CROI 2012 In stark contrast with the encouraging results from Partners PrEP—a clinical trial of Viread (tenofovir) and Truvada (tenofovir plus emtricitabine) pre-exposure prophylaxis in mixed-status heterosexual couples—a study focusing specifically on women at risk for HIV infection found no difference in infection rates between those using daily PrEP and those using placebo, according to results presented at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle.

Despite substantial counseling efforts in the study, Lut Van Damme, MD, PhD, of the Setshaba Research Center in Pretoria, South Africa, and her FEM-PrEP trial colleagues reported that inadequate adherence likely undermined the trial’s ability to fully assess the effectiveness of Truvada as PrEP in this particular population.

FEM-PrEP originally planned to enroll 4,000 women, before it was discontinued by its sponsor, Family Health International (FHI), in April 2011 because of efficacy concerns. According to Van Damme, 2,120 women residing in Kenya, Tanzania and South Africa were randomized to receive either daily Truvada or placebo before the trial was terminated.

Van Damme noted that the women enrolled in FEM-PrEP were considered to be at high risk for HIV infection. Roughly 60 percent of the women were younger than 25; about 12 percent reported having sex for gifts or money with non-primary partners; only half reported condom use; and 70 percent thought they had little or no perceived chance of contracting HIV.

Thirty-three of the 1,024 women in the Truvada group became infected with HIV during the study. Of the 1,032 women in the placebo group, 35 became infected. In other words, 4.7 percent of the Truvada-treated women and 5 percent of the women who received placebo were ultimately infected with the virus.

Van Damme and her colleagues estimated the overall effectiveness of Truvada in FEM-PrEP to be 6 percent, but this reduced risk was not statistically significant—it could have easily occurred by chance.

As for differences in safety, the researchers noted that nausea and vomiting were more frequent in the Truvada group. Mild-to-moderate increases in two liver enzymes (ALT and AST) were also more common in the Truvada group, though only the difference in ALT measurements was statistically significant. No differences in creatinine or phosphorous levels were seen between the two study groups.

Drug-resistance data were available for 35 women in the Truvada group and 40 women in the placebo group. Though no women in the study had HIV with the K65R mutation, which confers resistance to the tenofovir in Truvada (and Viread), three women in the active PrEP group and one woman in the placebo group developed resistance to the emtricitabine (and lamivudine).

Douglas Dieterich  

Lut Van Damme, MD, PhD, reviews results from FEM-PrEP at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle.
©Tim Horn Photos

 
Adherence Shortcomings

Similar to the other major PrEP studies—Partners PrEP as well as the iPrEx study in men who have sex with men and transgender women—rudimentary adherence measurements conducted by the FEM-PrEP researchers failed to hint at anything being remiss. According to Van Damme, 95 percent of the women said they took their pills as recommended in the study and an even greater number said they found the Truvada tablets or matching placebos to be easy to take. Pill counts suggested the adherence rate was 86 percent in the Truvada group and 89 percent in the placebo group.

Measurements of drug levels in study volunteers’ blood told a very different story. Though Van Damme and her colleagues were unable to measure drug levels precisely at the time the women were infected, they were able to look at samples collected during the visit before a subset of women were infected and during the visit at the time HIV was diagnosed.

In the women who became infected, roughly a quarter had blood levels of tenofovir at either visit, a finding that suggests most participants weren’t using the drug properly.

Results weren’t much better among women randomized to the Truvada group who didn’t become infected in the study. Roughly a third of these women had adequate levels of tenofovir in their blood during subsequent clinic visits.

FEM-PrEP vs. Partners PrEP

Biomedical prevention experts, including members of the Partners PrEP and FEM-PrEP study teams, are still attempting to make heads or tails of the different outcomes seen in both trials.

During a CROI press conference, held Monday, March 5, at the Washington State Convention Center, Partners PrEP investigator Jared Baeten, MD, noted one key difference: The women in Partners PrEP were in stable relationships and, thus, may have been encouraged by their HIV-positive male partners to adhere to treatment.

Baeten reiterated other major differences, including the facts that women in FEM-PrEP were younger than those enrolled in Partners PrEP and were more likely to have other sexually transmitted infections and that they largely considered themselves not to be at risk for HIV.

But it is adherence, Baeten said, that is the driver of PrEP efficacy and will ultimately need to be a major focus of follow-up studies and demonstration projects going forward.