Development of the AIDS Pandemic

In retrospect, it is clear that several characteristics of HIV/AIDS resulted in a serious underestimation of the importance of the epidemic by both individuals and societies. One feature of HIV/AIDS that is highly unusual for an infectious disease is its consistently long incubation period combined with a high rate of disease development. Most organisms cause clinical signs or symptoms in only a fraction of those they infect. When infection occurs, as in diseases such as measles or smallpox, the induction period is short. HIV/AIDS is unique in that it regularly causes lethal disease after a prolonged induction period that lasts several years. As a result, the vast majority of HIV-infected people are clinically asymptomatic and do not know they are infected unless they undergo serologic testing. Because HIV-infected asymptomatic people can transmit the virus to others, the epidemic accelerates robustly. In some settings, a significant fraction of the population becomes infected before disease and death have provided the most evident lesson of the need for vigilance.

HIV/AIDS is also difficult to control because it is a sexually transmitted disease. In most societies both leaders and citizens are reluctant to discuss sex. Although condoms are efficient in preventing infection, they are often not an available option, for example, when couples wish to have children. The image of AIDS as a sexually transmitted disease also contributes to the stigmatization of infected people, which in turn may cause many to avoid testing to determine their status.

The variability in clinical outcomes also contributed to the difficulty in controlling the spread of HIV, particularly during the early stages of the epidemic. Tuberculosis, Kaposi's sarcoma, and chronic diarrhea can all occur in the absence of HIV infection. In the absence of testing for HIV, it is still possible for AIDS patients with such outcomes, and their families, to deny the infection and perhaps avoid some of the associated discrimination and stigma. As a societal problem, AIDS is also devastating because it usually attacks young adults during their most productive years of employment and parenting. Because both parents are often infected, AIDS epidemics ordinarily leave large numbers of orphans behind.

Rates of HIV/AIDS in Africa

In its most recent projections, the Joint United Nations Programme on HIV/AIDS (UNAIDS) has estimated that about 40 million people are currently infected with HIV, of whom about 25.8 million, or 64 percent of the total, are in Sub-Saharan Africa (UNAIDS and WHO 2005). The estimates are that 4.9 million people became infected during 2005, of whom 3.2 million, or 65 percent, were in Sub-Saharan Africa. During the same year, 77 percent of an estimated global burden of 3.1 million AIDS deaths were projected for Sub-Saharan Africa. During recent years, the use of antiretroviral (ARV) drugs in the United States and other developed countries has dramatically reduced AIDS death rates, but until now, only a small proportion of AIDS patients in Sub-Saharan Africa have received treatment (see figure 17.1).

Figure 17.1

Disease Burden and Treatment of AIDS in Relation to Global Population and Economy Source: CIA 2006; UNAIDS 2004; UNAIDS and WHO 2005; WHO 2005.

Several factors account for the low fraction of AIDS patients receiving ARV treatment. One of the largest is the cost of the drugs. Until recently, all the major ARV drugs were prohibitively expensive in developing countries. This situation is now changing, but ARV drugs and medical care are still out of reach for the majority of AIDS patients in Africa. The global burden of AIDS is disproportionate in countries whose gross national productivity represents a small fraction of the global economy (see figure 17.1).

Wide variation in HIV prevalence rates also occurs within Africa (Essex and Mboup 2002). However, overall adult rates of HIV in Sub-Saharan Africa are about 7.2 percent, much higher than in other regions of the world, including other regions with large populations living in developing countries (see figure 17.2). Rates of HIV are low in North Africa, although countries that span the Sahara, such as Sudan, have higher rates than those countries on the northern coast.

Figure 17.2

Global Burden of HIV-1 Infection Source: UNAIDS 2004.

Within Sub-Saharan Africa, the AIDS epidemic was noticed first in central Africa (Clumeck et al. 1983). Soon after, the epidemic was observed in East Africa, and subsequently in West Africa (Essex and Mboup 2002). The epidemic seemed to occur last in southern Africa, although rates there are now the highest in Africa and in the world. Six countries of southern Africa have adult prevalence rates of 20 percent or higher, and the mean prevalence rate for all of southern Africa is about 18 percent.

The mean adult prevalence rate in Sub-Saharan Africa is 7.2 percent, whereas the mean rates in Asia are 0.4 percent (see table 17.1). Haiti, with a prevalence rate of 5.6 percent, has the highest outside of Africa, and Cambodia, with 2.6 percent, has the highest in Asia (UNAIDS 2004). Brazil, one of the few countries outside of the West that began ARV treatment at an early stage, has an estimated adult prevalence rate of 0.7 percent.

Table 17.1

HIV-1 Prevalence in Representative Regions and Countries.

The overall burden that HIV/AIDS has placed on Sub-Saharan Africa is unprecedented. It is now the most common cause of death in the region (WHO 1999). It has been estimated that by the year 2010 life expectancy at birth could be decreased by at least 15 years in most of the region and by 30 years or more in five countries (Stanecki and Walker 2002). Population growth rates would fall and infant mortality rates would increase. It has been estimated that mortality rates for children under five could experience a fivefold increase in Botswana and Zimbabwe (Stanecki and Walker 2002). All these projections, however, assume that ARV drugs are not being used to save lives in the region. This is an assumption that, fortunately, is no longer valid.

Retroviruses

Prior to the AIDS epidemic and the discovery of HIV, retroviruses were known to exist and were associated with certain leukemias of animals and people. Such "oncoretroviruses" were characterized by an ability to replicate without killing the cells they infect. Lentiretroviruses, which include the HIVs, usually replicate at higher levels and kill the cells they infect. All retroviruses use reverse transcription of the virion RNA to replicate, and they produce a proviral DNA form that can remain latent in host cell chromosomes. All retroviruses also generate a high rate of mutations when transcribing the RNA, but the error rate is highest for those viruses that replicate to high levels, such as HIV.

The high mutation rate facilitates a rapid rate of evolutionary change for HIVs. Another feature of the viruses that promotes rapid variation is the diploid nature of the viral RNA. With two complete copies of the genome packaged in each virus particle, recombinational events are also frequent, allowing progeny viruses to pick up large segments of somewhat different genetic information in a short period of time.

An extremely important aspect of the rate of evolutionary variation for HIVs is the selection pressure exerted by the host. This aspect is vividly illustrated by the rapid emergence of drug-resistant variations of HIV. Resistance occurs rapidly in a single individual, particularly when only one drug is used. The same type of competition occurs during host-mediated immunoselection pressure, in which viral variants emerge to avoid control by epitope-specific host immune responses. The process is repeated frequently and cyclically; the dominant clone of the virus elicits a new immune response, becomes controlled, and a new mutational variant takes over as the next dominant viral clone.

Many of the mutations and recombinational events result in the emergence of genomes that are incapable of replication. This occurs because viruses, to be viable, must fold their proteins in specific ways and retain reactive sites that signal key events. All HIVs, for example, must retain the ability to bind to the CD4 receptors and chemokine coreceptors, such as CCR5 and CXCR4, on T lymphocytes and macrophages. This in turn forces a certain level of convergent evolution.

As progressive cycles of HIV mutant clones begin to exhaust the immune control capacity of the host, the number of dying lymphocytes exceeds the capacity for cell replacement and the number of CD4 lymphocytes rapidly falls. As plasma viral load reaches levels of 50,000 copies per milliliter and above, and the number of CD4 lymphocytes drops to 300 per cubic millimeter and below, the ability of the body to resist opportunistic infections is largely lost, and clinical AIDS develops.

Regional Variation

Soon after HIV-1 was identified, other lentiretroviruses were identified in primates. These included a wide range of simian immunodeficiency viruses (SIVs) and a second category of HIVs in people in West Africa, designated HIV-2s (Barin et al. 1985). The SIVs naturally infected large fractions of populations of various species of African monkeys, apparently without causing disease (Kanki, Homma, et al. 1985). The SIVs did, however, cause clinical AIDS when artificially injected into Asian macaques (Daniel et al. 1985; Kanki, McLane, et al. 1985).

Some of the SIVs were virtually indistinguishable from HIV-2s at the genetic level, although SIVs and HIV-2s were usually 50 to 60 percent different from HIV-1s. HIV-2s also cause an AIDS-like disease in people, but with considerably less efficiency than HIV-1s (Marlink et al. 1994). HIV-2s were much less transmissible, both by sexual contact and by mother-to-infant transmission (Kanki, Sankale, and Mboup 2002). Presumably because of this dramatic reduction in transmission efficiency, HIV-2 has been largely limited to West Africa, and it has not caused any of the large epidemics typical of HIV-1.

Many different categories of HIV-1s have been identified, with at least six of them linked to major epidemics. The different categories of HIV-1s are usually designated clades, or subtypes, and viruses of one subtype differ from those of another subtype by an average of 20 to 30 percent in genetic sequence. Two of the six common categories of HIV-1s were found to be circulating recombinant forms (CRFs) (McCutchan 2000).

The first major category of HIV-1 to be identified and categorized was subtype HIV-1B, which is responsible for the epidemics in the Americas and Western Europe. These epidemics have been characterized by patterns that reflect primary transmission via homosexual contact and injection drug use. HIV-1B has also been found in other sites, such as India, South Africa, and Thailand. Even in these sites, HIV-1B infections have not been associated with heterosexual epidemics, although heterosexual epidemics due to other HIV subtypes have occurred concurrently in the same sites (Hudgens et al. 2002; Janssens, Buve, and Nkengasong 1997).

The most common HIV in the world and in Africa is HIV-1 subtype C (HIV-1C). HIV-1C accounts for as many infections as all other HIVs combined, both in the world and in Africa (Essex 1999). It is responsible for the massive epidemic in southern Africa, and all the countries in Africa that have the highest rates of HIV have HIV-1C epidemics. Along with an epidemic expansion that plateaued at the highest levels, the HIV-1C epidemic in southern Africa expanded faster than other HIV epidemics, although it started later (Essex and Mboup 2002).

The next most important HIV virus in Africa, and in the world, is CRF 02, a recombinant form that originated from an HIV-1A and an HIV-1G. This virus accounts for about 25 percent of the world's infections (Essex and Mboup 2002). It is largely responsible for the epidemics in West Africa and central Africa. Although mean prevalence rates in these regions are only 5 percent and 6 percent, respectively, they represent some sites with large populations, such as Nigeria. East Africa has had epidemics of HIV-1A and HIV-1D, often coexisting in the same populations (Rayfield et al. 1998). A few countries, such as Tanzania in the east and Cameroon in the west, have a wide variety of viruses present in the same site (Fonjungo et al. 2000; Renjifo et al. 1999). In Tanzania, for example, an earlier epidemic of HIV-1A and HIV-1D fused with the northward expansion of the HIV-1C epidemic. This apparently resulted in the generation of a large number of recombinant viruses (Renjifo et al. 1999). A schematic distribution of the major subtypes and CRFs in Africa is illustrated in figure 17.3.

Figure 17.3

Distribution of Major HIV-1 Subtypes and Circulating Recombinant Forms in Africa Source: Essex and Mboup 2002; UNAIDS 2004; UNAIDS and WHO 2005.

Phenotypic distinctions between the HIV-1 subtypes and CRFs are much less apparent than the differences between HIV-1s and HIV-2s. HIV-1C genomes ordinarily have three NFkB enhancer sequences, whereas other subtypes have only two, and in the case of HIV-2s, only one (Montano et al. 1997). This is almost certainly associated with the higher transcriptional activation rates seen for HIV-1Cs (Montano et al. 2000). It is also a possible explanation for the higher rates of genomic variation (Novitsky et al. 1999) and the higher viral loads reported for HIV-1Cs (Neilson et al. 1999). The efficient spread of HIV-1C is also compatible with this subtype's preference for the CCR5 coreceptor (Ping et al. 1999; Tscherning et al. 1998). HIV-1Ds and HIV-1Bs, for example, are much more likely to use the CXCR4 coreceptor than the HIV-1Cs (Tscherning et al. 1998), and neither HIV-1B nor HIV-1D has spread to cause large epidemics in Africa.

Coinfection of individuals with two different HIVs—different subtypes; different types, such as HIV-1 and HIV-2; or different variants within a subtype—can occur. These events appear to occur less often than might be expected (Travers et al. 1995), perhaps because of some level of cross-protection due to activation of chemokines, receptor competition, or specific immunity. When the same cells are coinfected, the opportunity for generation of infectious recombinants is substantial.

Progression of Infection

After initial exposure to HIV occurs, several weeks go by before the virus can be detected in blood. At least in the case of HIV-1B infections in homosexual men, an acute, influenza-like illness then occurs in the majority of the infected. This is characterized by high levels of virus replication reflected in the blood as viremia. Whether the same flu-like illness occurs at the same rate in heterosexual infections of other HIV-1 subtypes is unclear.

During the stage of acute viremia large numbers of T lymphocytes become infected in lymph nodes (Pantaleo et al. 1993), and patients are highly infectious to other potential contacts (Quinn and Chaisson 2003). The acute viremia then falls precipitously, presumably because of an effective immune response, albeit a response that later becomes largely ineffective as mutant variants emerge. The magnitude of the acute viremia and the depth of the subsequent resolution, sometimes called the set point, probably determine the subsequent rate of disease progression. For a minority of those infected, a rapid and well-controlled set point apparently results in the development of clinical AIDS only after a very prolonged period of time. Such individuals are sometimes called "long-term nonprogressors."

The length of time before disease development may also be related to other factors, such as the infected individual's genetic background (Winkler and O'Brien 2002), nutritional state, and parasite burden of coinfecting microorganisms. Antigenic stimulation of infected cells causes DNA synthesis, which in turn causes activation and replication of latent HIV. The tissue damage caused by other infections also stimulates the release of inflammatory cytokines, which also causes transcriptional activation of HIV (Montano et al. 2000). With all these variables, however, clinical AIDS rarely occurs before 4 to 5 years after infection, and almost always occurs within 10 to 12 years after infection. In the absence of therapy, death usually occurs within 1 to 3 years after the onset of clinical AIDS.

Prevention

Methods of preventing HIV infection can be divided into those that are currently available, such as education, and those that are not yet available but are being pursued through research, such as vaccines.

HIV transmission through blood transfusion, although an important issue at the early stages of the pandemic, now occurs only rarely. The serology tests used to determine if blood is contaminated are highly sensitive and specific, although an infectious unit of blood can occasionally be missed if the donor was infected within the two to three weeks before donation, before antibodies had time to develop. The use of contaminated needles or injection equipment is sometimes an important method of transmission in defined populations, but it is not nearly as important as sexual transmission, at least in Africa.

Voluntary testing and counseling programs are extremely important to reduce sexual transmission. A major limitation in most countries is the reluctance of most people to get tested and thus learn their status. Such reluctance may be particularly evident where infected individuals have few or no opportunities for treatment with ARV. In such situations concerns about stigma and death from the infection may provide disincentives for the individual to learn his or her status.

Condoms are highly effective when used properly. Abstinence provides a guarantee against sexual infection. But neither abstinence nor condoms allow couples to have children.

The use of ARVs for chemoprophylaxis is effective in preventing transmission of HIV from infected mothers to their infants. In the absence of intervention, 25 to 45 percent of infants born to HIV-positive mothers become infected. The infection occurs in utero, during the process of birth, and through breastfeeding. The use of ARVs, such as zidovudine (AZT), was shown to reduce neonatal transmission by as much as 67 percent in nonbreastfeeding populations if given at least six to eight weeks before birth (Connor et al. 1994). Even when given only at the time of labor, nevirapine (NVP) apparently reduced intrapartum transmissions by as much as 50 percent (Guay et al. 1999). The use of drug combinations early in gestation can presumably reduce in utero and intrapartum transmission to only a few percent.

Avoidance of breastfeeding can obviously eliminate post-natal infections by this route. However, in many cultures recommendations for formula feeding are not well received, in part because of the stigma associated with bottle feeding of the infant. The effectiveness of chemoprophylaxis to the infant or the mother, or both, while breastfeeding is being evaluated.

ARV drugs can also be used to block transmission of HIV by accidental needlestick infections, such as those that might occur among medical personnel treating AIDS patients (Bouvet, Laporte, and Tarantola 2002). The same three-drug combinations, such as AZT, lamivudine (3TC), and NVP, that are used for treatment of AIDS, are highly effective if given within hours after the presumed exposure. The same interventions can be used for victims of sexual violence.

Vaccines and Microbicides

Effective vaccines that exist against other viral diseases are based on the injection of either killed virus, purified viral surface proteins, or live attenuated virus. All three types are commonly used in people. The Salk polio vaccine is killed virus, the vaccine used against hepatitis B is a purified viral surface protein, and the Sabin oral polio vaccine is a live attenuated virus. The killed virus and viral protein approaches can function only by inducing virus-neutralizing antibodies. The live attenuated types of vaccine often induce both neutralizing antibodies and cytolytic T cell immunity.

The use of live attenuated HIV as a vaccine was largely dismissed, even at the earliest stages, because of safety concerns. Killed HIV was similarly dismissed for safety concerns and because it was assumed that subunit surface proteins would work as well as killed virus without the same safety concerns, as was true of the hepatitis B vaccine. As a result, almost all the initial experimental vaccines were based on the use of HIV proteins gp120 or gp160 that protrude from the outer surface of the virus.

As HIVs grown in cultured cell lines provided the highest titers for subsequent purification, the first vaccines were made from T-cell-line adapted gp120/160 proteins. It was soon recognized that the neutralizing antibodies these vaccines induced were ineffective against naturally occurring HIVs. Subsequently it was also recognized that monomeric gp120/160 proteins induced antibodies that would work only against the exact strain selected. The profound sequence variation seen among HIVs created a situation in which matching the vaccine gp120 to the field challenge strain was not possible.

The next wave of HIV vaccine research was based primarily on the development of cytolytic T cell (CTL) vaccines. Most were based on the use of nonvirulent viruses, such as vaccinia, the vaccine used for smallpox, or adenoviruses. Genes, or parts of genes, of HIV that were suspected of being able to induce CTL responses were inserted in the "vaccine vector viruses" through gene splicing. HIV antigens or "CTL epitopes" must be delivered in this way, because for immunity to be effective, recognition of the immunogen must be in conjunction with cell processing to match the HIV antigens to the histocompatibility antigens of the recipient.

Several CTL vaccines have now been evaluated in people for safety and immunogenicity. In general, they appear to be quite safe, but they do not appear to be sufficiently stimulating to elicit strong immune responses that are likely to be protective. Developing CTL vaccines using other viruses as vectors is an entirely new area of vaccine science. If these methods can be mastered, they could probably also be extrapolated for use in combating many other diseases.

A major part of the rationale for CTL vaccines was the assumption that they would be more broadly cross-reactive than gp120 vaccines. Viral core proteins are usually more genetically conserved than viral surface proteins, thus reducing antigenic variation and reducing opportunities for immune selection in the vaccinee to evade effectiveness. Even for CTL vaccines, however, it seems prudent to use the relevant HIV-1 subtype or regional strain to increase the likelihood of protection.

To maximize the chances that a vaccine may work, most researchers endorse the use of vaccines or vaccine combinations that might induce both neutralizing antibodies and CTL responses. This is ordinarily done using a"prime-boost" strategy of several inoculations, in which the first (prime) would allow the induction of CTL responses, and the boost would encourage both CTL and antibody responses.

Recently, research to design gp120 antigens that would induce cross-reactive neutralizing antibodies has also begun a new generation of vaccine approaches (Fouts et al. 2000). The concept is based on the stabilization of a conformational state of the HIV-1 gp120 at the time it interacts with the CD4 receptor or the CCR5 receptor or both. This and other approaches serve to illustrate that HIV vaccine research is alive and well in providing new designs, but is also unlikely to yield a final product of high efficacy in less than 5 to 10 years. Thus, the prevention of further spread of HIV within the next decade must be centered on other measures.

Therapy

The first phase of therapy using ARV drugs was AZT. Initially it was the only drug, and when used alone it often gave AIDS patients another six months or so in partial remission. Soon, other related drugs, nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as lamivudine (3TC), didanosine (DDI), and stavudine (D4T), were also available. One of these drugs used with AZT clearly worked better than using just one drug alone. However, their use posed two significant problems. One was drug toxicities, which ranged from gastrointestinal problems and anemias to peripheral neuropathies. The other was the rapid generation of drug-resistant variants of HIV, which soon grew just as well in the patient as before the drugs were first used. Using two drugs at once lowered HIV viremia even better than using one drug and delayed the time to development of drug resistance. However, even with two NRTIs, drug resistance often developed within a year, and resistance to one of the NRTIs often prompted resistance to other NRTIs of the same class.

The next class of drugs available was the nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (NVP) and efavirenz (EFV). These drugs were even easier for the virus to mutate around to cause drug resistance, and this happened within weeks when one of these drugs was given alone, as "monotherapy." However, when given with two or more other drugs, they could often be given for long periods of time.

The third major class of drugs, the protease inhibitors, work on an entirely different gene of HIV, so they provided an additional, separate mechanism to keep down virus replication. However, unlike the NRTIs and the NNRTIs, which could often be made "off patent" or as "generics," the protease inhibitors are still expensive and generally not available in developing countries.

The standard drug regimen for most developing countries is now a three-drug combination that includes two NRTIs, especially AZT and 3TC, and one NNRTI, such as NVP. In most cases this regimen works well, unless resistance to any of the drugs is already present. This happens, for example, if women have recently been treated with AZT or NVP alone, as part of a chemoprevention strategy to block infection of their infant. The use of NVP alone during labor, for example, can cause resistance to the whole NNRTI class of drugs in 20 percent or more of mothers, even when only one dose is given (Eshleman et al. 2001).

In the West, combination three-drug therapy usually begins earlier than the current recommendations projected for the developing world. In the United States, for example, drug therapy would usually be recommended by the time the patient fell below 350 CD4⁺ cells per cubic millimeter or a viral load of less than 25,000 RNA per milliliter. In Africa a consensus is building that the most logical time to initiate therapy is when CD4⁺ cells fall below 200, or when the patient has experienced an AIDS-defining illness. By this time, most patients have viral loads in excess of 50,000 RNA per milliliter. In early studies, disease-free one-year survival rates for patients given a three-drug combination with initiation below 200 CD4⁺ cells per cubic millimeter seem to be quite good (Djomand et al. 2003). Rigorous adherence to taking the drugs is essential to increase the time to development of drug-resistant variants. Many newer drugs and drug combinations reduce the difficulty of dosing because they are taken only once per day and have fewer gastrointestinal side effects.

Studies using several combinations of three drugs to treat AIDS patients have now been conducted in several African countries (Coetzee et al. 2004; Djomand et al. 2003; Laurent et al. 2002; Weidle et al. 2002; Wester et al. 2005). The results indicate a high degree of success. Despite the initiation of therapy at low levels of immune competence (for example, 10–200 CD4⁺ cells per cubic millimeter), responses have been good (Coetzee et al. 2004; Laurent et al. 2002; Weidle et al. 2002; Wester et al. 2005). These include survival rates of 85 percent or higher, and escalation of CD4 cell counts of 150 CD4⁺ cells per cubic millimeter or more by a year after drug initiation. Even patients who began drug therapy at cell counts below 50 CD4⁺ cells per cubic millimeter, most of whom would probably die within a year if left untreated, had surprisingly positive responses.

The positive responses occurred in part because most patients showed a strong commitment to adhere to the prescribed regimen of drugs. Although different viral subtypes may show different profiles of drug mutations (Quan et al. 2003; Turner et al. 2004), high levels of adherence reduced rates of clinical failure due to drug resistance (Coetzee et al. 2004; Laurent et al. 2002; Wester et al. 2005). It is too early to know whether HIV drug resistance will become a major problem in Africa. However, the widespread use of just one or two drugs in perinatal chemoprophylaxis clearly results in high levels of genotypic resistance in mothers who may soon need the same drugs for their own therapy. Whether such drug-resistant variants will be transmitted by sexual contact remains to be determined.

The cost of a basic three-drug regimen, such as AZT, 3TC, and NVP, is now as low as about US$1 per day. Although this is far below the original cost for the same drugs, it is still above a level that is possible for many in the poorest countries. The actual cost of treatment, including costs of health care personnel, infrastructure, and laboratory diagnosis and monitoring, is generally substantially higher than the cost of the drugs alone. Initiation on ARV therapy should be possible in many sites in Africa, but costs will also increase as patients become resistant to any of those drugs used in the "first-line" regimen. Switching to different regimens may require the use of protease inhibitors or other drugs that cost more, as do monitoring costs and the involvement of personnel with more specialized skills. The use of CD4 counts alone may be adequate for initiation, for example, but viral load tests and drug resistance tests may be necessary if drug failure occurs. The latter tests are more expensive, but they may be needed to validate the efficacy of second- or third-line drug regimens.

Conclusion

The epidemic of HIV/AIDS is unprecedented, having expanded from a new disease to the leading cause of death in Sub-Saharan Africa in just over two decades. Despite some clear examples of success, such as Senegal for prevention, and Uganda for control, major new measures are needed to avoid further devastation. The epidemic in Africa is uneven, with the greatest burden in southern Africa, where populations are already experiencing major reductions in life expectancy and a reversal of progress in the management of national economies.

About two-thirds of the world's HIV infections are in Sub-Saharan Africa in just 10 percent of the world's population. Because HIV/AIDS in the Americas and Europe is uncommon in women and rare in children, Africa holds more than 90 percent of the world's burden on such issues as child mortality and the care of orphans.

At present, prevention strategies are largely limited to education for changes in sexual practices and the use of condoms. Vaccines and microbicides represent an extremely important area of research, but useful products are not likely to be available in less than 5 to 10 years. ARV drug treatment programs have begun in Africa but are as yet very modest in impact. Operational research to maximize the benefits of ARV use will be important to address treatment efficacy and drug resistance, the impact on health manpower resources, and cost-effectiveness. The full devastation of AIDS in Africa has yet to be fully appreciated. Still, an increase in awareness and willingness to act should give cause for optimism.

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