VOICE trial underscores challenge of PrEP adherence

Issue: September 2015

The introduction of increasingly successful ART regimens over the past few decades has greatly reduced the impact of HIV, allowing those with the infection to live longer and maintain virologic suppression.

More recently, pre-emptive strategies such as pre-exposure prophylaxis (PrEP) now offer an additional approach to reducing transmission rates. Although these treatments have seen success in certain high-risk populations, recent data from the VOICE (Vaginal and Oral Interventions to Control the Epidemic) multisite trial appear to suggest that the next challenge in HIV may not be the disease itself, but the behavior of those at risk for infection.

“At first glance, the VOICE study appears to indicate that pre-exposure prophylaxis doesn’t work in women in Africa and that we should move on to explore other approaches to the prevention of HIV transmission in high-risk settings,” Michael S. Saag, MD, from the Center for AIDS Research at the University of Alabama at Birmingham, wrote in an editorial published in the New England Journal of Medicine. “On further review, the study indicates that much more work is needed, not so much in the realm of understanding the biologic basis of pre-exposure prophylaxis as a preventive treatment, but rather in the realm of understanding behavioral barriers in the setting of strong social stigma.”

Conducted by Jeanne M. Marrazzo, MD, MPH, professor of medicine at the University of Washington, and colleagues from the Microbicide Trials Network, the randomized, double blind, placebo-controlled VOICE trial assessed the efficacy of daily PrEP among 5,029 women from South Africa, Uganda and Zimbabwe. Three treatments were studied: oral tenofovir disoproxil fumarate (TDF), oral Truvada (tenofovir/emitricitabine, Gilead Sciences; TDF/FTC) and 1% vaginal tenofovir (TFV) gel. The researchers measured adherence through returned pills or applicators, self-reports, and drug levels in plasma.

Analysis revealed little or no HIV protection among all groups. The effectiveness of TFV gel was 14.5% (HR = 0.85; 95% CI, 0.61-1.21), while the effectiveness of TDF/FTC was –4.4% (HR = 1.04; 95% CI, 0.73-1.49) and TDF, –49% (HR = 1.49; 95% CI, 0.97-2.29).

These disappointing results may stem from the women’s poor adherence to their assigned regimens, according to researchers. Despite a 91% rate of retention, TFV plasma detection ranged from just 25% to 30% among a random subsample of participants who were not assigned placebo (n = 647).

“The big story was that adherence was just unbelievably low,” Marrazzo told Infectious Disease News. “There is a biological signal here, at least with tenofovir gel, but with the overall low levels of adherence we couldn’t really show it in a way that was as robust as we would have liked.”

Similarly, investigators for the FEM-PrEP trial found that prophylaxis with TDF/FTC did not significantly reduce the rate of HIV infection among women in Kenya, South Africa and Tanzania. The trial was stopped early in April 2011 due to a lack of efficacy, and drug adherence appeared to be low. In addition, the phase 3 FACTS 001 trial showed that PrEP adherence is a critical factor in its effectiveness.

In a follow-up study to VOICE, Marrazzo and colleagues reanalyzed the trial data while controlling for confounding factors such as adherence. Among those assigned vaginal TFV gel, they wrote, participants with detectable TFV had a reduced risk for HIV infection throughout the study period, results that imply that proper adherence could provide increased protection.

“Not only were the adherence rates incredibly low, they also were sadly differential by women’s risk,” Marrazzo said. “We found that the women who were most likely to be adherent were those characterized as being at the lowest risk for HIV.”

According to Marrazzo, women who were adherent were the most likely to be in stable relationships, employed, older and to have had more than one child — “all things to suggest a fairly stable, or at least relatively stable, kind of situation,” she said.

Women who did not adhere may have done so to avoid stigmatization among their peers, a concern that Marrazzo said requires more appreciation when planning HIV interventions. Furthermore, she said that when asked about adherence during follow-up interviews, a large portion of women admitted that their motivations to continue participation were free contraception and testing for STDs.

“We have to recognize why young women sought care and stayed in our study,” Marrazzo said. “They told us that they didn’t do it because they thought they were at risk of HIV … they wanted contraception and care.”

The CDC’s recent TDF2 open-label extension trial, however, has shown evidence of adherence to PrEP within a high-risk population — resulting in zero infections — most likely due to the fact that its participants understood the effectiveness of PrEP and had volunteered to receive it, according to study researcher Allan W. Taylor, MD, MPH, team lead for the clinical trials team in the CDC’s Division of HIV/AIDS Prevention.

“Our analysis found high adherence to daily PrEP among most men and women at high risk for HIV,” Taylor said in an interview with Infectious Disease News. “Subanalysis of women in the study showed that they were highly adherent to daily dosing. To us, this offers reassurance in the wake of the other recent studies we’ve seen — like VOICE, FEM PrEP and FACTS 001 — that showed that women hadn’t experienced protection against HIV because they weren’t taking PrEP as prescribed.”

In addition, evidence suggests that PrEP has been highly successful than among men who have sex with men in the United States.

Marrazzo said a run-in period or real-time drug monitoring in VOICE might have identified low rates of adherence earlier and prompted a shift in study design. One way or another, she said that clinical testing and prevention will need to overcome these obstacles to maximize the efficiency of large-scale trials and reduce the burden of HIV among these populations.

“We still don’t really have a highly acceptable and accessible prevention method for HIV in women,” Marrazzo said. “What we have in most of the world, where women are getting infected at those astronomical rates, are male condoms. That is just not a very negotiable option for many women.” – by Dave Muoio

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Disclosures: Marrazzo and Taylor report no relevant financial disclosures. Saag reports grant support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare.