RESEARCH TRIANGLE PARK, NC — Results announced today by the two clinical trial teams, Partners PrEP and TDF2, provide the first evidence that HIV infection among heterosexuals can be prevented by taking an oral, once-daily tablet. Pre-exposure prophylaxis (PrEP) is an HIV-prevention strategy in which HIV-negative people take an antiretroviral drug, commonly used to treat HIV, on a daily basis to reduce their risk of acquiring HIV.

Researchers at the University of Washington announced today that its Partners PrEP trial demonstrated effectiveness in preventing heterosexual HIV transmission among men and women in Kenya and Uganda. In a second announcement today, the U.S. Centers for Disease Control and Prevention (CDC) revealed that its TDF2 trial also demonstrated effectiveness in preventing heterosexual HIV transmission among men and women in Botswana.

FHI 360 congratulates the Partners PrEP and TDF2 teams and study volunteers for their landmark contributions to HIV prevention research.

The Partners PrEP Trial

Partners PrEP trial participants were HIV-discordant, heterosexual couples where one person was HIV-infected and the partner was HIV-negative. In some couples, the man was HIV-infected, while in some the woman was HIV-infected. The trial had three arms; the HIV-negative person was randomized to either a placebo, a daily, oral dose of tenofovir disoproxil fumarate (TDF, 300 mg; Viread®) or a daily, oral dose of Truvada®, which contains a combination of the antiretroviral drugs TDF (300 mg) and emtricitabine (FTC, 200 mg) in a single pill. TDF and TDF/FTC have been proven safe and effective as a treatment by preventing HIV from reproducing itself in individuals who are already infected with the virus. The study findings indicate that both TDF alone and TDF/FTC were effective in preventing HIV infection and that both men and women were protected.

The TDF2 Trial

In TDF2, study participants were given either a placebo or a daily, oral dose of Truvada, one of the same drugs used in the Partners PrEP trial. Overall, Truvada was found to be effective at preventing HIV infection in the TDF2 study population. The size of the TDF2 trial was not large enough, however, to determine conclusively the levels of HIV protection afforded to men and women separately.

These two results provide exciting and strong evidence that a strategy including daily, oral PrEP can prevent HIV infections in persons at risk of heterosexual infection. PrEP with Truvada was already proven effective among men who have sex with men in the iPrEx trial reported in late 2010.

The FEM-PrEP Trial

FHI 360 is closing its PrEP trial, FEM-PrEP, which is a Phase III, randomized, placebo-controlled clinical trial designed to assess the safety and effectiveness of a daily oral dose of Truvada (TDF/FTC) for HIV prevention among women in sub-Saharan Africa.

Following a scheduled interim review of the FEM-PrEP study data in April 2011, the trial's Independent Data Monitoring Committee (IDMC) advised that the FEM-PrEP study will be highly unlikely to demonstrate Truvada's effectiveness in preventing HIV infection in the study population, even if it continued to its originally planned conclusion. FHI subsequently concurred and initiated an orderly closure of the study over the subsequent few months.

When screening and enrollment stopped on April 18, 2011, a total of 4,054 women had been screened for the FEM-PrEP trial, and 2,119 had been enrolled. As of May 25, 2011, 602 had completed their follow-up and study exit visits. As of that date, there were a total of 66 incident HIV infections, still balanced between the two arms—those assigned to Truvada and those assigned to placebo. The total number of HIV infections will likely increase between now and the end of the study.

We previously reported that as of February 18, 2011, a total of 56 new HIV infections had occurred; an equal number of infections occurred in participants assigned to Truvada and those assigned to a placebo pill. In addition, observed pregnancy rates among study participants randomly assigned to the Truvada arm were higher than among the women randomly assigned to the placebo arm. This is unexpected and inconsistent with known drug interactions involving tenofovir and contraceptive hormones and with known metabolic effects of emtricitabine. The use of Truvada was associated with some known side effects, none of which were considered serious.

Possible Explanations for Preliminary FEM-PrEP Findings; Continued FEM-PrEP Analyses

Possible explanations for the preliminary HIV infection outcome of the trial include low adherence to the study pill, study pill sharing between the participants in the Truvada and placebo groups, biological factors, chance or a combination of factors. FHI 360 is conducting additional analyses to help understand the potential reasons for the interim findings. These analyses include a close examination of adherence through several mechanisms among women in the trial, including an assessment of antiretroviral drug levels in the blood, in-depth-interviews, pill counts and monthly structured interviews. Also, HIV strains from women who became infected during the trial are being examined for evidence of antiretroviral drug resistance.

Next Steps

Closing of the FEM-PrEP trial was initiated in April 2011 and is expected to be complete for the HIV-negative participants by August 2011. Follow up of women who became HIV-infected during the trial will continue for another year as per protocol.

As the trial is still ongoing, data analyses from FEM-PrEP are not yet complete. Ongoing data cleaning will be completed by the end of October 2011. Confirmation of all HIV infections, resistance testing and tenofovir and emtricitabine drug level testing will be conducted during August–December 2011, contingent upon receipt of the necessary approvals in each country for export of specimens. The primary statistical analysis will be conducted in November 2011. Publication of the main findings, along with dissemination of final results to site communities, is expected between late 2011 and early 2012. Secondary analyses and associated paper writing will occur in late 2011 and 2012. Follow-up of participants who seroconverted during the trial will be completed in August 2012, per protocol.

Comparison with Partners PrEP and TDF2

In light of the Partners PrEP and TDF2 results, there is a need to explore why FEM-PrEP and the other trials had different findings. In addition to possible differences in adherence to the study pills, it is possible that there may have been important differences in the study populations related to sexual activity, other sexually transmitted infections or levels of inflammation that can affect HIV susceptibility. FHI 360 will be working with scientists from the University of Washington and CDC to compare data from the three studies to better understand differences and similarities.

Continued Hope

The HIV epidemic continues to ravage many communities in the world. While we work to understand better why the outcome differed among participants in the Partners PrEP and TDF2 trials vs. the FEM-PrEP trial, the results of both Partners PrEP and TDF2 provide evidence that PrEP can play an important role in HIV prevention among heterosexuals.