In this review, we describe the epidemiology of the HIV/AIDS epidemic, both chronologically and by HIV transmission route, and highlight prevention interventions and other factors potentially affecting transmission and spread. We first discuss recognition of the epidemic, discovery of HIV transmission routes, and initial prevention efforts during the early to mid-1980s. We then examine how the epidemic and prevention approaches evolved during the pre-antiretroviral therapy (ART) era, and conclude by describing the current epidemic and prospects for control. In an earlier publication, we have discussed the broader implications of the world's three decades of experience with HIV/AIDS .
A medical mystery
What became known as AIDS was first described in a report published on 5 June 1981. Gottlieb and colleagues reported five young, previously healthy, homosexual men treated for Pneumocystis carinii (now Pneumocystis jiroveci) pneumonia (PCP) in three Los Angeles hospitals . Those tested had evidence of T-lymphocyte depletion, and two had died. Over the following months, additional cases of PCP, other opportunistic infections, and Kaposi's sarcoma among MSM were reported from several US cities. Although the cause of the immunodeficiency was unknown, cases in sex partners  along with the results of a national case–control study  strongly suggested a sexually transmitted infection.
By January 1983, the major transmission routes of the still unidentified ‘AIDS agent’ had been described. Heterosexual transmission was indicated by reports of similar immunodeficiency in female sex partners of men with AIDS in New York . Unexplained immunodeficiency and opportunistic infections in infants born to mothers with AIDS-related illnesses pointed to mother-to-child transmission . Several lines of evidence indicated transmission through blood and blood products, including cases in injection drug users (IDUs) and persons with hemophilia. Moreover, the development of the disease in an infant in San Francisco following receipt of a platelet transfusion from a donor with subsequent PCP was reported [7–9]. Later cases in healthcare workers (HCWs) with occupational exposure to blood were also consistent with blood-borne transmission .
By February 1983, the Centers for Disease Control (CDC) had received reports of 1000 persons with AIDS in the United States; mortality had been 39% . Almost all were MSM, IDUs, persons with hemophilia, or, perplexingly, recent immigrants from Haiti with undetermined risk factors. Seventy-two percent of affected MSM were non-Hispanic whites; in contrast, about three-quarters of affected IDUs were blacks or Hispanics. The report of the first thousand cases concluded that trends suggested ‘gradual extension of an infectious agent into new populations’.
Although HIV had not yet been identified, the US Public Health Service issued the first recommendations for AIDS prevention in March 1983 . The report noted that having multiple sex partners increased the risk of AIDS and recommended that members of groups at increased risk refrain from donating plasma and/or blood. Later that year, the causative agent was identified , and in 1985, antibody testing became available ; this test enabled further prevention measures such as deferral of seropositive persons from plasma and blood donation and heat treatment of clotting factor preparations to inactivate the virus. Guidelines were issued for HCWs to avoid occupational exposure to blood and for IDUs to avoid sharing needles and other injection equipment. Infected mothers were advised to consider delaying pregnancy until more was known about the risk to the infant .
Little was known at that time about HIV/AIDS outside of the United States. After AIDS had been diagnosed in Haitians recently entering the United States, cases were described in Haiti. Although initial reports of these cases suggested male bisexual activity and blood transfusion as important risk factors , follow-up studies indicated heterosexual transmission as the predominant mode of spread . Elsewhere, member countries of the WHO European Region had reported 267 cases through October 1983 , including cases among Africans seeking care . Initial studies in Africa revealed large numbers of cases in heterosexual patients in central African cities such as Kinshasa, Zaire (now the Democratic Republic of Congo), and Kigali, Rwanda [20,21].
Although HIV transmission routes had been established, some feared transmission through insect bites or ‘casual’ contact with infected persons. These fears persisted until studies from south Florida found no correlation between HIV infection and mosquito exposure  and studies from the Bronx, New York, found no casual transmission between AIDS patients and their family members .
An evolving epidemic
Over the next decade, perceptions of HIV/AIDS evolved from a medical quandary primarily affecting MSM in the United States to a pandemic of uncertain magnitude threatening diverse populations around the world. The pandemic was not one phenomenon but a patchwork of epidemics moving through different groups and countries at different times. They were characterized by waves of unapparent HIV infections followed by visible epidemics of disease and death. Peak HIV prevalence was useful as an indicator to compare the severity of epidemics between locations and over time .
Molecular epidemiologic studies have provided insights into the origin and broad geographic transmission patterns of HIV-1 . The virus is thought to have entered human populations in the early twentieth century through cross-species transmission of related chimpanzee retroviruses found in western equatorial Africa [26,27]. By the early 1980s, multiple genetic subtypes of HIV-1 were present in Kinshasa, Zaire . Examination of genetic sequences of HIV-1 recovered from early Haitian patients suggested spread of HIV-1 infection from Africa to Haiti in the 1960s and later introduction to the United States , although multiple introductions were likely.
By the mid-1990s, more than 20 million persons were estimated to be living with HIV/AIDS, the vast majority in sub-Saharan Africa . Largely reflecting the African epidemic, sexual transmission accounted for at least three quarters of all new infections, most in heterosexuals. Overall, women accounted for about 40% of infected adults. With exceptions of sub-Saharan Africa and Haiti, however, fears of a ‘generalized,’ self-sustaining, heterosexual epidemic throughout the world did not materialize. In retrospect, lack of generalized heterosexual spread in the large populations of Asia was one of the most important observations for understanding global HIV/AIDS epidemiology . In the United States, MSM continued to account for the majority of cases . Male-to-male transmission also predominated in western Europe, particularly in northern countries, in Australia and New Zealand, and in parts of Latin America [30,33]. The HIV/AIDS burden in western Europe, however, was also heavily affected by immigration from Africa, whereas southern Europe had relatively more IDU-associated HIV/AIDS.
Using a back-calculation method, Brookmeyer  reconstructed the AIDS epidemic in the United States and concluded that HIV incidence in MSM had peaked in the mid-1980s and then rapidly decreased. Substantial behavioral change among MSM contributed to early incidence declines [35,36], but high mortality among men most likely to transmit HIV must also have played a role. Further, the falling incidence predated substantial government funding for HIV prevention and likely reflected prevention efforts within the MSM community itself. Prevention guidelines for MSM emphasized the need for HIV testing, informing partners of infection status, and safe sex practices .
Early efforts to assess the burden of disease in Africa and elsewhere were based on reporting of AIDS cases to WHO using clinical case definitions . Despite incomplete diagnosis and reporting, these efforts usefully documented the occurrence of AIDS in specific countries and extension globally. Once serologic testing for HIV became available, the extent of HIV spread along with its risk factors and modes of transmission were studied systematically. Sentinel surveillance for HIV infection was initiated in pregnant women, who by definition were sexually active, relatively representative of the general population, and comparable between locations. This approach has remained an important basis for estimating HIV incidence and prevalence throughout the world [38,39], although such estimates have remained controversial [40–42]. But, despite providing important insights into populations at risk and epidemic trends [43,44], the practice of unlinked anonymous testing, especially the inclusion of pregnant women, has been questioned .
Silent spread of HIV from Central Africa began in the late 1970s, and by the early-to-mid 1980s, when AIDS was becoming apparent in Kenya, the majority of female sex workers in Nairobi were already infected [46,47]. Although ascertainment and reporting biases may affect our understanding, spread to countries of western Africa occurred later in the 1980s [48,49], with extension to southern Africa most intense from the 1990s onward. Studies in urban centers across the continent showed especially high rates of HIV infection in female sex workers and other persons with high numbers of partners [46,47,50].
In the African epidemic, genital ulcer disease, particularly chancroid, was a strong co-factor for HIV infection [51,52]. Other, nonulcerative, infections such as gonorrhea also appeared to increase transmissibility by increasing HIV shedding . As chancroid became less common in many locations, herpes simplex type 2 (HSV-2) emerged as the predominant cause of genital ulcer disease associated with HIV . Ecologic studies also demonstrated that African countries with low male circumcision rates (southern and, to a lesser extent, eastern Africa) generally had high HIV infection rates and vice versa (highly circumcised west African populations were less heavily infected with HIV) . These studies and analytic observations [51,52] provided evidence that lack of circumcision increased the risk for males acquiring HIV infection and prompted later research that culminated in intervention trials and subsequent programmatic implementation.
An additional complexity in the African epidemic was a second AIDS virus, HIV-2, first reported from west Africa in 1986 . Like HIV-1, this virus is thought to have entered human populations through cross-species transmission: a highly related retrovirus is present in sooty mangabeys in this geographic area [26,27]. HIV-2 is transmitted through sexual contact and blood, but very rarely from mother to child . Although the virus causes AIDS, it has a slower rate of disease progression than HIV-1 [58–60] and is overall less transmissible .
Initial prevention efforts in sub-Saharan Africa concentrated on limiting heterosexual transmission through the ‘ABC’ strategy: abstain, be faithful, and use condoms, a message communicated in culturally meaningful or colorful phrases such as ‘zero grazing’ and ‘condomize’ (, this issue). The fall in HIV prevalence in childbearing women in Uganda during the early 1990s has been attributed to this approach, although this interpretation is controversial [63,64]. But, as in the United States, massive numbers of deaths of potential HIV transmitters must have influenced epidemiology. A more clear-cut prevention success was Thailand's ‘100% condom campaign’, which targeted female sex workers and their clients [31,65,66]. Another early, oft-cited ‘prevention success’ occurred in Senegal, where HIV/AIDS never spread widely . Senegal was exemplary in its openness and political commitment. However, the predominance of HIV-2, concentration of HIV-1 in high-risk groups, universal nature of male circumcision, and traditional and religious cultures in the country may have been more powerful factors than specific HIV prevention campaigns.
In the late 1980s, studies in the former Zaire showed a 21% risk of HIV transmission from an infected mother to her infant in the perinatal period . Prolonged breast feeding, the norm in sub-Saharan Africa for cultural and socio-economic reasons, increased transmission by an additional 14% , resulting in an overall transmission risk of 30–45% . These breastfeeding findings caused difficult policy choices between advocating replacement feeding, associated with the risk of malnutrition, diarrhea, and respiratory disease, and continued breastfeeding, which increased the risk of HIV infection [69–71]. Not until the advent of interventions based on antiretroviral therapy (ART) could this conundrum begin to be addressed [72–74], (, this issue).
The global epidemic evolved somewhat differently in IDUs than in MSM. Most affected were IDUs in southern Europe, parts of south and south-east Asia, and countries of the former Soviet Union. For example, HIV prevalence among IDUs living in one Ukrainian city rose from less than 2% to more than 50% in less than a year . The US Institute of Medicine concluded that treating drug dependence, including the use of opioid agonist medications, was the preferred risk reduction approach for IDUs. However, the provision of clean injecting equipment was an effective intervention when treatment was not available or accessible . Unfortunately, the use of funds from the US government, the largest funder of HIV/AIDS programs globally, was prohibited for needle and syringe exchange.
Whereas donor deferral and HIV screening of blood almost eliminated transfusion-acquired HIV in industrialized countries, the risk remained in many developing countries. Contributing factors included lack of infrastructure for blood collection, storage, and HIV testing; use of paid or family members as donors; lack of high-risk donor exclusion; high rates of unnecessary transfusions; and increased transfusion needs by pregnant women and children because of malarial anemia [77,78]. Nonetheless, through WHO and donor leadership in prioritizing national blood transfusion services, numerous HIV infections were averted each year in sub-Saharan Africa . Further, the consensus belief that any transmission of HIV by blood transfusion was unacceptable helped prioritize prevention of this mode of transmission.
Additional studies in health care settings showed that the risk of infection in HCWs exposed percutaneously to HIV-infected blood, most often through a needle stick, was approximately 0.3%. This risk was shown to be reduced by about 80% with the use of zidovudine as postexposure prophylaxis . Another transmission risk in healthcare settings was reported in a CDC investigation of an HIV-infected dentist in Florida who transmitted the infection to five of his patients . Although the specific route of transmission could not be determined, subsequent guidelines established procedures for restricting the practices of infected HCWs who performed certain invasive procedures . Extensive HIV transmission occurred in the late 1980s among abandoned Romanian children living in chronic care hospitals and orphanages; only 10% of mothers of infected children were themselves HIV-infected and most children were thought to have contracted HIV from injections with contaminated needles and syringes or blood transfusions [83,84]. An outbreak of nosocomial infection was also documented in Benghazi, Libya, affecting almost 400 children . Despite the occurrence of such tragic events, they were not major contributors to pandemic spread .
A number of outbreaks of HIV infection have been recognized among blood or plasma donors in whom attention to sterility of equipment and to overall blood safety was inadequate. The most devastating experience was in China where up to 250 000 predominantly rural villagers across five provinces may have been infected with HIV through the commercial blood trade in the early 1990s [87,88]. Commercial blood and plasma donation was extensive in this region and hygienic practices were inadequate, such as pooling of cell fractions and return to donors after plasma separation. Although these practices were corrected in the mid-1990s, high rates of disease and death were documented a decade later [87,88].
A defining event, 15 years after AIDS was first described, were reports at the International Conference on AIDS in Vancouver in 1996 of lowering of viral load and delayed progression of HIV disease in persons taking combination ART . The advent of effective therapy for HIV disease meant that AIDS case surveillance no longer gave unbiased insight into earlier trends in HIV transmission but henceforth was influenced by late diagnosis, inadequate access to care, failure of adherence to medications, or drug resistance. In response, CDC shifted emphasis onto the reporting of HIV diagnoses for surveillance purposes .
Now and the future
Three decades after the first description of AIDS, an estimated 34.0 million (uncertainty range 31.6–35.2 million) people were living with HIV, 2.7 million (uncertainty range 2.4–2.9 million) had become newly infected with HIV over the previous year, including 390 000 children, and 1.8 million (uncertainty range 1.6–1.9 million) HIV-infected persons died . More than two-thirds of HIV infections, roughly 22.9 million persons, were in sub-Saharan Africa, which also accounted for close to 80% of women and 90% of children living with HIV. South and south-east Asia were home to some 4.0 million HIV-infected persons, and the Americas, including the Caribbean, to about 3.0 million. Although HIV/AIDS has caused appalling mortality in MSM and IDUs, the experience of sub-Saharan Africa has made HIV/AIDS the greatest challenge to global health in modern times. Moreover, there has been a severe secondary epidemic of HIV-associated tuberculosis, with an estimated 350 000 deaths among the 1 100 000 persons affected by both infections in 2010 .
In stark contrast to early observations from central Africa, southern Africa is now firmly established as the global HIV/AIDS epicenter: nine countries in southern Africa account for less than 2% of the world's population, but represent about one-third of global HIV infections and almost half of the world's HIV-associated tuberculosis. Lack of male circumcision and high rates of HSV-2 infection are frequently cited factors associated with high HIV prevalence . The suggested role of concurrent sex partners  and putative viral subtype-specific differences in transmissibility is controversial. Urbanization and population movement along with the sociopolitical changes that have occurred over the past two decades have also likely contributed to the southern African epidemic.
Globally, HIV incidence probably peaked around 1997 . In many countries such as the United States, however, incidence has remained relatively stable for over a decade , and without additional prevention efforts, the burden of HIV/AIDS continues. Determinants of current and future HIV/AIDS epidemiology include the natural history of regional and local epidemics themselves, social and behavioral trends, and the effects of public health and medical interventions. To what extent HIV/AIDS epidemiology in Africa could have been mitigated by early emphasis on proven public health measures and focus on groups at highest risk, especially sex workers and their clients, remains for discussion [94,95].
As we enter the fourth decade of the pandemic, biomedical approaches to prevention are emerging as more promising than current mass communication and behavioral interventions. Randomized clinical trials have provided strong evidence for the use of antiretroviral drugs, both as treatment and as preexposure prophylaxis, for preventing sexual transmission of HIV ([62,75], this issue). In particular, the high prevention impact of treatment among discordant couples in the HPTN 052 study , combined with ecologic evidence  and results of mathematical modeling , suggest that early and widespread initiation of ART in people with HIV could substantially reduce sexual transmission in generalized HIV epidemics in sub-Saharan Africa, as well as the incidence of HIV-associated tuberculosis . Randomized clinical trial data from sub-Saharan Africa also provided strong evidence that male circumcision partially prevents female-to-male sexual transmission [100–102], and led to policy guidance . Despite tremendous progress  and huge prevention potential [105,106], the extent to which these interventions can be brought to scale remains uncertain , as does their current population-level impact. For example, even in the United States, only 28% of HIV-infected persons are estimated to be on treatment and have suppressed viral loads .
Prevention of mother-to-child transmission has seen a step-wise introduction of evidence-based interventions, with impressive impact in industrialized countries (, this issue). In the United States, for example, near-universal testing of pregnant women, provision of appropriate antiretroviral treatment or prophylaxis, and avoidance of breastfeeding by HIV-infected mothers have virtually eliminated new pediatric HIV infections . The concern that the findings of the ACTG 076 study , which showed the benefits of zidovudine monotherapy, could not be implemented in Africa led to the search for simpler regimens. The HIVNET 012 study , which used single-dose nevirapine, was initially greeted with enthusiasm because of the simplicity, low cost, and relatively high efficacy of the regimen (about 50%). Unfortunately, challenges to program adherence, transmission through breastfeeding, and recognition that monotherapy was a risk factor for later drug resistance all became apparent, and single-dose nevirapine is now considered a suboptimal approach.
The most important intervention for preventing mother-to-child transmission of HIV is to identify and treat pregnant women who need ART for their own health, currently defined as those with CD4+ cell counts less than 350 cells/μl . Discussion continues about approaches that could replace WHO's complex current recommendations for pregnant women and infants , but a pragmatic approach being considered by some countries (e.g., Malawi) would be to provide immediate and lifelong combination ART for all HIV-infected pregnant women irrespective of CD4+ cell count.
United Nations Agencies have set a goal of reducing new pediatric HIV infections from the 2009 baseline of approximately 400 000 infections to less than 40 000 infections by 2015, a 90% reduction . Currently, available interventions can lower mother-to-child transmission rates in breastfeeding populations to less than 5%, and success will require much more aggressive uptake of HIV testing and provision of ART. Linkage of these interventions to other efforts to improve maternal and child health, including safe delivery in health facilities, will be essential, especially in Africa.
Globally, about 3 million IDUs are estimated to be infected with HIV, and drug injection accounts for almost one-third of HIV incidence outside of sub-Saharan Africa. The greatest number of HIV-infected IDUs resides in eastern Europe and south-east Asia , where their access to services is limited because of stigma, discrimination, and the definition of drug dependence as a law enforcement rather than public health issue. Along with HIV, IDUs suffer high rates of hepatitis B and C infections as well as tuberculosis, and can be an important source of sexual transmission of HIV. Experience in other parts of the world where HIV has been successfully controlled in IDUs illustrates that currently available interventions can be effective . Ecologic evidence also suggests that expansion of ART among HIV-infected drug injectors has a prevention benefit .
Perhaps the greatest challenge is among MSM, in whom there is little evidence of sustained prevention success . HIV has become endemic in MSM populations in the industrialized world; annual HIV incidence rates around 2–3% are common, as are prevalence rates of 10–30%. In the United States, HIV incidence in young MSM, especially young black MSM, continues to increase . In a venue-based study in 21 American cities, 24% of black MSM aged 20–29 years were HIV-positive; most were unaware of their infection .
While largely overlooked earlier in the epidemic, recent studies have documented populations of MSM in low- and middle-income countries, including in Africa . When HIV epidemiology is studied in these groups, high rates of infection are invariably found, typically higher than those in the general population. Using the Incidence by Mode of Transmission Model, UNAIDS and The World Bank have estimated that MSM may account for 7.5%–14% of all new HIV infections in Nigeria, for example . Studies in these countries often document extreme stigma, discrimination, and human rights abuses toward people who practice same-sex behavior – factors preventing openness and active HIV prevention. Even in more tolerant societies, however, such as in western Europe, prevention efforts are generally failing to reduce HIV incidence in men.
Although heterosexual transmission remains the dominant mode of spread worldwide, we have witnessed encouraging trends in Africa's generalized epidemics [120,121], evidence of efficacy of biomedical interventions (especially ART-based prevention and male circumcision) , and successful prevention program scale-up . ART-based prevention approaches have the potential to reduce all modes of transmission (, this issue). Cautious optimism is justified when this reality and the tools available are contrasted to the history of the pre-ART era. However, continued funding, intensified program implementation, massive scale-up of HIV testing, surveillance, and appropriate intervention and implementation science are critical to success.
Much more can be done to prevent and treat HIV infection in IDUs and sex workers, whose needs remain neglected and for whom targeted services can substantially reduce HIV transmission. Mother-to-child transmission of HIV is largely preventable, trends are encouraging, and the world's attention is now focused on this problem. Although continued efforts are needed to improve blood safety  and reduce healthcare-associated infections, blood transfusion and medical injections are not major modes of HIV transmission. Strikingly, HIV among MSM, the issue that first brought AIDS to attention, remains largely refractory to current interventions in all countries of the world. Because of treatment advances, HIV prevention may seem less important to MSM in high-income settings today than in earlier decades. In low-income and middle-income countries, however, HIV/AIDS in MSM is just beginning to be addressed. Without changes in attitudes of society as a whole and greater behavioral change by MSM themselves, HIV will remain highly endemic throughout the global community of MSM for the foreseeable future.
Collectively, we are at a pivotal moment in the HIV/AIDS epidemic. We now have the tools to change the course of the global epidemic. Whether we have the resources and political will to use those tools remains to be determined. It will be for future generations to judge whether we did all that we could.
Conflicts of interest
There are no conflicts of interest.
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