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Large-scale study of anti-HIV gel shows promise — What's the next step?
Look to upcoming results from Phase III trial of PRO 2000
Research findings presented at a February 2009 international conference indicate that an investigational gel known as PRO 2000 (Indevus Pharmaceuticals; Lexington, MA) proved about 30% effective in preventing HIV infection in women.1 The other candidate microbicide tested in the trial, BufferGel (ReProtect, Baltimore), did not reduce HIV risk among women. While the finding for PRO 2000 was not found to be statistically significant, the study is the first human clinical research to suggest that a microbicide might prevent male-to-female sexual transmission of HIV infection.
Women's health advocates now look to the results of a separate, larger clinical study that should definitively assess the effectiveness of PRO 2000 in preventing HIV infection. Sponsored by the Medical Research Council and the Department for International Development of the United Kingdom, the Phase III study involves some 9,400 African women and is set to conclude in August 2009.
The trial, labeled as HPTN 035, was conducted by the National Institutes of Health-funded Microbicide Trials Network. The combination Phase II/IIb clinical trial was designed to determine whether BufferGel or PRO 2000 demonstrated sufficient promise for testing in a larger Phase III clinical trial. Scientists did not design the trial to compare the two microbicides to each other, but rather to evaluate each against a placebo gel that contained no active ingredient and use of no gel at all. The Phase II portion of the study enrolled 799 women; the Phase IIb phase involved the initial 799 participants, as well as an additional 2,300 women. Women in the study were assigned randomly to one of four equal-sized treatment groups: BufferGel, PRO 2000, placebo gel, or no gel. All women in the study were counseled about the possible risks and benefits of trial participation prior to enrollment and were monitored closely throughout the study. In addition, they were counseled regarding safe sex practices, provided condoms, and tested and treated for sexually transmitted infections throughout the study. The study was conducted in six sites in Africa and one in the United States.
In the final analysis, 194 women in the study became infected with HIV. Of those infections, 36 occurred in the PRO 2000 group, 54 in the BufferGel group, 51 in the placebo gel group, and 53 among those who did not use a gel. Based on those findings, PRO 2000 was 30% effective, while BufferGel had no detectable effect on preventing HIV infection. Both microbicides were found to be well tolerated and did not result in any significant adverse events, researchers report.1
"We think it certainly is an encouraging piece of news," says Anna Forbes, deputy director for the Global Campaign for Microbicides, an international coalition of organizations working to accelerate new HIV prevention options, particularly for women. "The trial results were not ultimately statistically significant, but the subanalyses certainly suggest a trend in the right direction, which is that PRO 2000 may have had some protective effective."
Is progress being made?
Where do the results of the current trial place science in the development of an effective microbicide? Since the concept of a microbicide first was proposed almost 20 years ago as an HIV prevention strategy that women can initiate or control, there have been several effectiveness trials to assess impact on HIV infection, observes Salim Abdool Karim, MB, BCh, professor in clinical epidemiology at the Mailman School of Public Health at Columbia University in New York City and deputy vice chancellor of research and development at the University of Natal in Durban, South Africa. Abdool Karim, who led the HPTN 035 study as protocol chair, presented findings at the recent Conference on Retroviruses and Opportunistic Infections in Montreal.
Earlier microbicide trials include those of the nonoxynol-9 (N9) sponge, N9 film, N9 gel (COL-1492), Savvy, cellulose sulphate, and Carraguard prior to the release of the HPTN 035 results, recalls Abdool Karim. Unfortunately, those six products produced disappointing results, he says; two trials (N9 film and Carraguard) showed no impact on HIV; one trial did not produce a meaningful result due to lower-than-expected HIV incidence in the study population (Savvy); and three trials suggested that the product may be harmful (N9 sponge, N9 gel, and cellulose sulphate).
Against this backdrop, the HPTN 035 results showed that BufferGel and PRO 2000 were safe, observes Abdool Karim. BufferGel had no impact on HIV prevention; PRO 2000 demonstrated a 30% reduction in HIV infection in an intent-to-treat analysis; and the subgroup analysis provided evidence suggesting a potential protective effect of PRO 2000. The overall 30% level of protection is modest and is not statistically significant, says Abdool Karim. While it is a promising signal, it is insufficient to make any conclusive statement on PRO 2000 as a protective microbicide, he notes.
"In light of the sequence of disappointing results from the preceding six trials, HPTN 035 provides the first indication that a vaginally applied gel may be able to protect against HIV infection," says Abdool Karim. "The results of the current PRO 2000 effectiveness trial under way are now patiently awaited; these results are likely to determine if PRO 2000 will be able to assume the mantle of being the first effective microbicide."
It is a positive development that a major study has found a 30% protective effect against HIV transmission when women use a vaginal agent, says Robert Hatcher, MD, MPH, professor of obstetrics and gynecology at Emory University in Atlanta. The larger study of PRO 2000 now under way will confirm, he hopes, this initial report.
The good news is that there might be a product that a woman can use to lower her risk of being infected with HIV, Hatcher says. The bad news is that the results of the HPTN 035 trial indicate the gel is found to have only a 30% protective effect. "This raises the question: Could PRO 2000 use lead to decreased use of a far more effective method of preventing HIV transmission: male condoms?" Hatcher asks.
More options in line
Look for more research to emerge on other microbicides. The International Partnership for Microbicides (IPM), based in Silver Spring, MD, is testing a new generation of microbicide candidates that contain highly potent antiretrovirals that specifically target HIV. These microbicides are based on the same antiretroviral drugs being successfully used in HIV treatment and to prevent mother-to-child transmission of HIV. The IPM announced in February 2009 that it had received a total of US $130 million in grants from the United Kingdom Department for International Development and the Bill & Melinda Gates Foundation to pursue such product development.
IPM is eyeing use of the antiretroviral dapivirine in vaginal ring and gel delivery formulations, says Zeda Rosenberg, ScD, IPM CEO. Safety studies of the gel began in March 2009 in four U.S. cities: Baltimore; Birmingham, AL; Chicago; and Seattle. Research is expected to expand into South Africa and other African countries once regulatory approval is received, she reports. If successful, safety studies for dapivirine in ring and gel formulations are geared to move into large-scale efficacy studies in 2011, Rosenberg states.