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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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;

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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

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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

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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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THE DISEASE AND THE EPIDEMIC 77 high rates of HIV infection. Particularly high rates of seropositivity have been reported among drug users in Italy and Spain, indicating a potential for rapid spread in this group. In Scotland a crackdown on the availability of hypodermic needles that coincided with the introduction of HIV may have contributed to the high (50 percent) seropositivity rate in IV drug users. In southeast Asia, cases of AIDS have appeared in homosexual and heterosexual prostitutes in cities, despite the absence of much IV drug use in those groups. If HIV infection acts like other sexually transmitted diseases, the opportunity for amplification in that setting is worrisome. REFERENCES Abrams, D. I., B. J. Lewis, J. H. Beckstead, C. A. Casavant, and W. L. Drew. 1984. Persistent diffuse lymphadenopathy in homosexual men: Endpoint or prodrome? Ann. Intern. Med. 100:801-808. Abrams, D. I., T. Mess, and P. A. Volberding. 1985. Lymphadenopathy: End-point prodrome? Update of a 36-month prospective study. Adv. Exp. Med. Biol. 187:73-84. Barre-Sinoussi, F., J. C. Chermann, F. Rey, M. T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler-Blin, F. Vezinet-Brun, C. Rouzioux, W. Rozenbaum, and L. Montagnier. 1983. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868-871. Bell, A. P., and M. S. Weinberg. 1978. Homosexualities: A Study of Diversity Among Men and Women. New York: Simon and Schuster. Bernstein, L. J., B. Z. Krieger, B. Novick, M. J. Siddick, and A. Rubinstein. 1985. Bacterial infection in the acquired immunodeficiency syndrome of children. Pediatr. Infect. Dis. 4: 472-475. Biggar, J. R. 1986. The AIDS problem in Africa. Lancet 1:79-83. Britton, C. B., and J. R. Miller. 1984. Neurologic complications in AIDS. Neurol. Clin. 2: 315-319. Brun-Vezinet, F., C. Rouzioux, F. Barre-Sinoussi, D. Klatzmann, A. G. Saimot, W. Rozenbaum, D. Christal, J. C. Gluckmann, L. Montagnier, and J. C. Chermann. 1984. Detection of IgG antibodies to lymphadenopathy-associated virus in patients with AIDS or lymphadenopathy syndrome. Lancet I: 1253-1256. Burger, H., B. Weiser, W. S. Robinson, J. Lifson, E. Engleman, C. Rouzioux, F. Brun-Vezinet, F. Barre-Sinoussi, L. Montagnier, and J. C. Chermann. 1985. Transient antibody to lymphadenopathy-associated virus/human T-lymphotropic virus type III and T-lymphocyte abnormalit~es in the wife of a man who developed the acquired im- munodeficiency syndrome. Ann. Intern. Med. 103:545-547. Burke, D. S., W. Bernier, J. Voskovitch, R. Redfield, G. Jacobs, and J. Spiker. 1986. Prevalence of HTLV-III infections among prospective U.S. military recruits. P. 151 in Abstracts of the Second International Conference on AIDS, Paris, June 23-25, 1986. Bygbjerg, J. C. 1983. AIDS in a Danish surgeon. Lancet 1:925. Castro, K. G., M. A. Fischl, S. H. Landesman, J. M. Johnson, J. C. Compas, and J. C. Desgrange. 1985. Risk factors for AIDS among Haitians in the United States. Paper presented at the International Conference on AIDS, Atlanta, Gal, April 14-17, 1985. Centers for Disease Control. 1981a. Pneumocystis pneumonia-Los Angeles. Morbid. Mortal. Weekly Rep. 30:250-252.

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