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Final results of FEM-PrEP HIV-prevention study indicate great attention to adherence will be required in PrEP programs

July 11, 2012

RESEARCH TRIANGLE PARK, NC — Results of the FHI 360 FEM-PrEP HIV-prevention trial reinforce the key role of adherence in HIV-prevention studies and the need to determine better approaches to support adherence in future pre-exposure prophylaxis (PrEP) programs. Despite targeted counseling and support, adherence to the drug regimen was low, suggesting that women in the clinical trial population may have had difficulty adhering to a daily pill regimen. Because of low adherence, FEM-PrEP was unable to determine whether the study drug could reduce the risk of HIV infection, according to the final, primary analysis of study data published online July 11 in the New England Journal of Medicine (NEJM).

The FEM-PrEP clinical trial was designed to assess whether HIV-negative women, who are at higher risk of being exposed to HIV, can safely use a daily dose of the antiretroviral (ARV) pill Truvada® to help prevent HIV infection. Truvada, which contains the ARVs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), is approved for treatment of HIV in combination with other ARVs. The study was funded by the United States Agency for International Development (USAID), with early funding from the Bill & Melinda Gates Foundation. Gilead Sciences, Inc. provided the study pills.

The FEM-PrEP trial included 2,120 women randomly assigned to take Truvada or a placebo. Thirty-three HIV infections occurred in the Truvada arm and 35 in the placebo arm. Blood plasma drug concentration testing revealed that only 35-37% of uninfected Truvada recipients, who were matched to the infection window of participants who seroconverted, had evidence of recent drug use. Five HIV infections were FTC-resistant, including one in a participant randomized to placebo; no infections were TDF resistant. Truvada use was safe and well tolerated in the study, with higher rates of some side effects in women assigned to Truvada. These events were modest and consistent with known side effects of Truvada.

“Results from FEM-PrEP are important since they demonstrate clearly that achieving good adherence will be a key factor in successful PrEP strategies,” said Lut Van Damme, M.D., FEM-PrEP principal investigator. “We do not know why women in the trial population were not adherent to the daily drug regimen, and we would like to continue working with the trial communities to explore more.”

Results from other clinical trials have suggested the Truvada can provide a significant prevention benefit when used as PrEP. In November 2010, researchers from the iPrEx clinical trial showed that taking once-daily Truvada led to a 44 percent reduced risk of becoming infected with HIV-1 in the clinical trial population, in this case, men who have sex with men. iPrEx provided the first proof-of-concept that oral PrEP could prevent HIV infection. Overall, relatively low adherence levels were also observed in the iPrEx trial’s case-control analysis. Yet evidence of benefit was found. This might indicate that Truvada is more forgiving of imperfect use for rectal rather than vaginal exposure to HIV, possibly due to differential concentration of the active drug in rectal compared to vaginal tissues.

Two other studies from Africa published online July 11 in the NEJM demonstrate that taking ARVs can reduce the risk of sexually-acquired HIV infection in serodiscordant, heterosexual couples (Partners PrEP) and in HIV-negative heterosexual men and women (TDF2). Based on the iPrEX and Partner’s PrEP study results, an advisory committee recently recommended that the U.S. Food and Drug Administration (FDA) approve HIV prevention as an indication for the use of Truvada for men who have sex with men, serodiscordant couples and other high-risk populations. A decision by the FDA is expected by mid-September 2012.

Researchers from another major PrEP trial, VOICE (Vaginal and Oral Interventions to Control the Epidemic), recently announced the closing of two study arms because of lack of efficacy: oral tenofovir tablets (September 2011) and tenofovir vaginal gel (November 2011). An additional arm of the study testing daily, oral Truvada (as in FEM-PrEP) continues. Results of VOICE are expected in 2013. Final results about why these two interventions, already proven to prevent HIV infection, did not show efficacy in VOICE are not known at this time, but it is possible that low adherence played a role.

“From blood samples taken during monthly clinic visits, we found that less than 40 percent of a representative sample of HIV-negative participants had recently taken their study pills,” said Tim Mastro, M.D., an FHI 360 co-author of the FEM-PrEP paper. “Because of this low adherence, the study was unable to detect if Truvada use could prevent HIV infection in this group of African women. We studied a population at very high risk of HIV infection and in great need of better prevention methods.”

“We are currently investigating why women would come to the study clinic each month, have their blood samples taken but wouldn’t take their study pills,” said Amy Corneli, Ph.D., co-principal investigator on FEM-PrEP. “The rate of pregnancy among women who were taking daily oral contraceptives was high, suggesting that this population may have difficulty with a daily pill regimen. Interviews conducted during the trial suggest that many participants thought that their risk of becoming infected with HIV was low, which may be one reason that they did not regularly take their study pills. FEM-PrEP reinforces our need for greater comprehension of how to optimize adherence to ARV-based HIV-prevention methods.”