Disappointing end to an important study shows PrEP may not work in women

In the latest twist on the biomedical prevention roller-coaster, a trial testing Pre-Exposure Prophylaxis (PrEP) in women has ended early because it failed to show positive results. That is bad news. It is also surprising news given the same intervention seems to have worked with men who have sex with men. Why the FEM-PrEP Project did not show positive outcomes is not yet known. Adherence to the drug seems to have been high, but we do not yet know how adherence was measured. Too many biomedical prevention trials have relied on self-report adherence, making negative results difficult to interpret. It is also possible that the different HIV transmission dynamics of vaginal and anal intercourse account for the findings. In addition, risk reduction counseling, condoms, and repeated testing that all women received may have reduced the study's statistical power. We will have to wait for more information.

One thing is clear. The behavioral implications of PrEP remain as important as ever. Behavioral and social scientists working in AIDS should pay close attention to what we hear next and consider how 30 years of behavioral research may help move biomedical prevention technologies along. The Press Release is reproduced below.

FHI to Initiate Orderly Closure of FEM-PrEP

April 18, 2011

Following a scheduled interim review of the FEM-PrEP study data, the Independent Data Monitoring Committee (IDMC) advised that the FEM-PrEP study will be highly unlikely to be able to demonstrate the effectiveness of Truvada [emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] in preventing HIV infection in the study population, even if it continued to its originally planned conclusion.

FHI subsequently concurred and has therefore decided to initiate an orderly closure of the study over the next few months. The final analyses have not yet been conducted. At this time, it cannot be determined whether or not Truvada works to prevent HIV infection in women.

The FEM-PrEP clinical trial—implemented by FHI in partnership with research centers in Africa—is designed to study whether HIVnegative women who are at higher risk of being exposed to HIV can safely use a daily dose of a pill called Truvada to prevent infection.

This study was funded by the United States Agency for International Development (USAID), with early funding from the Bill & Melinda Gates Foundation.

The FEM-PrEP outcome is surprising and disappointing, given a number of earlier studies suggesting the promise of pre-exposure prophylaxis (PrEP) using antiretrovirals. Most recently, the iPrEX study showed that use of Truvada can prevent infection in men who have sex with men at risk of HIV.

There are a number of possible reasons for the study findings, including low adherence to study regimen, a true lack of effect of the product among women (versus men who have sex with men), or other factors still to be determined. FHI will be conducting further analyses and will share additional findings in the coming months. The IDMC commended the trial team on a study conducted to a high standard with good follow-up and careful attention to good clinical practice and ethical standards.

Only preliminary FEM-PrEP data are available at this time:

• As of February 18, 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. The most common reason for women not being enrolled was existing HIV infection.
• The overall HIV prevalence was 21 percent among women screened for enrollment across the sites.
• Preliminary data indicate about 90 percent of the participants were retained in the study.
• Adherence to study product was approximately 95 percent when the study product was available for use.
• Women reported an average of 3.7 vaginal sex acts in the 7 days prior to enrollment, consistent with the average of 3.6 acts reported during follow-up.
• As of February 18, the approximate rate of new HIV infections among trial participants was 5 percent per year. A total of 56 new HIV infections had occurred, with an equal number of infections in those participants assigned to Truvada and those assigned to a placebo pill.
• Women participating in FEM-PrEP used an effective method of contraception at the time of enrollment—66 percent were using injectables and 30 percent were using oral contraceptives. The overall pregnancy rate was 9 percent; the highest pregnancy rates were among women using oral contraceptives.
• The use of Truvada in FEM-PrEP was associated with some known side effects that were not serious.

Among study participants randomly assigned to the Truvada arm, observed pregnancy rates were higher than among women randomly assigned to the placebo arm. This is unexpected and inconsistent with known drug interactions involving tenofovir (TDF) and contraceptive hormones, and with known metabolic effects of emtricitabine (FTC). Possible explanations include differential pill adherence by group, previously undefined drug-drug interactions, chance, or a combination of factors (including yet unknown factors). FHI will conduct further analyses of these data.

FHI and its partners are especially grateful to the women whose willingness to participate and commitment to the study were essential. To the extent possible, all participants have been notified of the decision and are being asked to come to the study clinics for final visits. Study participants who became infected with HIV during the study are being followed by the study team for an additional year and are referred for appropriate medical care and treatment in their community.

When the follow-up of the HIV-uninfected women is complete in a few months' time, FHI will be conducting in-depth analyses of study data and blood specimens collected during the study to examine the factors contributing to the observed outcomes. FHI will also collaborate with scientists conducting other PrEP studies to compare

findings and to better understand the results.

When available, the final results from FEM-PrEP will make a strong contribution to our understanding of the use of antiretrovirals for HIV prevention. FHI, USAID, and research partners in Africa are committed to finding new technologies and developing new strategies to protect women from HIV.