Microbicides Finally Gel

You need not look further than the headlines today for the biggest news to emerge from the International AIDS Conference in Vienna. For the first time, a microbicide candidate was shown to reduce the risk of sexual transmission of HIV in women. The candidate, a 1% gel formulation of the antiretroviral tenofovir, reduced the risk of HIV infection by 39% in a South African trial known as CAPRISA 004, which involved 889 women.

"These groundbreaking results mean a lot to me personally," said Gita Ramjee, a microbicide researcher, at the opening of the special session in Vienna at which the CAPRISA 004 results were presented (a day after the embargo on the results was broken, allowing media organizations to report the findings). "Today we celebrate the proof of concept of microbicides."

And a celebration it was. The presentations on the gel's protective effect against HIV transmission, as well as infection with herpes simplex virus (HSV)-2, were greeted with multiple standing ovations from the conference delegates gathered to hear the results. "For a scientific finding to receive three standing ovations is a first," says Ward Cates, president of research at Family Health International, one of several organizations involved in the trial. "This is a remarkable finding."

The trial evaluated coitally dependent use of the microbicide in a dosing regimen called BAT24. Volunteers were instructed to insert the applicator containing gel within 12 hours before sex and as soon as possible but within 12 hours after sex, not to exceed more than two doses in a 24-hour period.

Perhaps the most significant part of these findings, pun intended, was that at every time-point after 12 months, researchers observed a statistically significant difference in the number of HIV infections that occurred between tenofovir gel and placebo recipients. This was a refreshing change for those familiar with the debates that ensued after the findings from the RV144 vaccine trial in Thailand were initially reported. "There was a certain feeling of ease and pleasure in looking at data that no matter how you slice it were statistically significant," says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases.

Sheen McCormack of the microbicide trials network said that while the RV144 results produced "a warm glow" in the HIV vaccine field, the CAPRISA 004 results produced "a hot flash" in the microbicide field, which was previously beleaguered with a series of negative outcomes from clinical trials evaluating non-specific compounds.

At 12 months, the tenofovir gel was found to reduce the risk of HIV infection by 50% (p value of 0.007). From one year on, the efficacy of the microbicide candidate decreased until the end of the 30-month trial when there was a 39% lower HIV incidence among tenofovir gel recipients.

Quarraisha Abdool Karim, who headed the study along with her husband Salim Abdool Karim, attributed the diminishing efficacy to less use of the gel over time. This will be an important issue. The effectiveness of any microbicide is obviously dependent on adherence. In this trial, women who were classified as "high adherers", those who used the gel more than 80% of the time, there was a statistically significant 54% lower HIV incidence rate compared to women who applied the placebo gel just as often. However, if use of the gel dropped off over time, even in the setting of a clinical trial during which women received monthly counselling on gel use, it may not bode well for consistent use of such products outside of a clinical trial setting.

But Salim Abdool Karim suggests that the opposite may be true. He thinks that if a microbicide is eventually licensed and women know that it offers protection, adherence may actually be even higher than in a clinical trial, during which they are repeatedly told that the gel may not work and that they may not even be receiving the experimental candidate.

Researchers emphasized that confirmatory trials will be necessary before a tenofovir-based gel will be licensed for public use. The VOICE study, which is already underway, is evaluating the efficacy of daily use of a tenofovir gel microbicide, in addition to oral administration of both tenofovir and Truvada (a combination of tenofovir and emtricitabine or FTC).

But in the meantime, there is a palpable sense of excitement in the HIV prevention field today. "The implications of this are really enormous," says Fauci.

Full coverage of the CAPRISA results will be available on soon and in the next issue.