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Confronting AIDS: Directions for Public Health, Health Care, and Research (1986)

Chapter: 2. Understanding of the Disease and Dimensions of the Epidemic

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Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 37
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 38
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 39
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 40
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 41
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 42
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 43
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 44
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 45
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 46
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 47
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 48
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 49
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 50
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 51
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 52
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 53
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 54
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 55
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 56
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 57
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 58
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 59
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 60
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 61
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 62
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 63
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 64
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 65
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 66
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 67
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 68
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 69
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 70
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 71
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 72
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 73
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 74
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 75
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 76
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 77
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 78
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 79
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 80
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 81
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 82
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 83
Suggested Citation:"2. Understanding of the Disease and Dimensions of the Epidemic." Institute of Medicine and National Academy of Sciences. 1986. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, DC: The National Academies Press. doi: 10.17226/938.
×
Page 84

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Untlerstanding of the Disease and Dimensions of the Epidemic In the middle of 1981, several outbreaks of Pneumocystis carinii pneumonia and Kaposi's sarcoma in previously healthy young male homosexuals were reported to the Centers for Disease Control (CDC), the division of the Public Health Service responsible for monitoring infectious diseases in the United States (Centers for Disease Control, 1981a,b). Before these reports, those diseases were essentially seen only in persons with recognized causes of immune system compromise, such as rare genetic diseases, immunosuppressive treatments for organ transplants, or cancer chemotherapy. Nevertheless, the sufferers of this novel and inexplicable syndrome demonstrated severely compromised immunologic defenses against a wide range of viral, bacterial, and parasitic infections. Although the syndrome was first seen in homosexual men, soon other groups also were found to be "at risk" for the disease, including intravenous (IV) drug users, recent Haitian immigrants, hemophiliacs, recipients of blood transfusions, sexual partners of persons who had the disease or were at risk, and infants of mothers with the disease or at risk. As a result, the general term "acquired immune deficiency syndrome" (AIDS) gradually became accepted (Centers for Disease Control, 1982a). By the end of 1982, the Centers for Disease Control had established a surveillance definition of AIDS that could enable its incidence in the United States to be monitored (Centers for Disease Control, 1982b). This definition described AIDS as "a reliably diagnosed disease process that is at least moderately predictive of a defect in cell-mediated immunity occurring in a person with no known cause for diminished resistance" 37

38 CONFRONTING AIDS (see Appendix E). Initially, 11 opportunistic infections and diseases were considered specific enough to be diagnostic for AIDS. This definition was designed with more emphasis on specificity than on sensitivity and has permitted the collection of useful data because of its precision and uniform acceptance. It also resulted in a broader recognition of the syndrome's prevalence and in early concerted attempts to identify the causative agent. It has been used uniformly since 1982, with minor changes made in June 1985 (Centers for Disease Control, 19851. Shortly after the recognition of AIDS, an array of other distinctive and pronounced clinical signs and symptoms were noted among homosexual men. These included persistent generalized lymphadenopathy (PGL) (Abrams et al., 1984; Metroka et al., 1983), fatigue, persistent fever, weight loss, diarrhea, and certain necrologic signs and symptoms. Some investigators suggested that these illnesses represented the early stages of AIDS, but at the time there was little understanding of whether all persons who manifested such symptoms would ultimately progress to clinical AIDS. Gradually the term AIDS-related complex (ARC) began to be employed to describe all of the clinical signs and symptoms that seemed to be related to AIDS but did not fully meet the CDC's criteria for the disease. Developing and improving the definitions of AIDS, ARC, and PGL have been important in understanding the epidemic. However, like other definitions designed for epidemiologic investigation, they are meant to be specific and easy to apply. When used in individual clinical situations, they are somewhat arbitrary and do not fully reflect the morbidity caused by the illnesses associated with them. Some patients with ARC experi- ence a rapidly fatal disease course, while a few people with an AIDS- related malignancy are in reasonably good health more than five years after diagnosis. It has been extremely difficult to arrive at any consensus regarding the definitions of ARC and PGL. Many persons with lymphadenopathy are asymptomatic. Patients with ARC have varying clinical symptomatology, ranging from mild problems such as occasional fevers and night sweats to fulminant disease courses, including dementia and death. Definitions of HIV-related conditions must therefore be applied cautiously. Neverthe- less, they are helpful in monitoring the progression of the epidemic in various groups of people. THE CAUSATIVE AGENT OF AIDS Because AIDS was first recognized in male homosexuals, initial hypotheses of the cause of the disease focused on exposures common to this group. Suggested causes included the use of amyl and butyl nitrites

THE DISEASE AND THE EPIDEMIC 39 (known as poppers) to heighten sexual pleasure, autoimmune reactions due to repeated exposure to sperm, "immune overload" due to repeated and varied infections, or an infectious agent. The appearance of AIDS in population groups other than homosexual males lent strong support to the hypothesis that the disease was caused by an infectious agent rather than by an exposure specific to some homo- sexuals. In particular, the early epidemiologic analysis of AIDS delin- eated a pattern of spread very reminiscent of hepatitis B. This pattern strongly suggested a transmissible infectious agent in the blood or body fluids of affected individuals. However, the search for such an agent was frustrated by the large number of other infections commonly found in AIDS patients. Well-known and prevalent viruses such as Epstein-Barr virus and cytomegalovirus were advanced as possible etiologic agents, yet none could account for the novel character of AIDS or for its appearance in diverse populations. Meanwhile, several contingents of medical scientists began exploring the possibility that the cause of AIDS might be a member of a family of viruses known as retroviruses. Such viruses are prevalent in certain species of animals but had only recently been described in human beings. In 1983, research efforts yielded very suggestive evidence for the involve- ment of a novel human retrovirus in AIDS. Shortly thereafter, the isolation and characterization of a previously unknown retrovirus vari- ously known as LAV (lymphadenopathy-associated virus), HTLV-III (human T-cell lymphotropic virus type III), or ARV (AIDS-associated retrovirus) led to its definitive identification as the cause of AIDS (Barre-Sinoussi et al., 1983; Gallo et al., 1984; Levy et al., 19841. These early isolates of immunosuppressive retroviruses were later recognized to be closely related, and a generic name human immunodeficiency virus (HIV) has been proposed for them and for subsequently isolated and related viruses (Barre-Sinoussi et al., 1983; Gallo et al., 1984; Levy et al., 1984~. Initial attempts to isolate novel retroviruses from persons with AIDS were stymied by an inability to grow the cells in which human retrovi- ruses proliferate a type of white blood cell known as a T lymphocyte. Rather than continuing to proliferate, T lymphocytes derived from AIDS patients showed short-term growth and then extensive cell death. How- ever, these T-lymphocyte cultures revealed the presence of viral particles resembling retroviruses and an enzymatic activity known as reverse transcriptase that is a marker for retrovirus production (Barre-Sinoussi et al., 1983; Gallo et al., 1984~. The viability of T lymphocytes markedly deteriorated soon after these still-uncharacterized retroviruses were pro- duced, an observation consistent with the expected effects of an "AIDS virus" (Klatzmann et al., 1984a; Popovic et al., 19841. Furthermore, the

40 CONFRONTING AIDS retroviruses derived from lymphocyte cultures of individuals with AIDS or associated conditions could easily be transferred to cultures of normal lymphocytes, where they would reproduce the pronounced cytopathic ejects seen in the original culture. The finding that the target for viral infection in vitro is a vitally important subset of lymphocytes fits well with the profound depletion of these cells seen in persons with AIDS (Dalgleish et al., 1984; Klatzmann et al., 1984b; see section on "Patho- genesis of AIDS," below). The next advance came in the identification of an immortal T-cell leukemia line that could be used to propagate the novel retroviruses without demonstrable cytopathic consequences (Popovic et al., 19841. It allowed the viruses to be produced on a large scale and characterized in detail. Furthermore, critical reagents could be prepared for use in epidemiologic studies and for delineating the modes of transmission of the virus. Testing of sera from AIDS patients and persons with AIDS-associated conditions disclosed the presence of antibodies reactive with the protein constituents of HIV in almost all instances, whereas sera from individuals not in "at risk" groups were uniformly negative (Brun-Vezinet et al., 1984; Safai et al., 1984; Sarngadharan et al., 19841. Serum samples from individuals in groups at risk for the development of AIDS demonstrated a prevalence of antibodies to HIV that correlated well with the time of appearance, extent, and geographic clustering of cases of AIDS and ARC. HIV can be isolated from lymphocytes from the majority of persons, including most AIDS and ARC patients, demonstrating serologic reactiv- ity with the virus (Salahuddin et al., 19851. (The failure to isolate the virus from all infected persons is most likely due to technical limitations in the lymphocyte culture methods and to the depletion of target cells in advanced stages of the disease.) The etiologic role of HIV in AIDS was further demonstrated by the study of AIDS cases associated with blood transfusions, which clearly showed that the virus could be transmitted to a previously uninfected person who could then develop AIDS (Feorino et al., 1985; Jaffe et al., 1985b). Because HIV can be isolated from most people with antibodies to it, all persons having antibodies to HIV must be assumed to be infected and, for practical purposes, capable of transmit- ting the virus. Features of Retroviruses The pathogenic features of the infectious agents that later became known as retroviruses were first described at the beginning of the twentieth century, when they were identified as the causative agents of certain leukemias and sarcomas in chickens. Since then, retroviruses

THE DISEASE AND THE EPIDEMIC 41 have been identified as the causes of many other malignant and nonma- lignant diseases in a wide variety of animals. Some of these animal diseases appear analogous to certain malignant or degenerative conditions in human beings, a similarity that caused many attempts to demonstrate the relevance of retroviruses to the pathogenesis of human diseases. But it was not until 1980 that a retrovirus was definitively isolated in a human disease, an unusual type of T-cell leukemia (Poiesz et al., 19801. This retrovirus, human T-cell lymphotropic virus type I (HTLV-I), is the cause of an aggressive form of leukemia known as adult T-cell leukemia that is common in certain parts of the world. A related but clearly distinct retrovirus known as HTLV-II was subsequently isolated from a person with a less aggressive type of leukemia (Kalyanaraman et al., 1982~. HIV (also known as HTLV-III) is the third type of human retrovirus to be isolated. The genetic information of retroviruses is transmitted as single-strand molecules of RNA (ribonucleic acid) in the virus particle. To be replicated and expressed in the cells that retroviruses infect, the information in these single-strand RNA molecules must be transferred into double-strand DNA (deoxyribonucleic acid), which is the form that can become integrated into the chromosomes of the infected cell (Varmus and Swanstrom, 19841. The backward, or "retro," flow of information from RNA to DNA the reverse of most genetic message movement gives the virus its family name. The retro movement is made possible by an enzyme, reverse transcriptase, encoded by the virus. Related Viruses The taxonomic family Retrovirinae is composed of three subfamilies: Oncovirinae, Lentivirinae, and Spumivirinae (Teich, 1984~. The oncovi- ruses (oncogenic, or cancer-causing, viruses) include the causative agents of a number of naturally occurring leukemias and lymphomas in cats, wild mice, birds, cows, and gibbons. HTLV-I and HTLV-II most closely resemble members of this subfamily, though they have a number of distinctive structural and functional attributes. Lentiviruses cause a number of naturally occurring, progressive, nonmalignant disorders in animals. They are responsible for a variety of protracted neurologic, musculoskeletal, hematologic, and respiratory diseases of hoofed mammals that generally arise after a long incubation period. HIV shares a number of genetic, structural, and biologic similar- ities with members of this group, although none of the previously described lentiviruses is known to directly affect the immune systems of infected hosts (Gonda et al., 1985; Sonigo et al., 19851. As discussed in Chapter 6, this classification of HIV as a lentivirus has a number of important implications for the analysis of the pathogenic mechanisms of

42 CONFRONTING AIDS AIDS and for the development of potential interventions to prevent the effects of HIV infection. Spumiviruses include bovine and feline syncytial viruses and simian and human foamy viruses. They persist in animals despite a host immune response and are not known to be involved in any disease processes. Following the identification of HIV, a syndrome of acquired immuno- deficiency that closely resembled AIDS was described in certain species of monkeys (Daniel et al., 1985; Kanki et al., 1985a; Letvin et al., 19851. Retroviruses isolated from the affected animals shared many biologic and immunologic characteristics with HIV. These related viruses have been named STLV-III (for simian T-cell lymphotropic virus type III) or SIV (for simian immunodeficiency virus). Although infection with this virus produces profound immunosuppression in certain species of monkeys, it results in no untoward effects in other species (Kanki et al., 1985b; Letvin et al., 19851. These related simian lentiretroviruses may provide ex- tremely useful models for HIV infection in humans. Very recently, analysis of newly discovered types of human retrovi- ruses termed HTLV-IV and LAY-2 has shown that they are more closely related to the simian viruses than to HIV. The relationship of HTLV-IV and LAY-2 to each other is presently unclear, because infection with HTLV-IV reportedly results in no apparent immunodeficiency, while LAY-2 has been isolated from individuals suffering from immunologic abnormalities typical of AIDS. PATHOGENESIS OF AIDS AIDS is primarily a disease of the body's immune system. The consequences of HIV infection are such that infected persons exhibit in an apparently progressive manner a spectrum of immunologic compro- mise. In its most extreme manifestation, this immunologic compromise results in an inability to counter many infections with an effective immune response. HIV infection may also result in symptoms such as necrologic damage (see Appendix A). The primary function of the immune system is to identify, isolate, and eliminate foreign (predominantly microbial) invaders of the body (Weiss- man, 19861. The human immune system is composed of a wide variety of differentiated cells that interact in an exceedingly complex and as yet poorly understood manner to provide protection against infectious dis- eases. Much of the future understanding of the pathogenesis of AIDS will derive from increasingly sophisticated insights into the human immune system. Most of the in viva measures of immune function are markedly depressed in patients with AIDS. Similarly, immunodeficiency is appar

THE DISEASE AND THE EPIDEMIC 43 ent in analyses of many of the in vitro measures of immune reactivity. Shortly after AIDS was first recognized, patients suffering from the syndrome were found to have reduced numbers of a subset of white blood cells known as T lymphocytes that expressed on their cell surfaces a molecule known as CD4 (such cells are also known as T4 cells). Such lymphocytes, most of which are included in what is functionally defined as the helper/inducer subset, constitute the major population of mature T cells. Another major subset of T cells express the CD8 molecule on their cell surfaces (such cells are also known as T8 cells). Most of these are classified as suppressor/cytotoxic cells. Normally, the CD4-to-CD8 ratio in humans is 1.5 to 2.0. In AIDS patients, however, this ratio is inverted, so that it is less than 1.0. Generally, this inversion has been found to be due to a decrease in the absolute numbers of CD4 cells, with the normal numbers of CD8 cells usually being preserved. Given the enormous complexity of the human immune system, the simple distinction between CD4 and CD8 cells is bound to be an oversimplification. But measurement of the CD4-to-CD8 ratio was the earliest marker for immunologic impairment in AIDS, and it has proved to be a reasonably sensitive measure. CD4 cells perform a multitude of essential functions in the immune system. They specifically recognize and proliferate in response to anti- gens (foreign molecules) that they encounter in the body, at the same time releasing a variety of proteins known as lymphokines that regulate other immune system cells. Upon signaling by CD4 cells, cells known as lymphocytes, recognizing antigens, secrete specific antibodies to neutral- ize or eliminate antigenic bacteria and viruses as they travel through body fluids between cells. Similarly, following recognition of antigens and signaling from CD4 cells, some CD8 cells called cytotoxic T cells become activated to kill cells infected with intracellular pathogens; others called suppressor T cells dampen an ongoing immune response. Furthermore, CD4 cells are known to modulate the activities of immune system cells known as natural killer cells and macrophages, which are involved in responses to infection and perhaps to incipient malignancies. The mechanisms by which CD4 cells might be depleted by HIV have remained mysterious (see Chapter 61. Once HIV was isolated, it was found in vitro to specifically infect a subset of CD4 cells and to initiate events leading to the depletion of most CD4 cells in the culture, accurately mirroring the depletion of CD4 cells in viva (Klatzmann et al., 1984a; Popovic et al., 19841. This led investigators to test whether and subsequently to prove that the CD4 molecule is the receptor used by HIV to initiate viral infection of these cells (Dalgleish et al., 1984; Klatzmann et al., 1984b). The CD4 molecule at the cell surface thus appears to distinguish potential target cells for HIV and to act as the receptor

44 CONFRONTING AIDS molecule that binds the virus and allows infection and subsequent viral replication. Recent experimental evidence has also suggested that the interaction between HIV and the CD4 molecule contributes to the cytopathic consequences of viral infection (Lifson et al., 1986; Sodroski et al., 19861. The immunodeficiency of AIDS clearly demonstrates the importance of CD4 T lymphocytes. Because of the loss of these cells, the remaining T lymphocytes from AIDS patients have diminished or absent responses to antigens, to certain chemicals known as mitogens that make T cells divide, and to blood cells from nonidentical individuals. In addition, T lymphocytes from AIDS patients show subnormal production of essential immunoregulatory factors, and due to their decreased numbers and functional capacity they are unable to fulfill their necessary role in providing direction for the maturation of B cells and cytotoxic T cells. The ability of AIDS patients to mount antibody reactions to new antigens is severely compromised, though paradoxically high levels of antibodies to previously encountered antigens, including HIV, are often present in patients' sera. NATURAL HISTORY OF THE DISEASE Since the initial recognition of the AIDS epidemic, much information has accumulated regarding the natural history of the disease. Prior to the identification of HIV as the causative agent of AIDS and the development of serologic testing to detect the presence of antibodies (and thus infection) in asymptomatic persons, information on the cause of the disease was limited to data on those who developed clinical dysfunction. Since the virus was isolated, however, it has become increasingly feasible to study HIV-infected individuals prospectively for development of laboratory abnormalities as well as disease manifestations. The earliest markers now known to indicate that HIV has been transmitted to an individual are either the isolation of HIV from that person or the detection of antibodies to the virus in the person's blood. The appearance of antibodies directed against HIV in the serum of exposed persons which is known as seroconversion appears to predate any detectable immuno- logic defects. Recent data suggest that seroconversion is accompanied within a five-year period by evidence of immunologic defects in more than 90 percent of individuals, including those who remain clinically asympto- matic (Melbye et al., 19861. Furthermore, the development of character- istic abnormalities, as revealed by certain laboratory measures of the immune system, often occurs very rapidly after the appearance of antibodies. The long-term health significance of these early alterations in

THE DISEASE AND THE EPIDEMIC 45 immune functioning are not yet fully appreciated, but they must be regarded as a cause for concern. r .1 _ _ _ 1 ~ :~_ The typical time between transmission of one virus anu sero`;~vc;~u~ has been estimated to be six to eight weeks, based on observation of cases in which an isolated exposure to the virus was known to have occurred (Melbye, 19861. This period is highly variable, however, with reported instances of seroconversion occurring up to eight months after an isolated exposure to HIV. Isolated and unusual cases have been reported in which individuals remained seronegative for long periods of time although they were infected,\as evidenced by cultivation of virus from the blood (Groopman et al.', 1985; Salahuddin et al., 19841. This possibility has implications for blood donation, as discussed in Chapter 4. The number of viral particles needed to initiate infection, the form in which they are transmitted, and the relationship of these factors to possible routes of entry are not known (see Chapter 61. Also, the earliest events of the infection process and the sites of replication of the virus in the body are not well defined. One hypothesis for the initial events is that HIV enters the blood directly. If this is the case, the virus might appear in the plasma, where presumably it could bind to CD4 lymphocytes and initiate infection. Other possibilities for the initial route of viral entry or site of infection include macrophages or other local antigen-presenting cells that populate the surface epithelial cell lining of the vaginal, urogenital, or gastrointestinal tracts, or other specialized cells of the immune system located near the site of viral entry. HIV is known to multiply in lymphocytes and macrophages, but there is no evidence that it can multiply in other cells, such as neurons. Involvement of dissemi- nated sites (including the central nervous system) during AIDS may be due to the migration of infected cells, such as macrophages, into the sites, or to infection of these cells in situ. It is not known what proportion of individuals who are seropositive for HIV antibodies will ultimately develop clinical AIDS (see Chapter 31. In one recent study in San Francisco of 33 homosexual men known to have been seropositive since 1978-1980 and followed for an average of 68.2 months, 15 percent have developed AIDS, 27 percent lymphadenopathy, and 24 percent only hematologic abnormalities; 39 percent have no abnormal clinical findings (Rutherford et al., 19861. Another major question has been whether cofactors in the form of environmental agents, genetic influences, or coexisting infectious dis- eases might increase the likelihood of HIV infection or the presence of clinical disease. The existence of such cofactors is often suggested, but there are no data to support the concept, with the possible exception in Africa of genital ulcers. Furthermore, some recent data fail to support the previously proposed association between either nitrite use or elevated

46 CONFRONTING AIDS cytomegalovirus titers and the development of clinical AIDS (Polk et al., 1986). Another area of great concern is whether PGL and ARC will in most cases advance to AIDS. Some investigators had suggested soon after the early description of AIDS and its associated conditions that these conditions might reflect containment or repression of HIV infection by the immune system. However, although many cases of AIDS have been preceded by some manifestations of these symptoms, PGL, ARC, and AIDS cannot be considered simply as stages of an orderly progression in the spectrum of HIV infection. It is not now known to what extent PGL or ARC may predict the eventual development of frank AIDS (Abrams et al., 19851. This important question has yet to be clearly resolved. There are no recorded cases of the spontaneous remission of AIDS, of related clinical conditions, or of immune defects in HIV-infected persons, and only anecdotal reports of reversion from seropositive to seronegative status (Burger et al., 19851. CLINICAL MANIFESTATIONS OF HIV INFECTION Of the many clinical conditions associated with HIV infection, most are the consequences of immunologic damage and not the direct result of HIV infection itself. These conditions range from those that are annoying but not in themselves life threatening to some of the most serious and uniformly fatal infections and tumors known. The significance of these manifestations lies in their role as a common cause of or contributing factor to death from HIV infection, in their importance for tracking the epidemiology of the disease, in their further elucidation of the pathogenesis of disease, and in their implications for determining future health care needs and costs. (See Appendix A for a more detailed discussion of the presentation, diagnosis, and treatment of the clinical manifestations of HIV infection.) The current CDC definition of AIDS reflects those opportunistic infections and cancers observed in the United States. The most common manifesta- tions of HIV infection are not the same in all parts of the world; they differ, for instance, between the United States and Africa. With longer experience, additional manifestations-opportunistic infections, cancers, or direct con- sequences of HIV infection may need to be added to those described below. Opportunistic Infections Opportunistic infections are caused by microorganisms that take ad- vantage of the opportunity offered by lowered immunity but would seldom cause disease in persons with normal defense mechanisms. The

THE DISEASE AND THE EPIDEMIC 47 occurrence of opportunistic infections in AIDS has been of central interest for at least two reasons. First, their unusual appearance in young, otherwise healthy men was one of the first indications that a new disease syndrome was emerging. Second, they are among the most common causes of death in AIDS patients. Opportunistic infections that have assumed a major role in the epidemic include Pneumocystis carinii pneumonia; toxoplasmosis; tuberculosis; viral infections due to herpes simplex, herpes zoster, and cytomegalovirus; cryptococcal disease (es- pecially meningitis); oral and esophageal candidiasis (thrush); and cryptosporidiosis (see Appendix A). As a group, these infections are the most common presenting clinical manifestations that ultimately lead to a diagnosis of AIDS. Traditionally, opportunistic infections have been associated with impaired immunity. However, therapy for these infections has been more successful in other immunocompromised populations, such as cancer patients and transplant recipients, than in patients with AIDS. Probably because the immune deficit is so profound, in AIDS patients these infections are characterized by an aggressive clinical course, resistance to therapy, a high rate of relapse, and a high incidence of drug toxicity during treatment. It is not known whether improved therapy for opportunistic infections would significantly lengthen the overall survival of patients with AIDS. Given the number of characteristic infections seen and the underlying immune defects of these patients, it seems unlikely that cure of any single infection would significantly change the ultimate outcome of the disease. However, an effective treatment for Pneumocystis carinii pneumonia might prolong average survival somewhat, since a high proportion of AIDS patients succumb to this infection. Kaposi's Sarcoma Kaposi's sarcoma is a cancer originating from the cells that comprise the lining of blood vessel walls. It was one of the earliest recognized manifestations of AIDS, and because it produces lesions of the skin and other body surfaces it remains the most visible (and often disfiguring) indication of AIDS, leading to severe social as well as medical problems. While it can directly cause death when it results in respiratory failure, its diagnostic significance is as a readily detectable indication of underlying immune deficiency. Patients with Kaposi's sarcoma are also often less severely immunocompromised than are other groups of AIDS patients, making this population the focus of several clinical therapy trials for the malignancy itself. For reasons as yet unclear, Kaposi's sarcoma is much more frequent in homosexual men than in other AIDS patients (Cohn and Judson, 1984;

48 CONFRONTING AIDS Des Jarlais et al., 1984), although its incidence in this population is said to be decreasing, also for unknown reasons. Both cytomegalovirus infection (Drew et al., 1982) and the use of inhaled nitrites (Marmor et al., 1982) have been suggested as possible cofactors responsible for the increased incidence of Kaposi's sarcoma in homosexuals, but data to support these hypotheses are lacking at this time. Kaposi's sarcoma can be readily recognized clinically by experienced physicians. Recently there have been anecdotal reports of a decline in the use of biopsies to confirm diagnoses (as required to meet the CDC definition of AIDS). The contribution of this trend to underreporting of AIDS cannot be determined at this time, but it illustrates the conflicts that can arise between clinical practice for individual patients and the need for accurate surveillance data on AIDS. Other Malignancies Since 1982, clinically aggressive (high-grade) non-Hodgkin's lympho- mas have been seen with increased frequency in patients at risk for AIDS (Ioachim et al., 1985; Kalter et al., 1985~. In 1985 this observation led the CDC to add this disease, when accompanied by a positive serologic test for HIV antibodies, to the surveillance definition of AIDS. Non-Hodgkin's lymphoma related to HIV infection occurs at unusual sites for that disease- e.g., the central nervous system, the rectum, and gastrointestinal sites. Many affected patients have a marked generalized lymphadenopathy that precedes by several years the diagnosis of lymphoma. Despite dramatic advances in the treatment of non-Hodgkin's lymphoma in the general population in the last decade, the prognosis for the disease among individuals infected with HIV is poor. Even with aggressive treat- ment these patients have a low response rate, a high incidence of associated opportunistic infections, and high relapse and mortality rates. People with HIV infection have also been reported to be at increased risk for the development of Hodgkin's disease (Schoeppel et al., 19851. While the disease appears to respond in a conventional manner to standard chemotherapy, treatment is more frequently accompanied by secondary opportunistic infections and is complicated by therapy-induced persistent and severe bone marrow failure. Several other cancers have been reported to occur with increased incidence in people with HIV infection, including squamous cell cancers, malignant melanoma, testicular cancer, and primary hepatocellular car- cinoma. These cancers are statistically associated with HIV infection, but there is no evidence of a direct causal relationship with HIV. HIV cannot be isolated from at least one malignancy in this group (Groopman et al., 1986), suggesting it is not the direct cause of the malignancy.

THE DISEASE AND THE EPIDEMIC 49 Neurologic Complications Associated with HIV Infection Neurologic complications are becoming increasingly recognized as an important cause of the morbidity and mortality associated with HIV infection. As many as 90 percent of patients dying from HIV-related conditions have histopathologic abnormalities of the nervous system at postmortem examination, and the majority of patients have some clinical manifestation of necrologic disease during their lifetime. Neurologic complaints are the initially evident symptom in about 10 percent of patients. Of the HIV-related necrologic complications, dementia is among the most severe and disabling. A wide variety of central and peripheral nervous system diseases are seen in AIDS patients (Appendix A). About 30 percent of these patients develop opportunistic infections of the central nervous system (CNS), including toxoplasmosis, cryptococcal meningitis, and disseminated herpes infection. Some 2 to 5 percent develop CNS neoplasms, particu- larly primary CNS lymphomas but also secondary lymphomas and metastatic Kaposi's sarcoma. Of patients with necrologic involvement, at least two-thirds develop a subacute encephalitis (mild brain inflammation) (Britton and Miller, 1984; Krupp et al., 1985), and 20 percent develop a myelopathy (Petito et al., 1985), both of which are thought to be related to primary infections of the central nervous system with HIV. In addition, peripheral neuropathies develop in approximately 25 percent of patients. Central nervous system involvement of HIV may lead to necrologic deficits that mimic many psychological problems, posing difficulties in diagnosis, and it may have a chronic course. The occurrence of severely debilitating necrologic disease, especially dementia, will place a major strain on the health care system and on society as a whole in caring for affected patients (see Chapter 51. There are many unanswered questions surrounding infection of the central nervous system by HIV. They include the timing and frequency of infection, the amount of time that may elapse between involvement of the central nervous system and the development of subacute encephalitis with dementia, and the primary site of infection in the central nervous system. The answers to these questions will have major implications for the design of future therapeutic agents, which will have to cross the blood-brain barrier; for social, ethical, and legal issues involving AIDS; and for the planning of future health care for AIDS patients. Pediatric AIDS The clinical manifestations of AIDS in children are significantly dif- ferent from those in adults. In contrast to the most common diseases

50 CONFRONTING AIDS associated with adult AIDS Pneumocystis carii~ii pneumonia and Kaposi's sarcoma the most common clinical manifestations of pediatric AIDS are recurrent bacterial (Bernstein et al., 1985), viral, and candidal infection; failure to thrive; lymphocytic interstitial pneumonitis; and en- cephalitis. Because there are so many different clinical findings in pediatric AIDS and because the diseases associated with AIDS in this population are similar to those seen in general pediatric populations, testing for HIV antibodies assumes more importance in children sus- pected of having AIDS than in adult populations. Some investigators believe that an attempt to fit observations from children into definitions for adult patients is unwise due to the broad and different presentations of AIDS in children (Parks and Scott, 19861. (See Appendix A for a detailed description of pediatric AIDS.) MODES OF TRANSMISSION OF HIV Transmission of an infectious agent requires five basic elements: (1) an infected source, (2) a vehicle or mechanism of spread, (3) a susceptible host, (4) an appropriate site of exit from the source, and (5) an appropriate site of entry into the susceptible host. Given these basic elements, infectivity will be related to such factors as the levels of the infectious agent present or the efficiency of possible mechanisms of transmission (see Chapter 61. Knowledge of the routes of transmission of infectious agents in human populations is derived primarily from epidemiologic data. Direct evidence related to the efficiency of specific routes of HIV transmission cannot be derived experimentally, because it is unethical to deliberately infect a human being. However, chimpanzees and other animals susceptible to HIV or related viruses may in the future be used as models in experimen- tal transmission studies. Isolation of an infectious agent such as HIV from certain secretions, body fluids, or tissues may suggest possible routes of transmission. But such findings do not imply that transmission by that route occurs, and the interpretation must be tempered by other evidence of transmission. Epidemiologic data indicate that transmission of HIV is limited to sexual, parenteral, and maternal-infant (possibly including in utero) routes. It has been postulated, but not proved, that adult infection may require direct blood exposure and may be enhanced by coincident damage to skin or mucous membranes to facilitate viral entry. There is no evidence for other routes of HIV transmission. In fact, there is now substantial evidence against transmission through so-called casual contact, including regular close contact (such as that occurring in sharing accommodations, eating utensils, or even toothbrushes), that

THE DISEASE AND THE EPIDEMIC 5~ does not involve parenteral or sexual exposure, despite the fact that HIV has been reported to have been occasionally isolated from saliva and tears in small amounts (Friedland et al., 19861. Sexual Transmission Numerous case-control studies have identified receptive anal inter- course (with ejaculation of semen) and having a number of sexual partners as the primary risk factors for HIV infection in homosexual men. Among men who practice receptive anal intercourse, rectal douching appears to further increase the risk, probably through trauma to the rectal mucosa or damage to normal protective barriers (W. Winkelstein, University of California, personal communication, 19861. Other factors associated with an increased risk of infection in homosexual men include manual-rectal intercourse ("fisting"), a history of sexually transmitted disease, recre- ational drug use (especially the use of amyl or butyl nitrites, known as poppers), IV drug use, and sexual contact with partners from bathhouses or from areas with a high prevalence of AIDS. These factors are frequently associated with the presence of HIV infection in potential partners or with the practice of anal intercourse and rectal douching; they are not regarded as independent primary risk factors for HIV transmission. The capacity of available studies to define precisely the risk of HIV infection associated with oral intercourse (including ingestion of semen) or the risk to the insertive partner in anal intercourse is limited by the small number of individuals available for study who practice only these behaviors. A risk of infection to those who practice only these behaviors cannot be ruled out, but it is probably lower than the risk from receptive anal intercourse (Winkelstein et al., 19861. Studies of homosexual men have identified couples with long-term, exclusive relationships in which one partner was infected with HIV and the other has remained uninfected over a considerable period, despite the seronegative partner's continued practice of receptive anal intercourse. Questions of possible individual variability in viral shedding and/or susceptibility need to be investigated further. Although the virus has been isolated from semen and saliva, numerous studies have found no evidence that HIV is transmitted between homo- sexual men through kissing, oral-genital sex, oral-rectal sex, or mutual masturbation. HIV may be transmitted by these routes, but at relatively low efficiency. HIV can also be transmitted during heterosexual intercourse. Saltzman and co-workers (1986) reported that 21 of 57 (37 percent) of persons who were long-term heterosexual partners of AIDS or ARC patients but had no other AIDS risk factors had confirmed antibodies to HIV; this included

52 CONFRONTING AIDS 17 of 48 (35 percent) female partners and 4 of 9 (44 percent) male partners. Redfield and co-workers (1986a) also reported approximately equal pro- portions of heterosexual partners with no other AIDS risk factors becoming infected in long-term sexual relationships with infected per- sons; 6 of 18 female and 2 of 6 male spouses became infected. In another study the Centers for Disease Control found 1 seropositive man among 20 husbands of women with transfusion-associated AIDS (T. A. Peterman, Centers for Disease Control, personal communication, 1986), as com- pared with 8 seropositive women among 50 wives of men with transfusion-associated AIDS. All of these studies suggested that vaginal intercourse was a route of transmission. Such findings document the existence of male-to-female and female-to-male transmission. The committee concludes that data are not presently adequate to assess the relative efficiency of male-to-male, male-to-female, or female-to-male virus transmission during anal or vaginal intercourse. Even if a particular direction (male to female or female to male) and mode of transmission are relatively inefficient, repeated exposure to infected single or multiple partners may result in a significant risk of infection. The high and nearly equal prevalence of seropositivity among men and women in central Africa and an age distribution of infected persons suggesting sexual transmission are other indications of female-to-male transmission (see section on "HIV Infection and AIDS Outside the United States," later in this chapter). The situation in Africa is compli- cated, however, by widespread heterosexual promiscuity among some groups and by the use of unsterile needles and syringes in some medical settings. It is not clear whether tissue trauma leading to breaks in genital mucous membranes is necessary for and/or enhances sexual transmission of HIV. However, the increased risk attributable to rectal douching for men who practice receptive anal intercourse suggests that this may be the case. Furthermore, one study in Africa detected an increased risk, independent of the numbers of sexual contacts, among men who have a history of genital ulcers, suggesting that the virus may have gained entry when normal skin or mucous membrane barriers were disrupted (K. K. Holmes, University of Seattle, personal communication, 19861. Parenteral Transmission Epidemiologic data have indicated parenteral HIV transmission in a number of populations, including IV drug users, hemophiliacs, and blood transfusion recipients. IV drug users commonly share injection paraphernalia (syringes and needles) and thereby transmit HIV through residues of blood. HIV can

THE DISEASE AND THE EPIDEMIC 53 disseminate very rapidly if there is sharing of injection equipment outside of small, closed circles of IV drug users for example, through the sharing of equipment with strangers that occurs in "shooting galleries" ~ ·, ~ T ~ ~ 1 ~ ~ (places common In N ew Y ore pity wnere ~ v Drug users `;an rent previously used injection equipment). Transfusion-associated HIV infections occurred primarily from the late 1970s until about mid-1985, when screening of the blood supply for HIV antibodies began (see Appendix B). The available studies demonstrate that many blood components or products can transmit HIV, including packed red cells, frozen plasma, clotting factors, whole blood, and platelets. Albumin has not been implicated in the transmission of HIV, probably because it is routinely heated during preparation, a process known to destroy the infectivity of HIV. Nor has gamma globulin been implicated, at least when prepared by cold ethanol fractionation, as is the case in preparations for intramuscular use. Follow-up of blood donors implicated in cases of transfusion-associated HIV infections has nearly always identified at least one donor who was a member of a high-risk group. More recently, studies have followed the recipients of units of blood that were found in retrospect to be seropositive. In the majority of cases, the recipient of a positive unit was later also found to be seropositive. Self-exclusion of donors who are members of high-risk groups (i.e., their refraining from donating blood) began in 1983 and no doubt reduced the risk of exposure to HIV among transfusion recipients. Screening donors for HIV antibodies has further reduced the risk related to transfusion or the provision of blood products. (As discussed in Appendix Cal the introduction of antibody testing has reduced the risk of HIV ~ . · · . 1 , ~ ~ ~ . ~ T T ~ transmission to blood recipients by more than 93 percent.) However, even screening cannot guarantee absolute safety of the blood supply, because transmission can occur when the virus is present (viremia) but before the appearance of HIV antibodies and because the sensitivity of the test for detecting antibodies (and hence infection) is less than 100 percent (see Appendix B). The current risk of HIV transmission from a blood product to a recipient depends on a number of factors. These include (1) the sensitivity of the screening testis) in detecting antibody, (2) the prevalence and duration of viremia prior to the appearance of antibody in the donor population, (3) the likelihood of donation during the phase of infection that precedes the development of antibodies, and (4) the number of units of blood or blood products the recipient receives. Of greatest concern to the general public is the risk of HIV transmission from packed red blood cells, which are the blood component most frequently transfused (although the much smaller number of patients who

54 CONFRONTING AIDS receive other nonsterile blood components or products are also at risk). Each donated unit of blood produces one unit of packed red blood cells. In the United States, approximately 10 million units of blood or blood components are transfused each year into approximately 3.5 million recipients. Thus, the average recipient is exposed to blood from three donors. The risk of HIV exposure for an average recipient of packed red blood cells is estimated, on the basis of reasonable assumptions, to be fewer than 1 in 34,000 (see Appendix C). Under slightly more optimistic assumptions, the risk should fall to fewer than 1 in 140,000. Under slightly more pessimistic assumptions, the risk rises to approximately 1 in 11,000. With the risk of HIV transmission to blood recipients reduced by more than 95 percent through antibody testing, instead of 4,000 infected units out of 10 million used, the baseline calculations presented in Appendix C project the transfusion of about 100 infected units each year. Since approximately half of transfusion recipients die of other causes relatively soon after receiving blood, the number of infections directly resulting from transfusion would be smaller. Most of the current risk in blood transfusion relates to the possibility of blood donation during the preantibody phase of HIV infection. These considerations reinforce the importance of continued self-selection by potential donors to exclude those who have engaged in high-risk behav- iors. Transmission of HIV to persons receiving blood-derived clotting fac- tors has also been demonstrated. In particular, hemophiliacs lack one of several blood proteins required for normal clotting and as a consequence are likely, without interventions, to endure severe and prolonged bleed- ing. Injected clotting factors (VIII for hemophilia A or IX for hemophilia B) concentrated from human plasma can alleviate this problem. Until recently, the procedures used to manufacture these concentrates, involv- ing plasma pooled from many donors, allowed HIV to be transmitted from an infected plasma donor to recipients. Since late 1984, however, most manufacturers have heat-treated concentrates in such a way as to inactivate HIV, and such products no longer pose a risk of infection. Exposures through accidental needlesticks have resulted in few infec- tions. A CDC study of nearly 1,000 health care workers with accidental needlesticks showed no clinical AIDS and only two seroconversions (McCray, 19861. In only one of these cases were there adequate data to clearly implicate transmission by the needlestick. There are isolated instances of seroconversion after needlestick, including a case report of HINI transmission by needlestick from an African AIDS patient reported from England (Lancer, 1984~. In this instance, whole blood was thought to have been injected at the time of the needlestick.

THE DISEASE AND THE EPIDEMIC 55 The greater risk of infection from transfusions as compared with that from accidental needlesticks suggests that the dose of virus is probably an important factor in parenteral transmission. This could also explain the apparently greater risk among IV drug users than that following needlesticks (IV drug users commonly draw blood into the syringe, and blood residues are injected when equipment sharing occurs). The fre- quency and direct IV route of exposure could also contribute to this difference. Hemodialysis units are potential sources of parenteral exposure to infectious agents, as is seen with hepatitis B virus (HBV) infections (Peterman et al., 19861. However, the extensive use of disposable equipment has greatly reduced the risk of HBV and other infections in this setting in recent years. HIV could easily be introduced into dialysis units either through prior blood transfusions or through other dialysis patients who are seropositive. Seropositive dialysis patients have, in fact, been identified. However, available data have not demonstrated trans- mission between dialysis patients, and it seems unlikely, given the current standards of hygiene practiced within most units. Questions have been raised about the possibility of HIV transmission from two other blood products: immune globulins and plasma-derived hepatitis B vaccines. The Centers for Disease Control actively monitors reported AIDS cases for evidence of an association with immune globu- lin. Thus far, none has been detected (Centers for Disease Control, 1984~. Prospective evaluation of immune globulin recipients, including some who have received hepatitis B immune globulin containing detectable HIV antibodies, has demonstrated no transmission of the virus. Further- more, the cold-ethanol treatment used to prepare immune globulin for intramuscular injection has been found experimentally to inactivate HIV. Thus, in the absence of flawed or altered manufacturing techniques, there is no reason to believe that intramuscular immune globulin can transmit HIV. A recent case report of HIV infection in a long-term recipient of intravenous immune globulin suggested the possibility that the virus was transmitted from this material, although other sources were not com- pletely excluded. The production steps for intravenous immune globulin would not be expected to inactivate virus with the same degree of certainty as those used for intramuscular preparations, and their ability to inactivate HIV has not yet been evaluated. Follow-up of recipients of the American and French plasma-based hepatitis B vaccines has shown no evidence of HIV transmission from these products, even though some of the plasma used in their manufacture is known to have contained antibodies reactive with HIV. Moreover, each of the three inactivation steps used for the American vaccine has

56 CONFRONTING AIDS been shown experimentally to inactivate HIV. These hepatitis B vaccines have therefore been convincingly demonstrated to be safe with regard to HIV transmission. An unusual case of apparent transmission from a child to his mother has been reported (Centers for Disease Control, 1986a). The child was born with congenital abnormalities and became infected with HIV as a result of a blood transfusion. The child required extensive hospital and home medical care, and the mother acted as nurse but did not adopt routine procedures such as the wearing of gloves appropriate to health care providers in such a situation. She was frequently and extensively exposed to bloody fecal material from the infant. This strongly suggests that the route of transmission would have been parenteral, with infection resulting from percutaneous exposure through microscopic (or unrecalled macro- scopic) breaks in her skin. Maternal-Infant Transmission Transmission of HIV from an infected mother to her infant probably occurs during pregnancy and/or delivery rather than postnatally, although the issue of transmission through breast-feeding is yet to be resolved. Some investigators suspect that HIV is transmitted in utero, because the time to development of AIDS in some infants is relatively short. Recently a series of cases has been reported in which HIV-infected infants were described who exhibited a distinctive dysmorphic appearance, which supports the possibility of early in utero transmission (Marion et al., 19861. Sprecher and co-workers (1986) have reported HIV transmission as early as the fifteenth week of gestation. Transmission in utero would preclude, at least for those cases, the possibility of providing immuno- prophylaxis to infants at high risk if elective means became available in the future. It is also important to determine precisely when (and how) transmis- sion can occur in order to assess the usefulness of procedures such as caesarean delivery (Chico et al., 1986; Lifson and Rogers, 19861. One case of HIV transmission to an infant via breast milk has recently been reported, suggesting the possibility that the virus could be transmit- ted orally to infants through breast-feeding (Ziegler et al., 1985~. This issue would be of special importance in the developing countries of central Africa, where breast-feeding is otherwise extremely desirable. The rate of maternal-infant transmission is unknown. In one study of 20 infants born to infected mothers who had already delivered 1 infant with AIDS, 13 infants (65 percent) had evidence of HIV infection several months after birth (Scott et al., 19851. This study may overestimate the average risk of transmission for all infected pregnant women, however, because the women were known to have previously transmitted the virus.

THE DISEASE AND THE EPIDEMIC 57 It appears that perinatal transmission is not inevitable; other studies have found transmission rates ranging from O to 22 percent (Centers for Disease Control, 1986b). Attempts are being made to screen women in high-risk categories for HIV antibodies and then to follow their infants prospec- tively (W. P. Parks, University of Miami, personal communication, 1986~. This approach should define the risk of maternal-infant transmission and clarify the factors related to that risk. It appears that pregnancy may increase the risk of developing AIDS or ARC for HIV-infected women. The Centers for Disease Control (1986b) has reviewed information on maternal-infant transmission and has made recommendations for assisting in the prevention of perinatal transmission of HIV. POPULATION GROUPS AT INCREASED RISK OF HIV INFECTION In the United States, homosexual males, IV drug users, neonates born to infected mothers, and persons such as hemophiliacs who received pooled blood products, including clotting factor, before testing for HIV antibodies have the highest risk of acquiring HIV infection. These groups have the most cases of AIDS and the highest prevalence of seropositivity. Homosexuals and IV drug users have a higher risk of infection because their behaviors and the prevalence of infection in those with whom they share these behaviors increase the likelihood of their being exposed to an infected person. However, individuals within all of the "high-risk groups" noted above have varying risks of infection depending on the extent of their exposure. Within the rest of the population, which is generally at lower risk of infection, there also exists a spectrum of risk largely dependent on behavior. Instances of infection with HIV and of AIDS have been documented in this low-risk population and have been attributed to . __Y ~r ~a_ heterosexual transmission of the virus. lily transmission from mc~1 to women has made up the majority of AIDS cases thus far attributed to heterosexual spread of the virus. These cases include spread to sexual partners of infected hemophiliac men, of IV drug users, and of bisexual men. There have also been some cases, cited as examples, of heterosex- ual spread to men from prostitutes (Redfield et al., 1985), but so far the number of such cases has been small. Homosexual Men The homosexual male population (which in this report is defined to include bisexual men) is probably the largest group in the United States at

58 CONFRONTING AIDS high risk of AIDS, but accurate demographic data on this population are extremely limited. There has not been a national estimate of the homo- sexual population in the United States since the Kinsey study, published in 1948 (Kinsey et al., 19481. The Kinsey report, which was based on a study of 5,300 white men between 1938 and 1948, estimated that 10 percent of males are more or less exclusively homosexual for at least three years between the ages of 16 and 55, and that 4 percent are exclusively homosexual throughout their lifetime. Extrapolations of the Kinsey data based on recent population figures give a rather wide range of estimates of the number of homosexual men, ranging from a low of 2 million or 3 million to a high of about 10 million in the United States. The Kinsey survey was a pioneering effort in the study of human sexual behavior. However, it was not based on either random or stratified sampling of the U.S. population; those interviewed were all volunteers. Because Kinsey and his colleagues deliberately oversampled some pop- ulations (such as criminal and delinquent males), Gagnon and Simon (1973) reanalyzed the Kinsey data for the 1,900 males in the sample who were under the age of 30 and attending college. They found 3 percent with exclusively homosexual histories and another 3 percent with bisexual histories, rates lower than the Kinsey projections. There have been other surveys of self-reported responses of sexual behavior among males (Hite, 1981) and females (Hite, 1976), but they are not representative of the population at large. The occasional demographic studies on this subject done since the Kinsey era seem to show that the percentage of male homosexuals has remained a stable percentage of the population (Bell and Weinberg, 19781. Yet with the advent of the gay liberation movement in the 1960s and 1970s, homosexual men and women have become more visible. This is especially true in the urban areas, such as San Francisco and New York City, to which they have gravitated. Homosexual men constitute a sizable proportion of the population over age 15 in a number of major American urban areas, although exact figures are not available. One study estimates that from 70,000 to 100,000 homosexual men reside in San Francisco, nearly a quarter of all of that city's male population aged 15 and over. Los Angeles, New York City, and Chicago probably have even larger num- bers of homosexual men. In the 1960s and 1970s many homosexuals asserted their claim to tolerance of their sexual orientation. At the same time they established a subculture where they could live openly in common parlance "come out of the closet" and hence into the public consciousness. The taboo against homosexuality was challenged in a number of quarters; homosexuals began in greater numbers to live openly as homosexuals, being frank about their sexual orientation with business associates, family, and friends.

THE DISEASE AND THE EPIDEMIC 59 One component of the sexual liberation of the 1960s and 1970s was a proliferation of bars and bathhouses that fostered frequent, sometimes anonymous sexual liaisons among a certain proportion of homosexual men (FitzGerald, 1986~. (Lesbians have tended to have more exclusive . . ~ ~ . 1 ~ ~1 1~.~1_~1^ ~ Arm thrill._ relahonshlps.' Rome homosexual men rep; {lUllUlOU~ Q1 ~v~l1 LllV"- sands of sexual partners during their lifetime. A consequence of this sexual freedom was a dramatic rise in the rates of syphilis, gonorrhea, amoebic dysentery, hepatitis, and other sexually transmitted diseases. While the danger of sexual contact with large numbers of anonymous partners had been established with regard to sexually transmitted diseases other than AIDS, those diseases were largely regarded as treatable. With ~ ~ ~ ~ ~ =~.~ll~ Otto ant AIDS, sexually transmitted disease became a more serious melter, al1U sexual practices came under intense scrutiny. Often, descriptions of sexual activity implicated in the acquisition of HIV infection and AIDS seemed to imply a condemnation of those engaging in that behavior. AIDS and the fear of AIDS may reveal just how tenuous are the tolerance and acceptance of homosexuals. In writing about AIDS, some have invoked explanations entailing divine retribution. There have also been calls for the incarceration of homosexuals and for eliminating future tax dollars for AIDS research. Though such recommendations remain extreme, there is still considerable institutionalized discrimination against homosexuals. In about half of the states, private consensual sexual activity between adults of the same sex remains a criminal offense. The U.S. Supreme Court upheld the right of states to pass such sodomy laws in an opinion issued in July 1986. Intravenous Drug Users The second-largest risk group for AIDS in the United States is IV drug users. According to the Centers for Disease Control, 17 percent of reported AIDS cases currently occur in people whose only known risk factor is IV drug use. As with homosexual men, accurate demographic data on IV drug users are very limited. However, experts in this field estimate that 750,0()() Americans inject heroin or other drugs intrave- nously at least once a week, while at least an additional 750,000 inject drugs less often (D. C. Des Jarlais, New York State Division of Substance Abuse Services, personal communication, 19861. Demographic data on IV and non-IV drug users who enter treatment programs are readily available, but data on IV drug users who do not seek treatment are scant. Within the former population, the median age is 28 years, and approximately 75 percent are men. There is a recognized urban concentration of "hard core" IV drug users who are mostly from lower

60 CONFRONTING AIDS socioeconomic strata. Typically, members of such groups have low- paying jobs or are unemployed and have received far fewer years of education than the average. Blacks, who make up approximately 13 percent of the nation's population, are nearly 40 percent of the IV-drug- using population (Ginzburg and Weiss, 19861. In prison populations, IV drug users are known to be overrepresented, because IV drug use is an important factor predisposing to crime and incarceration. A national study of 12,000 state prison inmates in 1979 indicated that 30 percent of the inmates had used heroin at some time and that 12 percent had used heroin in the month prior to the crime for which they were imprisoned (U.S. Department of Justice, 1983~. Hemophiliacs Hemophilia is a lifelong, hereditary blood-clotting disorder that affects males almost exclusively. The development of federally supported re- gional treatment centers and the introduction of clotting-factor concen- trates in the 1970s markedly increased the life expectancy of hemophili- acs. The median age of persons with hemophilia rose from 11.5 years in 1972 to 20.0 years in 1982. As of 1986, more than 9,500 severe hemophil- iacs (close to half of the total hemophiliac population in the United States) were being served by these centers. Because of the pooling of plasma from numerous donors for the production of clotting-factor concentrates, a person with severe hemo- philia may be exposed to as many as 100,000 blood donors per year. This exposure led to extensive, initially unrecognized transmission of HIV through these plasma concentrates beginning as early as 1980. The first cases of AIDS in hemophiliacs were diagnosed in 1982 (Evatt et al., 19841. Since 1984, the risk of transmission of HIV from these plasma products has been very markedly reduced by virus inactivation steps in their production, but a large proportion of hemophiliacs (including 60 to 80 percent of severely affected hemophiliacs) now test positive for HIV antibodies (Johnson et al., 19851. Recipients of Blood Transfusions In early 1983, with the growing realization that the etiologic agent of AIDS might be a virus that could be bloodborne, national guidelines were developed to have persons in the recognized AIDS risk groups refrain from blood donation. How many transfusion recipients received HIV- infected blood or blood components from the late 1970s until the routine adoption of this national policy is difficult to estimate, but it is likely to have been many thousands. Thus far, nearly 400 AIDS cases have been

THE DISEASE AND THE EPIDEMIC 61 reported to the Centers for Disease Control among the recipients of whole blood, packed red blood cells, or platelets. By March 1985, tests capable of detecting HIV antibodies had been developed and licensed; they allowed blood from most persons poten- tially capable of transmitting the virus to be identified. With donor screening in this manner and self-exclusion from blood donation by members of high-risk groups, the current risk of HIV transmission via transfusion is exceedingly small (see section on "Modes of Transmission of HIV," above, and Appendix C). Heterosexual Contacts of HIV-Infected Persons The heterosexual contacts of persons infected with HIV include heterosexual partners of IV drug users, female sex partners of bisexual men, sexual partners of infected hemophiliacs or of persons infected through transfusions, clients of infected prostitutes, and the heterosexual partners of other infected individuals. Accurate estimates of the numbers and characteristics of the spouses of infected hemophiliacs and persons infected through transfusions are either available or could be obtained. However, such data are only recently becoming available for the hetero- sexual contacts of IV drug users, of bisexual men, and of female prostitutes and other persons infected by HIV. These groups are poten- tiallv large, and they constitute the major threat for increasing transmis- sion of HIV to the heterosexually active population, especially to those individuals who are currently at some risk of contracting a sexually transmitted disease (Winkelstein et al., 19861. . _ . Infants and Children Infants and children infected with HIV have been placed in a separate category for national surveillance because their clinical manifestations differ in many respects from those of adults (see Appendix A). Pediatric AIDS was first recognized in 1980-1981, and since then the number of reported cases has been rising rapidly-to a total of 348 cases in children under 13 years of age as of September 8, 1986. This number represents approximately 1.5 percent of all reported AIDS cases in the United States. Half of these cases have occurred in children under one year of age. Of the children with AIDS, 60 percent have been black, and 21 percent Hispanic; 55 percent have been male; and 59 percent have died. About three-fourths of the AIDS cases in children have occurred in four states: New York (38 percent of the total in the four states), California (34 percent), Florida (14 percent), and New Jersey (14 percent).

62 CONFRONTING AIDS The proportion of reported AIDS patients who are children under 13 years of age has not changed greatly over time. Of all the pediatric cases, approximately 54 percent have been children of IV drug users. An additional 10 percent have been children of parents who have AIDS or who are in other AIDS risk groups. About 15 percent of pediatric AIDS patients have received blood transfusions, while 4 percent have hemophilia. Thirteen percent are children of Haitian-born parents. Information on risk factors is incomplete or missing for the remaining 4 percent of cases. Infants who acquire their infection from an infected mother are generally the offspring of female IV drug users, female sexual contacts of male IV drug users, female sexual partners of bisexual males, and women from Haiti or central Africa. As HIV infection continues to spread within the general heterosexual population, it would be expected that more children infected with HIV will be born to women with multiple sexual partners or to women whose male sexual partners have had contact with multiple sexual partners. Thus, pediatric AIDS may serve as an important marker of the heterosexual spread of HIV infection. In addition, it is theoretically possible that some children infected with HIV may survive to sexually active adulthood, thereby constituting a continuing reservoir of potential infection. Health Care Workers Health care workers comprise a significant segment of the labor force in the United States, accounting for about 6.3 million (5.3 percent) of the approximately 117 million persons employed in the United States. These workers have a wide range of earning levels and of educational and racial backgrounds. Many health care workers are considered at increased risk for infec- tions such as hepatitis B because of their occupational exposure to infected blood, primarily though needlestick-type exposures or abrasions of the skin (e.g., in dentistry). Because HIV can be readily transmitted between IV drug users by the sharing of needles and syringes, its potential for transmission by occupational exposure among health care workers has been studied. The CDC recently conducted a prospective study of 938 health care workers who had a reported parenteral or mucous membrane exposure to blood and other bodily fluids from AIDS patients. Of 451 of these workers tested, 2 (0.44 percent) were found to have developed HIV antibodies (McCray, 19861. In a comparable study of persons exposed to patients testing positive for hepatitis B surface antigen, about 26 percent developed infection. Other studies have also reported a low risk of HIV infection among health care workers following occupational exposure (Henderson et al.,

THE DISEASE AND THE EPIDEMIC 63 19861. However, there have been a few reports of health care workers who have seroconverted after accidental needlestick injuries, which underscores the need for attention to safety precautions when caring for AIDS and HIV-infected patients or when handling blood in laboratories (Stricof and Morse, 19861. As of early 1986, about 4 percent, or almost 800, of the more than 20,000 reported AIDS cases in the United States had occurred among health care workers. This percentage is similar to the proportion of the population employed in health care. In all cases fully investigated, risk factors other than being a health care worker were identified. EPIDEMIOLOGIC STUDIES AND FINDINGS Surveillance Since the initial recognition of AIDS in 1981, public health surveillance of the epidemic has collected data essential to the understanding of the epidemiology of this disease. By September 1982, the Centers for Disease Control was using a case definition of AIDS designed for epidemiologic investigation (see Appendix E), and a CDC-organized national surveil- lance system was in place. Reporting of AIDS to public health officials has been required in most states since 1983. The CDC definition of AIDS was designed for precision, consistent interpretation, and specificity. Though modified slightly in June 1985, its primary purpose is still for epidemio- logic rather than diagnostic use (i.e., to help track the disease rather than facilitate treatment of individuals). The national surveillance system has been responsible for charting the growing magnitude of the AIDS epidemic, for delineating the occurrence of AIDS in the major risk groups, and for monitoring geographic patterns and trends in the occurrence of the disease. These surveillance efforts have been an overall success, but a method of case reporting designed for surveillance purposes cannot always be expected to yield data useful in answering research questions concerning disease pathogenesis, transmis- sion, or outcomes. National Disease Reporting In the United States infectious disease surveillance is carried out primarily through a so-called "passive" reporting system by which physicians or hospitals send case reports to local and/or state health departments. State laws and regulations for the reporting of infectious diseases vary. In most states the list of reportable diseases consists of 40 to 60 infectious diseases, which generally include most of the

64 CONFRONTING AIDS diseases that the CDC requests be reported nationwide. Reporting by states to the CDC is voluntary; the CDC can request reports but cannot require states to report. However, states routinely comply with such requests. Because of the severity of AIDS, the medical and media attention it has received, and the measures used to supplement the normal reporting procedures, the reporting of AIDS cases meeting the CDC surveillance definition (Appendix E) has been relatively complete. Studies of this issue in several cities have shown the reporting of hospitalized cases to be higher than 90 percent (Chamberland et al., 19851. Underreporting from hospitals probably does not obscure a large number of AIDS cases, because the majority of large city health departments visit hospitals and laboratories where most AIDS cases would be diagnosed. More under- reporting may occur with nonhospitalized cases, partly because of physicians' concern for maintaining confidentiality. Such concerns un- doubtedly lead to underreporting on death certificates, but this would have a more negative effect on research projects using death certificates than on national surveillance data. With the increasing availability of the HIV antibody test to assist in determining infection status, there have been anecdotal reports that skin biopsies to diagnose Kaposi's sarcoma definitively and bronchoscopy to diagnose Pneumocystis carinii pneumonia are being obtained less fre- quently. This may be contributing to a gradual decline in verified diagnoses meeting the CDC surveillance criteria for AIDS even though such diagnoses would be made if appropriate diagnostic studies were performed. In some areas, particularly in nonurban areas, clinical inex- perience in the diagnosis of AIDS, plus the general lack of appropriate laboratory testing, may also have resulted in missing some AIDS cases. Finally, some illnesses due to HIV infection that are very severe and life threatening do not fit the CDC definition even if all of the appropriate laboratory tests are done. In May 1986 the CDC introduced a clinical classification system for HIV infections (Appendix F). This classification system is intended primarily for public health purposes and was not designed or intended to be useful as a research classification or as a means of staging or classifying the clinical severity of symptoms or of making prognoses. Others have developed a clinical staging system (Redfield et al., 1986b). According to the CDC, its new classification system does not imply any change in its surveillance definition of AIDS for national reporting. However, the CDC is developing criteria for a "presumptive" diagnosis of AIDS that can be considered for national reporting. The original CDC surveillance definition of AIDS was tailored to fit adult cases and was not particularly useful or sensitive for pediatric cases,

THE DISEASE AND THE EPIDEMIC 65 because the types of conditions and clinical presentations in infants and children are significantly different from those in adults. Definitions for pediatric use have recently been developed by the Centers for Disease Control. All cases of AIDS in which no risk factor is identified are referred for further investigation to local health departments. Of those cases for which additional information is obtained, most are reclassified into one of the known risk groups. Of the remainder, most stay in this "no identified risk" category because of incomplete information. Because the CDC has not requested national reporting of ARC, no data on it are currently available from this source. Such reporting has not been requested for two main reasons. First, homosexuals have expressed concern that public health agencies will not maintain absolute confiden- tiality for such data. (However, no personal identifiers are transmitted to the CDC.) Second, there is no nationally accepted definition of ARC, and operational definitions can range from very mild signs and symptoms to severe illness and death. The new CDC classification system for clinical manifestations of HIV infection should eventually lead to a better definition of ARC. In time it may contribute to an accepted national definition of ARC that for practical reasons, if not for prognostic reasons, could be subdivided into categories ranging from mild to severe. As with ARC, the CDC has not requested national reporting of asymptomatic HIV infections. Nevertheless, a few states have followed Colorado in requiring the reporting of persons who have tested positive for HIV antibodies. Many public health epidemiologists believe that the data collected from mandatory reporting of laboratory results are incom- plete and of little use. In addition, such mandatory reporting runs counter to current PHS recommendations that all persons at increased risk for HIV infection seek antibody testing on a strictly voluntary, confidential, and, if requested, anonymous basis (see Appendix G and Chapter 41. The confidential reporting of seropositive individuals is desirable at blood banks. Epidemiologic Research Epidemiologic research, in contrast to surveillance, usually involves more detailed study of a population selected for characteristics of interest. In AIDS, such populations have usually consisted of high-risk groups, such as homosexual men or transfusion recipients. With the isolation of HIV and the general availability of antibody tests, epidemio- logic studies began to measure the prevalence and to some extent the incidence of infection among various population groups.

66 CONFRONTING AIDS Epidemiologic research in AIDS has been centered largely in the National Institutes of Health's intramural and extramural programs, in universities, in city and state departments of public health, and at the CDC. Descriptive prospective epidemiologic studies, which have been in progress for only about three years, have included only populations currently known to be at high risk and have had to rely predominantly on volunteers. Therefore, the data from such studies, while valuable, are limited by potentially biased population samples, incomplete ascertain- ment, and small study sizes. Case-Contro! Studies Shortly after the recognition of AIDS, many case-control studies of AIDS patients were carried out to supplement data collected from the initial clinical and laboratory studies. Case-control studies are generally not expensive to carry out, but they require personnel and resources that are not overly abundant in most local or state health departments today. Case-control studies carried out during the past few years have provided valuable information on specific risk factors associated with AIDS in different population groups. In one of these studies the CDC compared male homosexual AIDS patients to healthy homosexual men selected from outpatient clinics and the practices of private physicians (Jaffe et al., 19831. The most important variables differentiating AIDS cases from controls were measures of homosexual activity. AIDS patients had a larger number of male sexual partners per year, began having sex at an earlier age, and were more likely than controls to have had syphilis and some form of hepatitis. Another case-control study, carried out in New York City, compared men with Kaposi's sarcoma to homosexual controls from a private physician's practice (Marmor et al., 1984~. This study also found that the number of male sexual partners in the year prior to diagnosis was significantly higher for AIDS patients than for controls. Other important variables identified included receptive anal intercourse and other trau- matic sexual practices. Other studies have since borne out the findings implicating sexual transmission and receptive anal intercourse. A case-control study conducted in New York and Miami showed significant differences between Haitian men with AIDS and Haitian men who acted as controls (Castro et al., 19851. The men with AIDS were more likely to report a history of gonorrhea and sexual contacts with female prostitutes. Among female Haitian AIDS patients, the variable most significantly associated with disease was having been offered money for sexual acts. This case-control study strongly implicated hetero

THE DISEASE AND THE EPIDEMIC 67 sexual contact as the predominant route of transmission in this population group. Prospective Cohort Studies The need for comprehensive longitudinal investigation of the natural history of AIDS was recognized early in the epidemic. The systematic and uniform collection of epidemiologically well-characterized biologic spec- imens was also needed as new test methods were developed. Several cohorts of homosexual men were enrolled in New York City, San Francisco, and other cities beginning in the late 1970s to participate in hepatitis B vaccine field trials. Study of these cohorts has continued, but the emphasis has shifted primarily to the retrospective and prospective study of risk factors associated with HIV infection and disease. To supplement those studies, the National Institutes of Health provided funding in 1983 for collaborative prospective cohort studies of homosex- ual men in five cities. During 1984 and 1985, the centers that conducted these studies enrolled more than 5,000 volunteers (R. A. Kaslow, National Institutes of Health, personal communication, 19861. In contrast to the cohorts from the other four cities, the San Francisco cohort was recruited from a probability sample and thus can be consid- ered representative of the census tracts from which it was drawn. The other cohorts were recruited mostly from sexually transmitted disease clinics and from advertisements directed to homosexual populations. These groups must therefore be considered to represent a different population than the San Francisco cohort. Participants in all of these cohorts are now being followed at least semiannually to collect social and sexual histories and biologic specimens or until they reach designated clinical milestones, such as ARC or AIDS. Serologic Surveys With the increased use of the HIV antibody test, public health surveillance of the AIDS problem will increasingly shift to serologic surveillance. The surveillance of the clinical manifestations of HIV infection will still be important, but such illnesses resect infections that occurred an average of several years before the onset of signs or symptoms. Serologic studies of cohorts of homosexual men or periodic cross-sectional serologic surveys can provide valuable information on the current prevalence of HIV infection. Also, when compared with prior surveys, they can give some indication of the incidence of infection. Serologic studies can accurately document the continuing spread of HIV infection in the known high-risk groups. They can also monitor the

68 CONFRONTING AIDS potential spread of HIV to heterosexuals. In addition, antibody studies can help evaluate the effectiveness of education and prevention measures or other programs designed to limit the spread of the virus. Routine serologic testing is currently being done in the United States in the following situations: 1. About 12 million blood donors are being screened per year. Al- though there is some geographic variation (e.g., positive results are more common in high-incidence areas like New York City), early data indicated that an average of about 4 donors per 10,000 donors were antibody positive (with confirmatory testing) (Schorr et al., 19851. 2. All applicants for entry into the military services and all active-duty military personnel are being screened. These programs have just started, but preliminary data indicate that the seropositivity of recruit applicants aver- ages 1.6 per 1,000 applicants nationally but can be as high as 2 percent in census tracts where the reported AIDS rate is highest (Burke et al., 19861. 3. Beginning in 1985, alternative test sites which are physically separated from blood banks were established to provide testing for persons who might be at some risk for HIV infection. Without alternative test sites it was felt that these persons might consider donating blood at a blood bank in order to be tested. The availability of such alternative test sites varies considerably throughout the country. The data obtained from these sites will be of limited value, because most of them provide testing on an anonymous basis and because repeat testing may be frequent. The difficulty of fostering confidence in provisions to ensure confiden- tiality of test results continues to be a major obstacle to the full public health use of the HIV antibody test. Because of concerns over this issue, some jurisdictions have passed very strict consent and disclosure laws to prevent potential misuse of these tests. Thus, the routine testing of persons attending public sexually transmitted disease clinics cannot be carried out in many areas without the specific, written consent of the person to be tested. Such restrictions make it difficult but not impossible to carry out epidemiologic surveillance. Except for contact notification (discussed in Chapter 4), public health use of information related to test results generally does not in itself appear to require identification of individuals. Various population groups are being routinely tested by unlinking personal identification information from the collected blood specimen. General demographic data are ob- tained in such unlinked testing, but the result of any test cannot be connected to any individual. The CDC is planning to carry out a national serologic study on a selected sample of hospital patients throughout the country on an unlinked basis to monitor the possible spread of HIV infection to other population groups.

THE DISEASE AND THE EPIDEMIC 69 Findings of Epidemiologic Studies The Prevalence of HIV Infection Epidemiologic and surveillance efforts have demonstrated that HIV infection is far more common than is AIDS, and that HIV infection causes a wide spectrum of illnesses. To put the current magnitude of the AIDS problem in perspective, the prevalence of HIV infection must first be estimated. Most of the studies of HIV infection published to date have been based on individuals who may not be representative of the risk groups to which they belong. Most of the studies carried out in homosexual men have been based on patients from sexually transmitted disease clinics and on patients visiting private physicians for an illness. These men are likely to be among the most sexually active in a given population and are therefore more likely to have been exposed to HIV. In addition, many are already ill, possibly as a result of having AIDS or ARC. Results from such studies indicate that the estimated prevalence of seropositivity among homosexual and bisexual men during 1985 ranged from 44 percent in a cohort from Washington, D.C., to 68 percent for men in San Francisco (Jade et al., 1985a). Data from a different cohort of homosexual men in San Francisco drawn from a probability sample indicate that in 1985 about 50 percent of these men were infected. Som limited survey data from nonurban areas of California and from other U.S. cities where the prevalence of reported AIDS in 1985 was low indicate the prevalence of seropositivity among homosexual men in these areas to be about 20 percent in 1985. Most studies of HIV infection conducted among IV drug users are also potentially biased, since the majority of these patients are recruited from methadone treatment or detoxification programs. Published estimates of infection range from a low of 9 percent in San Francisco to a high of 64 percent in New York City. These large differences are believed to reflect in part that HIV infection was introduced into IV drug communities earlier on the East Coast than on the West Coast. Other factors related to patterns and practices of IV drug use in these areas may also be involved. From studies of HIV infection among homosexual men and IV drug users, it is clear that a large number of persons in the two largest AIDS risk groups have been infected. Using estimated prevalence of infection and estimates of the size of these risk groups, estimates of the total number of infected persons in the United States can be derived. Using this method, the Public Health Service estimated as of mid-1986 that this number is somewhere between 1 million and 1.5 million (Appendix G). The estimate corresponds reasonably well with the estimate (approxi

70 CONFRONTING AIDS mately 1.25 million) derived using an infected-to-AIDS-case ratio of 50 to 1 (Curran et al., 19851. Morgan (Centers for Disease Control, personal communication, 1986) has estimated that there are between 50,000 and 125,000 cases of ARC in the United States, although this number is uncertain and depends on the definition adopted. AIDS Cases By Risk Group Because of the long incubation time for AIDS, disease trends will lag several years behind trends in infections. Between June 1, 1981, and September 8, 1986, the CDC received reports of 24,576 patients (24,228 adults and 348 children under 13 years of age) meeting its surveillance definition of AIDS (Centers for Disease Control, 1986c). While the number of reported AIDS cases has increased steadily, the increase has not been exponential. The doubling time for AIDS cases has increased from about four months in 1981 to almost one year in 1985-1986. A total of 23,426 of the adult AIDS patients have been identified as being in one of the known HIV transmission categories: homosexual men with a history of drug abuse (8 percent); homosexual men who are not known IV drug users (65 percent); heterosexual IV drug users (17 percent); persons with hemophilia (1 percent); heterosexual cases (4 percent) i.e., sexual partners of persons with AIDS, HIV infection, or at risk for AIDS (413 cases) and persons with no other identified risks who were born in countries where heterosexual transmission is believed to play a major role even though precise means of transmission have not yet been fully defined (525 cases); and recipients of transfused blood or blood components (2 percent). Cases with more than one risk factor other than the combinations listed above are tabulated in the first category only. About 55 percent of the heterosexual cases are persons born outside the United States e.g., in Haiti or central Africa. It is believed that most of the remaining 762 cases that fall in no identified transmission category could be assigned to a risk group if additional information were obtained either from the patient or from family members and friends. In a recent follow-up study of those cases initially not found to be in an identified risk group, 40 percent had a history of some other sexually transmitted disease such as gonorrhea or syphilis, suggesting that sexual contact may account for a significant number of these cases (Lifson et al., 19861. The relative proportion of reported cases among the largest AIDS risk groups has remained remarkably stable over time. In the smaller risk groups, slight but statistically significant changes have occurred. AIDS cases among people born outside the United States, primarily in Haiti, have become proportionately less. Haitians accounted for 4.5 percent of

THE DISEASE AND THE EPIDEMIC 7 ~ total U.S. cases before 1984 but only 1.5 percent in 1986. The reason for this may be that the early cases were in Haitians who migrated to the United States from 1978 to 1981 and who were infected prior to their entry into this country. The proportion of cases associated with blood transfusions has in- creased slightly, from 1.1 percent in 1983 to 1.9 percent in 1986, though the absolute number remains small. This increase represents additional cases among persons infected before an effective mechanism for donor screening was available. It may also represent increased recognition of the disease among transfusion recipients. With the long incubation period of AIDS, more cases are to be expected from the prescreening era. But with the institution of routine donor screening, the number of transfusion- associated AIDS cases should begin to decline as a proportion of total cases before the end of this decade. The proportion of AIDS cases in the heterosexual contact risk group has also increased significantly over time, rising from 1 percent in 1983 to 1.4 percent in 1985 to a projected 2 percent in 1986, though the total number of such cases is still small (cumulatively totaling 413 cases as of September 8, 19861. However, in addition to those cases identified as caused by heterosexual exposure, it is likely that an undefined proportion of the cases among persons in no known risk group (totaling 762 cases) was caused by heterosexual transmission. AIDS Case Trends by Geographic Area The distribution of reported AIDS cases by geographic region has changed markedly over time. Relative to the New York City Standard Metropolitan Statistical Area (SMSA) and the San Francisco SMSA, the proportion of cases from the rest of the United States has increased significantly. This proportional change is greatest relative to New York City. It is primarily among homosexual men, but it is also seen among IV drug users and in the remaining risk groups. The most recent doubling time of reported AIDS cases was 14 months in New York City, 13 months in San Francisco, and 10 months in the rest of the country. At least three hypotheses may account for the observed changes in the geographic distribution of AIDS cases. First, because the virus was introduced in New York City and San Francisco earlier than in the rest of the country, there has been more time for those persons who engage in high-risk activities to become infected. Second, in these cities the groups at highest risk are probably becoming relatively saturated with HIV infection and thus the incidence of new infections is slowing. Third, the intensive educational programs instituted in these cities may also have resulted in a marked reduction of unsafe sexual activities (see Chapter 4~.

72 CONFRONTING AIDS Additionally, changes in the methods of diagnosis or the consistency of reporting could at least in part account for these trends. The national surveillance data can easily mask trends that differ within particular geographic areas. The overall proportion of reported cases by risk factor has changed little over time, but substantial and significant changes have occurred in individual areas. In New York City the proportion of AIDS cases in IV drug users (irrespective of sexual preference) has increased slightly- from 35 percent to 38 percent. In Newark, New Jersey, the proportion of cases in IV drug users has declined over time- from 67 percent to 61 percent. AIDS Case Trends by Sex, Race, and Age The distribution of AIDS cases by sex and race has not changed significantly over time, although there has been a slight increase in the average age of cases. Ninety-three percent of the reported cases in the United States are men. By race, 60 percent are white, 25 percent are black, and 14 percent are Hispanic. Less than 1 percent of the nonpedi- atric AIDS patients in the United States are between 13 and 19 years of age. About 90 percent of adult AIDS patients are between 20 and 49, with almost 50 percent between 30 and 39 years of age. There are differences in the age, sex, and race distribution of cases by geographic region, but these are primarily because of differences in the patient risk groups. For example, in San Francisco the majority of AIDS cases are among homosexual men, and fewer than 1 percent of cases have been reported in women. By contrast, in New York City, which has a higher percentage of cases involving IV drug use and heterosexual contact, 10 percent of reported cases are in women. The slight increase in the age of AIDS patients does not necessarily indicate an increasing rate of new infection among older persons. AIDS Case Trends in Disease Presentation and Mortality Pneumocystis carinii pneumonia (PCP), the most common disease seen in AIDS patients, has been diagnosed in 64 percent of reported cases. Kaposi's sarcoma (KS), the second most common disease, has been diagnosed in 23 percent of cases (Centers for Disease Control, 1986c). PCP is common in all adult patient groups, while the vast majority (95 percent) of patients with KS are homosexual men. The distribution of these two diseases is changing over time. PCP is accounting for an increasing proportion of AIDS-associated disease diagnoses, while KS is accounting for relatively fewer. Of the opportu- nistic diseases diagnosed before December 1984, PCP accounted for 34

THE DISEASE AND THE EPIDEMIC 73 percent and KS for 20 percent. Since then, PCP has accounted for 45 percent and KS for 14 percent. The decline in the proportion of KS and the increase in PCP can be seen in all adult risk groups. The trends are statistically significant in cases in New York City, San Francisco, and some other areas of the United States. The reasons for this apparent shift in disease presentation are unclear, but at least three explanations have been hypothesized: (1) the occurrence of KS is associated with some cofactor, such as a second infection (e.g., cytomegalovirus) or the use of toxic substances (e.g., butyl and amyl nitrites), and the incidence of the cofactor is decreasing; (2) there is less reporting of KS, a condition somewhat more likely to be diagnosed and managed on an outpatient basis without biopsy-confirmed diagnosis; (3) there are relative differences in the distribution of incubation times for KS and PCP. After PCP and KS, Candida esophagitis is the most common opportu- nistic disease, being seen in 14 percent of AIDS cases. This is followed by cytomegalovirus disease (7 percent), cryptococcosis (7 percent), chronic herpes simplex (4 percent), cryptosporidiosis (4 percent), toxoplasmosis (3 percent), and other opportunistic infections (3 percent). These percent- ages underestimate the number of diseases diagnosed in a given group of patients because health care providers frequently do not provide follow- up information on diseases that occur after a case has been reported initially. Approximately 55 percent of all AIDS patients reported to the CDC are known to have died. The reported one-year mortality is 48 percent and increases to approximately 75 percent two years after the initial diagnosis is made (Centers for Disease Control, 1986c). These values, particularly the two-year estimate, are low because of underreporting of deaths. The type of opportunistic illness initially diagnosed in AIDS patients relates significantly to short-term mortality. In one follow-up study of more than 1,000 AIDS cases, the median survival time after diagnosis for those with PCP was only 8 months, compared with a median survival of 30 months for those with KS alone. HIV INFECTION AND AIDS OUTSIDE THE UNITED STATES The fact that there are cases of AIDS in more than 80 countries has clearly demonstrated that HIV infection and its resulting diseases are a growing international problem. In an era of intercontinental travel, HIV has spread rapidly, and all countries share interests in finding and implementing effective control measures. Furthermore, analysis of the differences in the epidemiology of HIV infection from country to country can offer important clues to the biology of the virus and new opportuni

74 CONFRONTING AIDS ties, through international cooperation, to exploit those clues for control purposes. African Countries Infection with HIV appears to be widespread in central Africa and rapidly increasing in prevalence in eastern and southern Africa. Most available data are from central Africa. In Kinshasa, Zaire, the annual incidence of AIDS in adults as of February 1985 was estimated to be 38 per 100,000, up from 24 per 100,000 the previous July (Mann et al., 1986a). In October 1983 the estimated annual incidence in Kigali, Rwanda, was 80 per 100,000 (Van de Perre et al., 19841. AIDS has been seen in epidemic form in Zambia and Uganda since 1982, and subsequently in Tanzania (Bigger, 19861. High rates of infection, at that time without much disease, were noted in Nairobi in 1985, with some evidence of transmission from central Africa (Kreiss et al., 19861. Seropositivity has also been found in some areas of western Africa. Whether this resects infection with HIV or with a related retrovirus is unknown. By December 1985 AIDS had been diagnosed in citizens of at least 23 African countries. The presence of simian retroviruses with considerable genetic and immunologic homology to HIV raises the possibility that the virus arose in Africa and recently passed from monkey to human populations, although it could also have recently spread from an isolated human population to urban centers. The recent recognition that infection by retroviruses distinct from HIV and more closely resembling these simian retroviruses is also widespread in Africa has significant implications for public health measures and the improved understanding of the pathogen- esis of HIV infection (see Chapter 6~. Preliminary indications suggest that this spectrum of related viruses may cause varying degrees of im- munosuppression and disease. AIDS seems to have been rare and perhaps nonexistent in Africa before the mid-1970s. Cases consistent with AIDS occurred in a European visitor to Zaire in 1976 and in a Zairian citizen in Europe in 1977 (Bygbjerg, 1983; Vandepitte et al., 19831. Until the 1980s, however, cases were not seen with sufficient frequency to attract attention. The vast majority of reports of high rates of seropositivity in sera collected in the 1960s and 1970s are questionable, in view of an apparent lack of specificity in the initial antibody tests. Clinically, AIDS cases in Africa differ from those in North America and Europe. There is a paucity of instances of documented Pneumocystis carinii infections in Africa, and a high frequency of oral candidiasis and tuberculosis, especially extrapulmonary (Bigger, 1986; Mann et al., in press). Salmonella, Pseudomonas, disseminated strongylosis, and

THE DISEASE AND THE EPIDEMIC 75 Entamoeba infections have also been noted in African AIDS patients. "Enteropathic AIDS," or "slim disease," is a syndrome seen in Africa and characterized by wasting, recurrent fever, and diarrhea. Endemic Kaposi's sarcoma was more common in Africa than in the developed world before the AIDS epidemic and does not appear to be associated with AIDS, but an increasing number of aggressive Kaposi's sarcoma cases are. As in the United States, these cases typically involve the lymph nodes and viscera, produce plaques on the trunk and face, and are rapidly fatal. Several lines of evidence suggest that transmission of HIV in Africa is largely through heterosexual activity. The majority of cases are in adults. Unlike the situation in the United States, where the ratio of cases in men to those in wo~nen is greater than 10, in most African populations studied the ratio is approximately unity. In Kinshasa, the risk in men relative to women has been estimated to rise from 0.4 in those 20 to 29 years old to 4.0 in those 50 to 59 years old (Mann et al., 1986a). Striking clusters of AIDS cases among heterosexual partners have been anecdotally reported (Plot et al., 1984~. Men with AIDS report an average 10-fold more heterosexual contacts than do controls (Clumeck et al., 1985), and up to half of the women with AIDS in some series are reported to be prostitutes (Van de Perre et al., 19841. Furthermore, seropositivity has been found in 31 to 66 percent of Nairobi women who are prostitutes and in 8 percent of men attending a Nairobi clinic for sexually transmitted diseases, in contrast to 2 percent of medical personnel (Kreiss et al., 19861. A survey of seropositivity in household contacts of AIDS patients and controls in Kinshasa showed a statistically significant increase in the seropositivity rate in spouses (61 percent in cases versus 4 percent in controls) but not in other contacts (4.8 percent in case households versus 1.6 percent in control households) (Mann et al., 1986b). Little information exists on the particular sexual activities that transmit HIV or on the relative efficiency of transmission from women to men and men to women. Practices of scarification and "female circumcision" (genital mutilation) in some African societies have led some to wonder whether anal intercourse or trauma during vaginal intercourse might contribute to heterosexual transmission of HIV in Africa. However, the distribution of AIDS cases in Africa does not correspond closely with the practice of female circumcision, and anal intercourse is reported to be rare. Among Nairobi prostitutes, seropositivity was greatest (66 percent) in the lower socioeconomic class, whose clients were mainly Kenyan. In this group, only vaginal intercourse was reported to be practiced, but the average number of sexual encounters was 963 per year. Among higher- priced prostitutes, whose clients were mainly African and non-African tourists and businessmen, seropositivity was 31 percent, receptive oral

76 CONFRONTING AIDS sex (but not anal sex) was practiced by about 25 percent, and the average number of encounters was 124 per year. The risk of seropositivity seemed more closely linked in this study to the number of sexual encounters than to a particular sexual practice. The importance of parenteral transmission of HIV in Africa is unknown but potentially great. Frequency of injections has been shown to be a risk factor for HIV infection there, a finding that might have been predicted from the practice in many medical clinics of reusing needles without sterilization. One of the common occasions for intramuscular injections in urban areas is treatment of sexually transmitted diseases, so it has been difficult to separate the role of the injection from that of the sexual encounter itself in contributing to transmission. The issue is confounded further by the observed statistical association of genital ulcers with seropositivity (K. K. Holmes, University of Seattle, personal communi- cation, 19861. Interpretation of this association is difficult; the ulcers might be sites of inoculation of the virus, or they could have been a reason for attendance at a sexually transmitted disease clinic, where the virus might have been transmitted through unsterile needles or syringes. Other Countries The problem of AIDS in Haiti was recognized early, because initially some 40 percent of U.S. cases in which no known risk factor was found were in Haitians. Epidemiologic studies in Haiti have shown a ratio of cases in males to those in females of 4, which is intermediate between the ratios in the United States and Africa. Cases continue to increase rapidly and seem to be concentrated in urban centers. Several lines of evidence point to both heterosexual and homosexual transmission of HIV in Haiti. Half of the men among recent cases are bisexual. Also, women with AIDS are much more likely to be sexually promiscuous than are their sisters, female friends, or the female sexual partners of men with AIDS (Pape et al., 19861. A striking association has been observed in Haiti between AIDS and the receipt of an intramuscular injection in the preceding five years (Pape et al., 1986~. As in Africa, the use in Haiti of unsterile needles and syringes is common. In one series, 7 of 34 cases, including 4 of 8 women, gave a history of a blood transfusion in the preceding five years. However, the overall degree of risk associated with blood transfusions in Haiti has not been determined. The pattern of AIDS in Europe largely mirrors that in the United States. A large proportion of cases occur in homosexual men and IV drug users, with small numbers in heterosexual partners of people in high-risk groups, recipients of blood products, and travelers from countries with

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