which often follows other viral diseases. It may have the same autoimmune pathogenesis, although other causes are possible. While AIDP is found in patients without HIV infection, its occurrence should alert clinicians to consider HIV infection as a diagnosis. Symptoms include ascending flaccid paralysis. Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive sensorimotor polyneuropathy. Patients often present with a subacute onset of sensorimotor deficit occurring over a period of 1 to 2 months. Weakness and sensory loss are prominent symptoms. On testing, reflexes generally are reduced, cerebrospinal fluid protein is usually elevated, and there is evidence of demyelination (Cohen, 1997; Sadler & Nelson, 1997a). For both AIDP and CIDP, corticosteroids, immune globin,

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and plasmapheresis have proved useful. Spontaneous remission has also occurred (Cohen, 1997). Mononeuropathy multiplex may have several forms. Sometimes it can be due to multifocal CMV infection of the nerve, and in other cases an autoimmune vasculitis may be the cause (Price, 1997). This has been seen rarely, and usually the legs or feet have been affected, with sensory or motor deficits in the distribution of multiple spinal, cranial, or peripheral nerves. Footdrop and paresthesias have been prominent (Dalakas et al., 1989). One of the most common neuropathies seen in persons with AIDS is a distal symmetric polyneuropathy that is predominately sensory. It occurs in about 30% to 35% of HlV-infected adults (Cohen, 1997; McArthur, 1997; Sadler & Nelson, 1997a). Severe, painful paresthesias occur, which patients may describe as walking on broken glass or feeling as if their feet have been set on fire (McArthur, 1997). Symptoms often begin on toes or the soles of the feet, with numbness, burning or a pins-and-needles sensation. Some patients can walk only on their heels, because the soles become so tender. This may progress to involvement of the entire foot, with contact hypersensitivity becoming a major problem. Ankle and knee jerk reflexes are diminished. Weakness of the feet may be seen. The hands can also be affected, and a glove and stocking distribution can occur. This polyneuropathy can continue throughout the course of HIV disease, causing disability. The direct cause is unknown, but possibilities include direct infection of neurons of the dorsal root ganglia by HIV, CMV infection, the elaboration of cytokines, or toxic, metabolic, or nutritional factors that are not yet identified (Swanson, Zeller, & Paice, 1998). Although many physicians do not view the polyneuropathy as a serious complication of AIDS, it is very troubling and disabling to affected patients, and various therapies should be tried to obtain success. These include analgesics and tricyclic antidepressants (Cohen, 1997; McArthur, 1997; Sadler & Nelson, 1997a). Human nerve growth factor is being tested in a clinical trial (McArthur, 1997). Lumbosacral polyradiculopathy, is usually seen when the CD4+ cell count falls below 50 cells/mm3, which occurs in about 2% of persons with AIDS. It often manifests with radiating low back pain followed by an asymmetric flaccid paraparesis with decreased or absent reflexes. Sphincter dysfunction leading to both fecal and

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urinary incontinence is an accompaniment. Motor deficits are more prominent than sensory ones. CMV has been associated with this disorder, but its role is not clear. Cidofovir, ganciclovir, and foscarnet have been used without much success, and death is usually the sequela of this syndrome (Cohen, 1997; Sadler & Nelson, 1997a). The most frequent myopathy seen in AIDS is polymyositis or inflammatory myopathy. It generally presents with subacute proximal muscle weakness, sometimes in association with skin rash. Muscle enzymes are elevated, especially creatine kinase. The cause is unknown but may result from direct HIV invasion of the muscles, by organisms such as CMV, or by an immune-mediated mechanism (Cohen, 1997; Dalakas & Pezeshkpour, 1988). Myopathy suggestive of mitochondrial involvement has been associated with zidovudine, and discontinuing it may cause resolution (Cohen, 1997).

CONSTITUTIONAL SYMPTOMS AND HIV WASTING SYNDROME HIV wasting syndrome was recognized as an AIDS-defining condition in 1987