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HIV prevention trial halted What's the next step in clinical research?
FEM-PrEP study stopped Interim results indicate unlikely effectiveness
Investigators have discontinued the FEM-PrEP study of oral emtricitabine and tenofovir disoproxil fumarate (Truvada, Gilead Sciences, Foster City, CA) to prevent HIV infection in women in Africa after interim results indicated the research would be unlikely to prove effectiveness in the study population.
The study was a randomized, placebo-controlled, clinical trial of the effectiveness of daily, oral Truvada for HIV prevention among HIV-uninfected women in Kenya, South Africa, and Tanzania, lead by the Research Triangle Park, NC-based Family Health International (FHI). FEM-PrEP began in July 2009 with plans to enroll about 3,900 women; final results were anticipated in 2013. As of February 2011, the study had screened 3,752 women and enrolled 1,951: 739 in Bondo, Kenya; 764 in Pretoria, South Africa; 432 in Bloemfontein, South Africa; and 16 in Arusha, Tanzania. FEM-PrEP was funded by the U.S. Agency for International Development, with early support from the Bill & Melinda Gates Foundation.
As part of the final analysis, the study team will assess whether adherence to the study drug was sufficient to measure an effect of Truvada, says Timothy Mastro, MD, FACP, DTM&H, FHI vice president of health and development sciences. Adherence to study product is measured in three ways, says Mastro: participant self-report, on which FHI already has shared preliminary data; pill counts; and the presence of tenofovir and emtricitabine in blood samples. If adherence was low, then the study team will need to understand why women chose not to take their study pills, especially given the focus on participant-centered and goal-oriented adherence counseling, Mastro explains.
The study team also will attempt to analyze contraceptive hormone levels in blood specimens among Truvada users compared with placebo users, including hormone levels prior to pregnancy. In addition, the team will assess factors associated with pregnancy including use of study product, the use of other medications, contraceptive adherence, and adverse events, Mastro notes. All women in the trial were using effective contraception; 66% were using injectables, and 30% were using oral contraceptives.
Among women who were randomly assigned to the Truvada arm and used oral contraceptives, researchers report observed pregnancy rates were higher than among women randomly assigned to the placebo arm. This finding is unexpected and inconsistent with known drug interactions involving tenofovir and contraceptive hormones, and with known metabolic effects of emtricitabine, they note. Some possible explanations include differential pill adherence by group, previously undefined drug-drug interactions, chance, or a combination of factors.
"The sexual behaviors among trial participants will also be analyzed to determine if study participation resulted in risk compensation," Mastro states. "Risk compensation occurs when a participant increases risky behaviors because she feels the study pill will protect her from HIV."
Why didn't it work?
There are several possible reasons for the FEM-PrEP study findings, suggest FHI officials. These include including low adherence to study regimen, a true lack of effect of the product among women, or other factors still to be determined.
HIV prevention experts held much hope for the FEM-PrEP trial following release of the Pre-exposure Prophylaxis Initiative (iPrEx) trial. In that study, researchers found that among men who have sex with men who took Truvada, subjects experienced an average of 43.8% fewer HIV infections than those who received a placebo pill.1
The FEM-PrEP trial, despite its early closure, yet might provide useful scientific and behavioral insights, says Yasmin Halima, MPH, director of the Washington, DC-based Global Campaign for Microbicides. "Despite our excitement over the iPrEx results last year that showed that oral daily Truvada reduced HIV transmission in men who have sex with men, FEM-PrEP did not show conclusive proof that daily Truvada helps protect women from HIV," she notes.
Why is it important that research continue in prevention interventions? The huge level of new HIV infections that occur in women living in Sub-Saharan Africa underscores the urgent need for interventions that work in women, says Halima. "One in five women who screened for FEM-PrEP were not able to join the trial because they already came infected with HIV," she notes. "So it is imperative that we continue our search."
Look to more research
Scientists might be close to learning whether Truvada or another antiretroviral drug, tenofovir, helps to prevent HIV in women, says Halima. For example, in the VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial, scientists are looking at oral tenofovir and Truvada taken daily, as well as tenofovir 1% vaginal gel, says Halima. Such investigation will help researchers understand not only whether these interventions are effective in women, but also about women's preferences whether women like an oral pill versus topical microbicide, she notes.
VOICE is continuing to enroll participants in its study; more than 4,200 women have been enrolled to date. The study began in September 2009 and will involve about 5,000 women. Researchers expect to report results in early 2013.
Another ongoing trial, which is evaluating Truvada, as well as oral tenofovir, is the Partners PrEP study. This study includes men and women in Kenya and Uganda in serodiscordant relationships, in which one partner is HIV-infected and the other is not. The study has reached its target enrollment of 4,700 couples; study results are expected in early 2013. The Centers for Disease Control and Prevention is sponsoring a study in Thailand to assess the safety and efficacy of daily tenofovir to prevent parenteral HIV infection among injection drug users. That trial is continuing to enroll participants.
Prevention specialists are heartened by the results of the 2010 CAPRISA 004 clinical trial of tenofovir gel. In that study, the microbicide was found to be 39% effective in reducing a woman's risk of becoming infected with HIV during sex and 51% effective in preventing genital herpes infections in the women participating in the study.2 Results of that clinical trial represent the first "proof of concept" for a vaginal microbicide.
There are several novel antiretroviral-containing candidates in the pipeline, such as slow-release vaginal rings and long-acting agents, which might offer more options for women, says Halima. Research must continue, given the scope of the epidemic, says Halima.
"The Global Campaign for Microbicides continues to advocate for the development of new tools designed for women, particularly women who remain most vulnerable to HIV," she notes. "We as scientists, government, and advocates can't and won't stop until we collectively meet that challenge."