CAPRISA 004 enrolled 889 HIV-uninfected women, ages 18–44 in KwaZulu-Natal, South Africa, who were randomized to pericoital use of 1% tenofovir gel or placebo, dosed by the BAT24 strategy (for Before and After sex, not to exceed Two doses in 24 hours). The event-driven timing was developed from dosing of nevirapine to HIV exposed infants for HIV prevention. In CAPRISA 004, tenofovir gel reduced the risk of HIV acquisition by 39% (HR 0.61; 95% CI 0.40–0.94 p=0.017) [15]. Notably, HIV incidence was 9.1 per 100 women-years in the placebo arm, an extraordinarily high rate. No significant viral resistance to tenofovir (i.e., the K65R mutation) was detected using population sequencing in viruses obtained from HIV seroconverters. In subgroup analyses, efficacy was 54% in women who reported >80% adherence to gel use with sex acts in the prior month (p=0.025). In a case-control analysis of cervicovaginal tenofovir levels, women with levels >1000ng/mL had a 74% lower risk of HIV infection than those with <1000 ng/mL [16], providing further evidence of an adherence-efficacy relationship. An unexpected ‘bonus’ finding in the study was a 51% reduction in HSV-2 incidence in the tenofovir arm,, which is consistent with in vitro work demonstrating mucosal concentrations achieved with 1% tenofovir gel have direct anti-herpetic activity [17]. Concentrations of tenofovir diphosphate in vaginal tissues are approximately 1000-fold higher with 1% tenofovir gel dosing compared to oral dosing using TDF, which likely explains the efficacy of topical dosing in spite of low systemic absorption [18].

The iPrEx study of 2499 HIV seronegative MSM and transgender women from the Americas, South Africa and Thailand into a placebo-controlled trial of daily oral FTC/TDF showed that FTC/TDF reduced HIV acquisition risk by 44% (95% CI 15–63). Subgroup analyses indicated higher efficacy (73%) among those with ≥90% adherence [19]. Importantly, plasma and intracellular drug levels demonstrated that only 8% of seroconverters and 54% non-seroconverters had detectable tenofovir or emtricitabine; having detectable drug was strongly associated with lower risk of HIV (OR 12.9, 95% CI 1.7–99.3). Resistance to emtricitabine (i.e., M184 I/V mutations) was detected in 2 participants randomized to FTC/TDF who were seroconverting at randomization; these resistance mutations were no longer detectable by ultrasensitive resistance testing six months after seroconversion and withdrawal of PrEP [20]. Safety was high with no substantial differences in the rate of serious adverse events, including laboratory events, by arm. A 1% reduction in bone mineral density was observed in the FTC/TDF arm, compared with placebo, with no difference in fracture rate [21]. No risk compensation was observed based on self-reported condom use during anal sex. Thus, iPrEx indicates excellent safety and moderate efficacy in the context of moderate adherence, as indicated by drug levels [22]. Rare resistance was detected -- among two subjects who initiated PrEP during acute seroconversion. Uptake, adherence, risk behaviors, and efficacy in the context of known efficacy of FTC/TDF PrEP is being studied among former iPrEx participants and a subset of new enrollees in a recently-initiated open-label extension study (iPrEx OLE).

The FEM-PrEP study enrolled 1951 high-risk HIV-uninfected women from Kenya, South Africa, and Tanzania into a placebo-controlled trial of daily oral FTC/TDF. The study was stopped by its Independent Data Monitoring Committee in April 2011 due to futility: an equal numbers of infections (n=28) were seen in the two study arms [23]. Potential explanations for the lack of efficacy include low adherence, which is being evaluated by drug levels, differential adherence by arm, and possibly tolerability or drug-drug interactions with hormonal contraception, given a higher pregnancy rate in the active FTC/TDF arm. Final analyses of the FEM-PrEP trial will be available in early 2012.

The TDF2 study enrolled 1200 heterosexual men and women between the ages of 18 and 40 in Botswana into a placebo-controlled trial of daily oral FTC/TDF; enrollment was terminated early due to larger-than-expected rates of loss-to-follow-up. The study reported results in July 2011: 62.6% efficacy (95% CI 21.5–83.4) for HIV protection due to PrEP. The trial was underpowered to demonstrate sex-based differences with 33 seroconversions, but the point estimates were protective for both men (80.1%, p=0.03) and women (49.4%, p=0.1). Safety and tolerability of FTC/TDF were high. There was no evidence of behavioral risk compensation.

The Partners PrEP Study (for which we are the lead investigators) is an ongoing 3 arm placebo-controlled trial of daily oral TDF and FTC/TDF among 4758 HIV serodiscordant couples from Kenya and Africa among whom the HIV-infected partner is not eligible for ART according to national guidelines; the HIV-uninfected partners are randomized to receive PrEP or placebo [24]. On July 10, 2011, the study’s Data Safety Monitoring Board recommended that the placebo arm be discontinued due to meeting pre-determined stopping guidelines for efficacy. Overall, 62% efficacy of TDF (95% CI 34–78) and 73% efficacy of FTC/TDF (95% CI 49–85) compared to placebo, were observed; the difference between TDF and FTC/TDF was not statistically significant (p=0.18). Both TDF and FTC/TDF significantly reduced HIV risk for both men and women [25]. Adherence to study drug was very high based on clinic-based pill counts of unreturned study medication, and in 3 sites, electronic monitoring and home visits for unannounced pill counts [26]. Drug concentrations and resistance testing in seroconverters is underway. Safety of both drugs was high and no evidence of risk compensation was observed.

The VOICE trial is a 5 arm study among 5028 HIV uninfected women from South Africa, Uganda, and Zimbabwe in which daily 1% tenofovir gel, daily oral TDF, and daily oral FTC/TDF are being evaluated for safety and effectiveness compared to respective gel/oral placebos. The Data Safety Monitoring Committee for the VOICE trial recommended discontinuation of the oral TDF arm in September 2011 due to inability to demonstrate efficacy. Specifics of the numbers of infections in that arm have not been released since the trial is ongoing, so as not comprise the integrity of the trial. The VOICE trial is anticipated to be completed by mid-2012, and will provide comparative efficacy of daily topical 1% tenofovir gel on HIV and HSV-2 acquisition, and daily oral FTC/TDF among at-risk African women.

The CAPRISA 004 trial demonstrates proof-of-concept that peri-coital use of tenofovir gel significantly reduced HIV risk in a very high incidence population. Adherence measures, including drug levels, indicate that high vaginal concentrations of tenofovir are achieved with vaginal dosing, and are associated with protection from HIV and likely account for the protective effect against HSV-2. The VOICE trial is anticipated to have critical efficacy data on daily 1% tenofovir gel for HIV and HSV-2 acquisition in 2012. The recently-launched FACTS 001 study is a confirmatory study of the peri-coital BAT24 strategy among a more diverse population of South African women than CAPRISA 004. VOICE and FACTS 001 will provide essential data on safety and effectiveness of 1% tenofovir gel in order to hopefully move an effective microbicide forward to licensure and wide-scale sue. Tenofovir gel has recently been reformulated for rectal application and will be evaluated for safety and pharmacokinetics among among MSM in a clinical trial initiating in 2012.

The iPrEx trial demonstrates that daily oral FTC/TDF has moderate efficacy (44%) among young, high-risk MSM who were recruited from diverse settings in the Americas, South Africa and Thailand. Importantly, efficacy appeared to be strongly associated with adherence. The iPrEx-OLE study will determine whether knowledge of efficacy of PrEP significantly increases adherence and alters risk behaviors among MSM – arguably, open-label studies like iPrEx OLE will determine whether PrEP is a viable public health strategy for MSM.

The Partners PrEP and TDF2 trials provide strong evidence for PrEP efficacy among African heterosexual populations, who make up the largest portion of the global epidemic. In Partners PrEP, both TDF and FTC/TDF were highly effective in both men and women. The study enrolled HIV serodiscordant couples who recognize their risk of HIV, and achieved high adherence to daily oral PrEP. HIV serodiscordant couples in Africa account for a substantial proportion of new HIV infections in Africa and ARV-based prevention, including PrEP targeted to the highest-risk couples before the HIV infected partner elects or is able to initiate ART, is an important prevention strategy to be piloted [28].

While awaiting findings from recently-completed and ongoing trials of oral and topical tenofovir-based PrEP in women and injection drug users, it is important to recognize the importance of these initial trials to demonstrating proof-of-concept of ARV-based primary HIV prevention. Much more needs to be understood about targeting of these strategies to those at highest risk in order to be a cost-effective intervention [29], evaluating program delivery models to reduce the risk of PrEP use in acute HIV infection, motivating and monitoring adherence to PrEP, and messaging about PrEP as part of a combined risk reduction strategy given its partial efficacy for HIV prevention. Longer-term safety, adherence, and efficacy needs to be assessed in the context of less frequent visits and briefer counseling than was provided in the intensive proof-of-concept trials.. Importantly, safety of these products needs to be studied in pregnant and breastfeeding women, and adolescent women, who are at high risk of HIV acquisition and need new prevention strategies.

Some persons would prefer to use PrEP intermittently, which requires greater understanding of the pharmacokinetics and adherence to intermittent dosing of tenofovir-based PrEP, as will be assessed in smaller studies being initiated in 2011–2. While macaque studies demonstrate biologic feasibility of intermittent oral PrEP dosing, human studies are needed to determine the extent to which individuals at high risk of HIV are able to anticipate sexual activity and achieve sufficient pre-exposure and post-exposure dosing to confer protection.