when used in conjunction with behavioural counselling, condom use and other methods of prevention (5). A large prospective, randomized controlled clinical trial (6) dramatically fortified the evidence for this approach. Among more than 1700 heterosexual couples in which one partner was living with HIV and the other was not, starting combination antiretroviral therapy immediately in the partner living with HIV – when blood tests indicated his or her immune system was still strong – resulted in a 96% reduction in HIV transmission to the uninfected partner relative to deferring treatment until the same tests showed the immune system to be weaker.
Various test-and-treat strategies are being pursued in various populations, and several strategies are being evaluated to achieve effective uptake and sustained delivery of the complete HIV testing, linkage, treatment and retention platform. These strategies include approaches to increase demand for HIV testing and new ways to improve adherence, including mobile phone–based reminders.
At least three randomized clinical trials (one study enrolling men who have sex with men and two heterosexual couples) have suggested that oral pre-exposure prophylaxis (in which
an individual at higher risk for HIV infection takes one or two antiretroviral drugs daily) may be effective, substantially reducing seroconversion.
In the iPrEx study, which enrolled 2500 men who have sex with men, the group taking pre-exposure prophylaxis had 44% fewer HIV seroconversions than the placebo group; the efficacy more than doubled among men with detectable study drugs in their blood (7). In the TDF2 study conducted in partnership between the United States Centers for Disease Control and Prevention and Botswana’s Ministry of Health, 1200 HIV-negative men and women in Botswana were randomized to take oral pre-exposure prophylaxis or placebo daily. Pre-exposure prophylaxis reduced the risk of acquiring HIV infection by 63%. The risk reduction was even greater (78%) among individuals believed to be taking the study drugs (8).
In the Partners PrEP Study, the uninfected partners in nearly 5000 HIV-serodiscordant heterosexual couples in Kenya and Uganda were randomized to take two-drug pre- exposure prophylaxis, one-drug pre-exposure prophylaxis or placebo. Relative to placebo, two-drug pre-exposure prophylaxis was associated with a 75% reduction in risk of acquiring HIV infection, and one-drug pre- exposure prophylaxis was associated with a 67% reduction in risk (9). The protective effects were similar for both men and women. Significantly, the study found no evidence of
“Treatment as prevention
has the potential to
dramatically reduce HIV
incidence and to be
10 20 30 40 50 60 70 80 90 100 0
STUDY EFFECT SIzE
(95% confidence interval)
Antiretroviral therapy in an HIV-positive partner
HPTN 052/Africa, Asia, Americas 96% (73–99)
Pre-exposure prophylaxis (oral emtricitabine/tenofovir; tenofovir) for heterosexual discordant couples Partners PrEP/Uganda, Kenya
75% (55–87)
67% (44–81)
Pre-exposure prophylaxis (oral emtricitabine/tenofovir; tenofovir) for heterosexual men and women TDF2/Botswana
63% (22–83)
Pre-exposure prophylaxis (oral emtricitabine/tenofovir; tenofovir) for men who have sex with men IPrEX/Americas, Thailand, South Africa
44% (15–63)
Microbicide (1% tenofovir vaginal gel)
CAPRISA 004/South Africa 39% (6–60)
HIV vaccine
RV144/Thailand 31% (1–51)
Selected HIV prevention technologies shown to be effective in reducing HIV transmission in randomized controlled trials
increased risky sexual behaviour in any of the three study arms. In two additional studies, however, pre-exposure prophylaxis showed no benefit in protecting heterosexual women from infection (10,11), perhaps because of poor adherence and/or dosing regimens that did not result in sufficient levels of drug at the vaginal mucosa (11–14).
Many questions about pre-exposure prophylaxis remain, especially its cost and safety and the danger of complacency with safer sex practices. Nevertheless, we anticipate that pre-exposure prophylaxis will prove useful and cost-effective as a targeted HIV prevention for certain individuals.
Topical gels and vaginal rings containing antiretroviral drugs also have shown promise as HIV prevention tools that could be applied to the vagina or rectum before sexual intercourse to block HIV infection. The CAPRISA 004 study demonstrated that using 1% tenofovir intravaginal gel before and after sexual intercourse was 39% more effective in preventing HIV infection than a placebo gel
(15). Subsequently, a second study found no advantage to the daily use of a tenofovir-gel based microbicide over placebo gel (16,17), perhaps because of lower adherence and suboptimal drug levels in vaginal tissues with the daily dosing regimen (12,14). A vaginal ring containing the antiretroviral drug dalpivirine was
safe and well tolerated in a study of African women and is scheduled to move into expanded safety and efficacy studies in 2012 (18).
On the horizon
Over the past two years, an accelerated research effort has been directed towards determining the exact mechanisms of HIV persistence and developing interventions to eliminate or permanently suppress HIV. The effects of a cure would be significant for an individual, obviating the need for lifelong daily therapy, and for society, reducing treatment costs and HIV transmissions (19).
Compelling evidence from animal studies and data from a large randomized clinical trial in Thailand have shown that an HIV vaccine is possible (20–22). These studies provided important leads to the types of immune responses that may contribute to a vaccine’s protective effect, and this information can help to guide efforts to develop improved vaccines. Other data, such as identifying and structurally characterizing epitopes on the HIV envelope recognized by antibodies that can neutralize a broad range of HIV strains, are providing researchers with a way to design new components for next-generation vaccine candidates (23).
Anthony S. Fauci is the Director of the National Institute of Allergy and Infectious Diseases at the United States National Institutes of Health. Elly Katabira is the President of the International AIDS Society.