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Women's PrEP Study Halted due to Disappointing Findings

A trial of Truvada pre-exposure prophylaxis for women in Africa was discontinued this week after an interim review found that the study was unlikely to show a reduction in HIV infections.

Family Health International (FHI) announced on April 18 that it will wind down the FEM-PrEP trial of pre-exposure prophylaxis (PrEP) to prevent HIV infection among heterosexual women.

The study was testing a combination of tenofovir plus emtricitabine, the 2 antiretroviral drugs in Gilead's Truvada combination pill. Study participants were tested for HIV every 4 weeks and received risk reduction counseling and free condoms, which they were encouraged to use along with the study medication.

FHI and trial investigators decided to halt the study after a planned interim review by an independent data monitoring committee indicated it was "highly unlikely" that the study would be able to demonstrate statistically significant evidence of effectiveness in reducing new HIV infections. Participants have been asked to come for final study visits and those who became infected are receiving referrals for medical care.

Between May 2009 and February 18, 2011, the study screened 3752 women and enrolled 1951 participants in Kenya, South Africa, and Tanzania. The planned enrolment was 3900 and the study was scheduled to last through December 2012.

The most common reason for exclusion was existing HIV infection, with an overall prevalence of 21% in among women screened. Participants reported an average 3.7 acts of vaginal sex during the week prior to enrollment, which remained consistent during follow-up.

Women in the study were randomly assigned to take either Truvada or placebo every day. A total of 56 new HIV infections had occurred at the time of the interim analysis, according to FHI, an approximate rate of 5% per year. The same number of infections was seen among women assigned to take Truvada and those receiving placebo.

About 90% of the participants remained in the study and the self-reported Truvada adherence rate was about 95%, but this high rate may be exaggerated. Researchers will analyze blood samples to measure drug levels.

The pregnancy rate during the study was also surprisingly high, at 9%, even though women in the trial were supposed to be using effective contraception (66% injectable, 30% oral). Pregnancy was more common among Truvada recipients than in the control group, which was not expected based on known drug interactions with hormonal contraceptives or metabolic effects of tenofovir or emtricitabine.

Pending a final data analysis, FHI stated, "At this time, it cannot be determined whether or not Truvada works to prevent HIV infection in women." That is, it is too soon to declare that PrEP definitely does not protect heterosexual women against HIV.

These "surprising and disappointing" FEM-PrEP results come on the heels of the much-lauded iPrEx trial findings announced last fall, showing that Truvada reduced new HIV infections among gay/bisexual men and transgender women by 44% overall, and by 73% among participants who achieved the best adherence.

The U.S. Centers for Disease Control and Prevention issued a "Dear Colleague" letter cautioning against use of PrEP for women at this time, reinforcing the agency's earlier guidance emphasizing that the iPrEx findings only apply to high-risk men who have sex with men. "We will not know if PrEP is effective for women, couples, or injection drug users until the conclusive results of this and other trials are reported," according to the letter.

To date it is unclear why the FEM-PrEP and iPrEx findings were so divergent. One possible explanation is that oral tenofovir reaches a higher concentration in rectal tissue than it does in vaginal tissue. FHI intends to collaborate with researchers conducting other PrEP studies to compare findings in an effort to better understand the disparate results.

In the meantime, the latest findings give support to researchers and advocates who have urged caution in going forward with widespread PrEP implementation despite the enthusiasm generated by the iPrEx data.

4/23/11

Sources

Family Health International. FHI to Initiate Orderly Closure of FEM-PrEP. Press release. April 18, 2011.

K Fenton and J Mermin, Centers for Disease Control and Prevention. Results of FEM-PrEP Clinical Trial Examining Pre-Exposure Prophylaxis (PrEP) for HIV Prevention Among Heterosexual Women. CDC advisory. April 18, 2011.