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Tenofovir gel was associated with a 39% lower risk of HIV acquisition overall, and a 54% reduction among women who achieved the best adherence. "We now have evidence that a vaginal gel can help prevent HIV," said Global Campaign for Microbicides director Yasmin Halima. "This is good news for women, good news for the field, and a good day for science."

CAPRISA 004 is the first trial to evaluate an antiretroviral microbicide in humans, following disappointing results using products that did not contain active HIV-fighting agents. Tenofovir is the nucleotide reverse transcriptase inhibitor (NRTI) in the Viread pill, and also in the Truvada (tenofovir/emtricitabine) and Atripla (tenofovir/emtricitabine/efavirenz) fixed-dose coformulations.

The Phase 2b trial enrolled 889 women at 2 CAPRISA (Centre for the AIDS Programme of Research in South Africa) sites -- 1 urban and 1 rural -- in KwaZulu-Natal. The study ran from May 2007 through March 2010. Background HIV incidence in these areas is estimated at about 16% and 11%, respectively.

Participants were aged 18 to 40 years and not pregnant at study entry; all were initially HIV negative but sexually active (vaginal sex at least twice in the prior 30 days) and considered at high risk for infection. Women with untreated sexually transmitted infections (STIs), genital ulcers, or reduced creatinine clearance (a potential sign of impaired kidney function) were excluded.

The women were randomly assigned (1:1) to use either 1% tenofovir gel or inert placebo gel, inserted into the vagina within 12 hours before and 12 hours after sex (but no more than twice in a 24-hour period). Both gels looked the same and were dispensed in pre-filled applicators with identical packaging. All participants also received regular HIV risk-reduction counseling, condoms, and treatment of other STIs.

Follow-up continued for an average of 18 months. HIV serostatus, safety, gel and condom use, and sexual behavior were assessed at monthly follow-up visits for 30 months. Participants underwent quarterly pelvic exams and colposcopies if needed. Researchers also collected data on all health complications, genital adverse events, and systemic toxicities.

Results

• A total of 38 new HIV infections occurred in the tenofovir gel arm and 60 in the placebo gel arm.
• HIV incidence rates were 5.6 per 100 person-years in the tenofovir arm, compared with 9.1 per 100 person-years in the placebo arm, a statistically significant difference (incidence rate ratio 0.61; P = 0.017).
• Tenofovir gel reduced the likelihood of HIV acquisition by an estimated 39% overall.
• Adherence to gel use was estimated to be about 72% of all sex acts.
• Among women with good (> 80%) adherence, HIV incidence was 54% lower in the tenofovir arm compared with the placebo arm (P = 0.025)
• Among women with intermediate (50%-80%) adherence, HIV incidence in the tenofovir arm was 38% lower.
• Among those who only managed poor adherence adherers (< 50%), the reduction in HIV incidence in the tenofovir arm was 28%.
• Use of tenofovir gel was also associated with about a 50% reduction in the risk of herpes simplex virus type 2 (HSV-2, the usual cause of genital herpes).
• Tenofovir gel was generally well-tolerated.
• Most women (about 94%) experienced some adverse events, but these were usually mild to moderate and not considered study drug-related.
• There was no overall increase in rates of adverse events (including kidney toxicity, a possible side effect of tenofovir) in the tenofovir compared with the placebo arm.
• Among the small number of participants who did become HIV infected, there were no observed changes in viral load or evidence of tenofovir resistance.
• More than 97% of study participants found the gel to be acceptable and said they would use it if it prevented HIV.

Based on these findings, the investigators concluded, "Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use."

"The protective effect of coitally-related tenofovir gel use was evident soon after initiation and peaked at 50% after 12 months of gel use," they elaborated in their discussion. "This protective effect is evident irrespective of sexual behavior, condom use, herpes simplex type 2 virus infection or urban/rural differences."

"Tenofovir gel has a potential dual effect in preventing HIV," CAPRISA director Salim Abdool Karim explained in a press release issued by CONRAD. "Since women with genital herpes are much more likely to become infected with HIV, the additional protection of tenofovir gel against herpes creates a second mechanism whereby the gel may have a bigger impact in preventing HIV."

Importantly, CAPRISA was designed to look at the feasibility of tenofovir gel as a microbicide candidate, but was not powered to rigorously evaluate its effectiveness. Given these promising findings, the gel is now expected to move into larger Phase 3 efficacy trials.

Reaction to the News

Word of the findings -- which were released Monday evening in Vienna (as well as in Johannesburg and Washington, DC) prior to the scheduled Tuesday conference session -- drew responses from a wide range of health and public policy agencies.

"We are giving hope to women," said UNAIDS executive director Michel Sidibe. "For the first time we have seen results for a woman initiated and controlled HIV prevention option...If confirmed, a microbicide will be a powerful option for the prevention revolution and help us break the trajectory of the AIDS epidemic."

"For years, antiretroviral medicines have been effectively used to treat HIV infection," said U.S. National Institutes of Allergy and Infectious Diseases director Anthony Fauci. "Through the successful conduct of the CAPRISA 004 study, we now have proof that an antiretroviral drug, in this case tenofovir, can be formulated into a vaginal gel that can protect women against HIV infection."

"The results of the CAPRISA trial provide new hope and direction for not only HIV prevention, but also broader efforts under the Global Health Initiative," said U.S. Global AIDS Coordinator Eric Goosby. "We recognize that microbicides will be a great asset to HIV prevention efforts, and the U.S. government is pleased to support this important research."

"This study has established proof of concept that a vaginal microbicide containing an [antiretroviral] can protect women from HIV," said Sharon Hillier, principal investigator with the Microbicide Trials Network. "For all of us in the HIV prevention field, this result has shown that it may be possible to leverage this initial success using a single [antiretroviral] at the time of sex into more potent approaches that could be 50, 60 or even 70% effective for prevention of HIV."

MTN is currently conducting a related trial called VOICE (Vaginal and Oral Interventions to Control the Epidemic) tested tenofovir gel used daily rather than only at the time of sex.

Investigator affiliations: Centre for the AIDS Program of Research in South Africa (CAPRISA), Durban, South Africa; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; University of KwaZulu-Natal, Durban, South Africa; National Institute for Communicable Diseases, Johannesburg, South Africa; FHI, North Carolina.

CAPRISA 004 was conducted by a consortium that included CONRAD and FHI, with funding provided by the U.S. Agency for International Development and the South African Department of Science and Technology. Gilead Sciences provided tenofovir to be used in the gel; the company has licensed the drug to CONRAD and the International Partnership for Microbicides to develop and distribute as a preventive microbicide in low-income countries.

For more information about the CAPRISA 004 trial, see www.global-campaign.org/CAPRISA004.htm.

7/20/10

Reference

Q Abdool Karim, SS Abdool Karim, JA Frohlich, and others. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science (Abstract). July 19, 2010 (Epub ahead of print).

Other Sources

CONRAD. Study of microbicide gel shows reduced risk of HIV and herpes infections in women. Press release. July 19, 2010.

Global Campaign for Microbicides. CAPRISA 004 trial shows moderate protection against transmission of virus. Press release. July 19, 2010.

Microbicide Trials Network. Results of CAPRISA 004 a turning point for HIV prevention, say MTN researchers conducting VOICE tenofovir gel used before and after sex reduced HIV by 39 percent, raises bar for VOICE Study testing daily gel use and ARVs for preventing HIV in women. Press release. July 19, 2010.

NIAID. Statement of Anthony S. Fauci, M.D., on the results from the CAPRISA 004 microbicide study. Press release. July 19, 2010.

World Health Organization and UNAIDS. WHO and UNAIDS welcome ground breaking proof of concept study results for vaginal gel showing reduced risk of HIV infections in women. Press release. July 19, 2010.