Results Likely Due to Very Low Levels of Product Use With Young, Single Women Least Likely to Use Strategies
Three antiretroviral-based strategies intended to prevent HIV infection among women did not prove effective in a major clinical trial in Africa. For reasons that are unclear, a majority of study participants -- particularly young, single women -- were unable to use their assigned approaches daily as directed, according to findings presented today by one of the study's co-leaders at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta.
The Vaginal and Oral Interventions to Control the Epidemic (VOICE) study, or MTN 003, was designed to evaluate the safety and efficacy of three HIV prevention strategies compared to placebo. The trial tested an investigational vaginal gel containing the antiretroviral drug tenofovir, a pill form of tenofovir (brand name Viread), and a pill containing a combination of tenofovir and emtricitabine (brand name Truvada). The study was sponsored and largely funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
In the trial, the three strategies were tested among 5,029 sexually active women 18 to 45 years of age at 15 sites in South Africa, Uganda and Zimbabwe. Nearly half of the study participants were under the age of 25, and most were unmarried (79 percent). Participants in each of the three groups were counseled to use their assigned pill or gel once daily and received free condoms, ongoing counseling on how to reduce their HIV risk, and testing and treatment for sexually transmitted infections. Prior to enrollment, all potential study participants engaged in an oral and written consent process explaining the details of the study.
Study results presented today indicate that most VOICE participants did not adhere to the daily use schedule. Moreover, single women 25 years of age and younger were the least likely to use the investigational products and the most likely to become infected with HIV. The rate of new HIV infections among these young women was nearly 10 percent at some of the study sites in South Africa, reflecting a very high incidence of HIV infection among young women in these communities.
"We do not know why many participants in the VOICE study did not adhere to daily use of these HIV prevention strategies," said NIAID Director Anthony S. Fauci, M.D. "We must continue to conduct research to find additional HIV prevention tools that women will find acceptable and use consistently to protect themselves against infection."
In other HIV prevention studies involving different study populations, including men and women, both oral Truvada and oral tenofovir have demonstrated an ability to reduce the risk of HIV infection when used consistently. However, the VOICE study results are consistent with another clinical trial known as the FEM-PrEP study, which tested daily use of oral Truvada among a similar population of women. Like the VOICE study, researchers found that the majority of FEM-PrEP participants did not follow the daily regimen.
The VOICE study, which launched in 2009, was led by co-investigators Zvavahera Mike Chirenje, M.D., of the University of Zimbabwe in Harare, and Jeanne Marrazzo, M.D., M.P.H., from the University of Washington, Seattle. In fall 2011, oral tenofovir and tenofovir vaginal gel were dropped from the VOICE trial after separate routine reviews of the study data by an independent data and safety monitoring board determined that while each product was safe, neither was effective in preventing HIV compared with placebo. Researchers continued to evaluate oral Truvada until the study's scheduled conclusion in August 2012. Results presented today at the CROI meeting by Dr. Marazzo provided an analysis for each of the study's three product arms.
Of the 5,029 women who enrolled in the VOICE study, 312 became infected with HIV for an overall 5.7 percent rate of new HIV infections -- reflecting a very high overall rate of infection among women in these areas. Twenty-two women were found to be HIV-infected at time of enrollment; therefore, the study's primary analysis was based on 5,007 participants.
There was no statistically significant difference in the rate of new infections between women assigned to the three investigational products and women using placebo. Among the 994 women who were assigned to daily use of Truvada, 61 women became infected with HIV (4.7 percent rate of new infections) compared with 60 of 1,008 women who became infected in the oral placebo group (4.6 percent rate of new infections). Of the 1,002 participants in the daily oral tenofovir group, 60 women acquired HIV. However, the rate of new HIV infections was calculated to reflect what had occurred up until Oct. 3, 2011, when study sites began informing participants that testing of oral tenofovir would end. At this time, 52 women acquired HIV (6.3 percent rate of new infections) compared with 35 of 1,008 women who became infected in the placebo arm (4.2 percent rate of new infections). Of the 1,003 women assigned to use daily tenofovir gel, 61 became infected with HIV (5.9 percent rate of new infections), and 70 infections occurred among the 1,000 women in the placebo gel group (6.8 percent rate of new infections). Women who became infected with HIV during the VOICE study were referred to local sites for appropriate medical care and treatment.
During the course of the study, adherence to each of the three approaches was anticipated to be roughly 90 percent based on what study participants reported to clinic site staff and monthly counts of unused gel applicators and leftover study pills that were returned to the sites. However, in a blood sample analysis of 773 participants, including 185 participants who became HIV-infected, it became clear that adherence was low across each of the study's three investigational product groups. Drug was detected in the blood of 29 percent of the women in the Truvada group, 28 percent in the oral tenofovir group and 23 percent among those in the tenofovir gel group. When examining the data by age, young, single women were less likely to use their assigned treatment strategy. For example, among the women assigned to use oral Truvada, drug was detected in the blood of only 21 percent of young, single women compared to 54 percent of those married and over the age of 25.
"Based on our findings, it is clear that young, single women in Africa continue to be at very high risk for HIV infection and may need the greatest assistance with using prevention strategies consistently," said Dr. Marrazzo. Among VOICE study participants, the rate of new HIV infections was nearly 9 percent among unmarried women under the age of 25 compared to 0.8 percent for older married women, a statistically significant difference.
Through two ongoing behavioral studies involving VOICE participants, researchers are hoping to gain insight as to why the women did or did not use the investigational products. Results from those two studies are expected later this year.
NIAID funded the VOICE study with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, also part of the NIH. The trial was conducted by the NIH-funded Microbicide Trials Network (MTN). Gilead Sciences, Inc., of Foster City, Calif., donated the tenofovir and Truvada tablets. CONRAD of Arlington, Va., provided the tenofovir gel and applicators used to insert the product.
For more information about the VOICE study, see the MTN site.