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HIV breakthrough: Trial results offer promise
The search for a female-controlled form of HIV prevention just took a giant step. Results of a Phase IIB trial of a tenofovir gel indicate that use of the gel before and after sex provided moderate protection against sexually transmitted HIV.1
The study, known as CAPRISA 004, was conducted to establish whether the vaginal use of a gel containing tenofovir, an antiretroviral drug, is safe and whether it can prevent male-to-female sexual transmission of HIV. Results of the study, announced at the July 2010 XVIII International AIDS Conference in Vienna, Austria, indicate that use of the vaginal gel reduced a woman's chance of becoming infected with HIV during sex by 39% compared with a control group that used a placebo gel.1
The study also showed that the gel was effective in preventing transmission of genital herpes simplex virus (HSV-2). The women using the tenofovir gel had 51% fewer cases of HSV-2 infection than the control group.1
The CAPRISA 004 trial was conducted by a team of South African and American researchers headquartered at the Centre for AIDS Programme of Research in South Africa (CAPRISA) at the University of KwaZulu Natal in Durban. Funds were provided by the United States Agency for International Development (USAID) and South Africa's Technology Innovation Agency, with product supplied by CONRAD in Arlington, VA, and collaborating support from Family Health International (FHI) in Research Triangle Park, NC. Principal investigators for the study were Salim Abdool Karim, MD, MPH, and Quarraisha Abdool Karim, PhD, director and associate director of CAPRISA and both professors of clinical epidemiology at the Mailman School of Public Health at Columbia University in New York City.
The results of the CAPRISA 004 trial were an HIV prevention "first" in many ways, says Willard Cates Jr., MD, MPH, director of research at FHI. The trial represents the first microbicide proof-of-concept, the first antiretroviral-based pre-exposure regimen, and the first vaginal gel effective for women, says Cates. In addition, the research represents the first in-country investigator-led trial, supported by U.S. technical expertise; the first study jointly funded by the United States and South Africa; and the first to secure voluntary product license for Africa upfront, Cates notes.
Look at the science
The CAPRISA 004 study was designed as a two-group, double-blind, randomized, controlled trial to assess the safety and effectiveness of 1% tenofovir gel in 889 sexually active HIV-uninfected urban and rural women at risk for HIV infection in South Africa. After undergoing the informed-consent process, each participant was randomly assigned to one of the two study groups: tenofovir gel or placebo. All women were provided with a supply of single-use, pre-filled gel applicators and were counseled to apply a first dose of the assigned study product within 12 hours prior to sexual intercourse and to insert a second dose as soon as possible within 12 hours after sex. Women were counseled to use no more than two doses of gel in a 24-hour period. Participants in both gel groups also received condoms, extensive risk-reduction counseling, and treatment of symptomatic sexually transmitted infections.
After 12 months, researchers found 50% fewer instances of HIV infection among women who used the gel compared with the placebo group. After two and a half years, there were 39% fewer cases among those using the tenofovir gel. The degree of protection was proportional to the degree to which the women complied with the instructions. Women who reported using the gel more than 80% of the time they engaged in sexual relations had a 54% reduction in HIV infection, whereas those who used the gel less than half the time had a 28% reduction.2
More research needed
While the results of the CAPRISA 004 trial are encouraging, more research is needed. The trial was designed as a proof-of-concept study; a larger Phase III trial would provide more conclusive data regarding the gel's potential effectiveness for preventing the sexual transmission of HIV.
"We need studies now to be done in other settings, in other countries in Africa, to see if they can also find this protective effect, so that we know that the effect is much more broadly present and not unique to just one setting," says Salim Abdool Karim, MD, MPH, one of the study's principal investigators.
If adequate confirmatory data becomes available through additional studies, the CAPRISA 004 consortium of investigators would then work with manufacturers and sponsors to gain regulatory approval of the product by relevant drug regulatory authorities.
The results of CAPRISA 004 can be considered a "game changer" in HIV prevention research, says Cates. Since the trial established proof-of-concept for a topical antiretroviral regimen, used intermittently, the finding might throw many in the HIV-prevention field into a spin, Cates observes. Some scientists had questioned whether a topical microbicide would ever be effective in preventing HIV acquisition, notes Cates. Now their thinking may be changed.
The belief structure was that the oral regimen, used daily, would have the greatest likelihood of demonstrating proof-of-concept. As a result, most of the prevention trials of pre-exposure prophylaxis with antiretrovirals were oriented toward the oral daily regimen, explains Cates. The theory was that the daily oral approach would produce better adherence and higher concentrations of drug in tissues, thus it represented the best first step, says Cates. Only after success with the daily oral regimen, the other approaches, such as intermittent topical and oral dosing, could be evaluated for their relative effectiveness, he says.
"However, CAPRISA 004 has leapfrogged this projected development timeline," says Cates. "We need to go back to the drawing board."
More information on tenofovir will come from the VOICE (Vaginal and Oral Interventions to Control the Epidemic ) trial, an ongoing study evaluating daily use of tenofovir gel, regardless of when participants have sex. The trial also is testing daily use of oral antiretroviral tablets (tenofovir alone or tenofovir plus emtricitabine). The trial should help determine how well each product works compared to its control (placebo gel or placebo tablet) and which approach gel or tablet women prefer to use. Investigators plan to enroll about 5,000 women at sites in four countries in southern Africa. About 1,000 women are enrolled in the study so far.
The VOICE trial will provide not only the essential evidence to support or challenge the CAPRISA 004 findings, but also will contribute to understanding the relative value of the oral versus topical regimens in preventing HIV acquisition in women, says Cates.