Tenofovir is an antiretroviral drug that works by preventing HIV from growing inside human cells and, taken in pill form, tenofovir is a common component of various three-drug cocktails that are used to treat HIV infections. In 2006, Gilead Sciences granted a co-exclusive, royalty-free license to CONRAD and the International Partnership for Microbicides to develop tenofovir into a vaginal gel that could be used by women in developing countries to prevent HIV.
CONRAD researchers conducted a number of preclinical and safety trials to develop a gel that would be safe to test in women. In 2010, researchers at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) completed a study (CAPRISA 004) of 889 women who inserted tenofovir gel in their vaginas before and after sex, and found that it was 39% effective in reducing a woman’s risk of becoming infected with HIV and 51% effective in preventing genital herpes infections. The CAPRISA researchers found that the protective effect against HIV increased as use of tenofovir gel increased: women who used the gel in more than 80% of their sex acts had a 54% reduction in HIV infections, whereas those who used the gel in less than half of their sex acts had a 28% reduction in HIV infections. Research has shown that women with genital herpes are more likely to become infected with HIV, so the additional protection against genital herpes infection creates a second mechanism whereby the gel may have an even bigger impact in preventing HIV.
Daily use of tenofovir gel for HIV prevention in women was studied by the Microbicide Trials Network in the VOICE study, along with daily use of oral antiretrovirals. Adherence in all arms of the study was too low to confirm effectiveness. Final results were published in the New England Journal of Medicine.
The FACTS 001 trial, which tested whether tenofovir gel could replicate the results of the CAPRISA 004 trial, was completed last year and results were announced on February 24th, 2015 at the CROI conference in Seattle. Disappointingly, the study did not confirm pericoital TFV gel effectiveness. Overall, out of 2059 enrolled participants, a total of 123 HIV infections occurred, with 61 in the TFV arm and 62 in the placebo group (Rees et al., 2015). Under intent-to-treat analysis, this was a very clear result showing no difference in HIV incidence rates between the arms. Participants used the gel during an average of 50-60% of sex acts per month, based on returned applicators and self-reported number of sex acts, with 13% of the participants using gel during greater than 80% of sex acts. A case-cohort analysis of 214 participants in the TFV-treated group showed that detection of TFV in genital fluids was significantly associated with a 52% reduction in HIV acquisition. In the same analysis, women who did not use the gel at all (no drug detected in genital samples) were significantly more likely to become infected. Therefore, the gel only showed a protective effect when used consistently and covered most of the sex acts, but most women in this trial were unable to use it in this manner. While the gel appeared to be acceptable and easy to apply, for most of this population of young, unmarried women, the majority of whom still live with their parents, using the gel consistently proved to be very challenging.
Future development of TFV gel is currently under consideration. Method choice is the best approach to increase population uptake and coverage, and, although clearly not for every woman, the gel might still be a preferred method for women who are willing and able to use it consistently. HSV-2 data from FACTS 001 will be analyzed to see if these results support previous findings from CAPRISA 004 and VOICE showing protection against genital herpes primary infection. Additionally, the Microbicide Trials Network continues to evaluate a reduced glycerin formulation of TFV gel for rectal use in men who have sex with men and in transgender women, and CAPRISA 008, an open-label study which provided gel to uninfected women from CAPRISA 004, has begun exiting participants and will provide valuable data on implementation and adherence.