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 Miss...

Author: Jerry D. Durham PhD RN FAAN; Felissa R. Lashley RN PhD ACRN FACMG CIC

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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


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.


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


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


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


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


9

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

10


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-


11

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,

12


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


13

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

14


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


15

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

16


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


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

18


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.


19

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-

20


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.


21

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

22


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


23

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

24


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


25

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

26


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


27

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.

28


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.


29

(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.

30


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


31

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

32


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


33

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.

34


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


35

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

36


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


37

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

38


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


39

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

40


(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


41

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

42


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


43

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

44


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


45

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

46


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-


47

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

48


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


49

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;

50


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-


51

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

52


(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


53

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


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.


55

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.

56


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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Vogt, M. W., Witt, D. J., Craven, D. E., Byington, R., Cra\vford, D. F., Schooley, R., & Hirsch, M. S. (1986). Isolation of HTLV-III/LAV from cervical secretions of women at risk for AIDS. Lancet, 1, 525-527. Wain-Hobson, S. (1998). More ado about HIV's origins. Nature Medicine, 4 ( 9 ) , 10011002. Walker, T. S. (1998). Microbiology. Philadelphia: W. B. Saunders. Ward, J. W7., & Duchin, J. S. (1998). The epidemiology of HIV and AIDS in the United States. AIDS Clinical Review, 1997/1998, 1-45. Webber, M. P., Schoenbaum, E. E., Gourevitch, M. N., Buono, D., & Klien, R. S. (1999). A prospective study of HIV disease in female and male drug users. AIDS, 13, 257-262. Weber, J. (1984). Is AIDS an epidemic form of African Kaposi's sarcoma?: Discussion paper. Journal of the Royal Society of Medicine, 77, 575-576. Whittle, H. C., Ariyoshi, K., & Rowland-Jones, S. (1998). HIV-2 and T cell recognition. Current Opinion in Immunology, 10(4), 382-387. Wiley, C. A., £ Achim, C. (1994). Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome. Annals oj Neurology, 36, 673-676. Withrington, R. H., Cornes, P., Harris,]. R. W., Seifert, M. H., Berrie, E., TaylorRobinson, D.. & Jeffries, D. J. (1987). Isolation of human immunodeficiency virus from svnovial fluid of a patient with reactive arthritis. British Medical Journal, 294, 484. Wofsy, C. B., Cohen, J. B., Hauer, L. B., Padian, N. S., Michaelis, B. A., Evans, L., & Levy, J. A. (1986). Isolation of AIDS-associated retrovirus from genital secretions of women with antibodies to the virus. Lancet, 1, 527-529. World Health Organization. (1985). Acquired immune deficiency syndrome (AIDS). Weekly Epidemiological Record, 60, 342. (1998). Global AIDS surveillance. Weekly Epidemiological Record, 73, 193-200. Wortley, P. M., & Fleming, P. L. (1997). AIDS in women in the United States. Journal of the American Medical Association, 275(11), 911-916. Zeigler,}. V., Cooper, D. A., Johnson, R. O., £ Gold, J. (1985). Postnatal transmission of AIDS-associated retrovirus from a mother to an infant. Lancet, 1, 896-897. Zhu, T., Korber, B. T., Nahmias, A.J., Hooper, E., Sharp, P. M., £ Ho, D. D, (1998). An African HlV-1 sequence from 1959 and implications for the origin of the epidemic. Nature, 391, 594—597.

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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,

90


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.


91

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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REFERENCES Aiken, C., Konner, J., Landau, N. R., Lenburg, M. E., & Trono, D. (1994). Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell, 76, 853-864. Alien,]. E., & Maizels, R. M. (1997). Thl-Th2: Reliable paradigm or dangerous dogma? Immunology Today, 18, 387-392. Ameisen, J. C. (1992). Programmed cell death and AIDS: From hypothesis to experiment. Immunology Today, 13, 388-391. Brennan, C., & Porche, D.J. (1997). HIVimmunopathogenesis.yoMrna/o/fA^/liiorzation of Nurses in AIDS Care, 8, 7-22. Carr, A., & Cooper, D. A. (1997). Primary HIV infection. In M. A. Sande & P. A. Volberding (Eds.), The medical management of AIDS (5th ed., pp. 89-106). Philadelphia: W. B. Saunders. Clerici, M., & Shearer, G. M. (1992). The use of in vitro T cell immune function to monitor the course of HIV infection. In G. Janossy, B. Autran, & F. Miedema (Eds.), Immunodeficiency in HIV infection and AIDS. EC/FERS/MRC workshop on immunodeficiency in HIV-1 infections, Windsor, Surrey, 1991 (pp. 64-75). Basel, Karger. . (1994). TheThl/Th2 hypothesis of HFV infection: New insights. Immunology Today, 15, 575-581. Cunningham, A. L., Dwyer, D. E., Mills, J., & Montagnier, L. (1996). Structure and function of HIV. Medical Journal of Australia, 164, 161-165. Dyer, W. B., Geczy, A. F., Kent, S. J., Mclntyre, L. B., Blasdall, S. A., Learmont, J. C., & Sullivan, J. S. (1997). Lymphoproliferative immune function in the Sydney Bolld Bank Cohort, infected with natural n

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