Center researchers celebrate microbicide milestone

A clinical trial involving more than 3,000 women in seven sites (six in Africa; one in the United States) has demonstrated for the first time that a vaginal microbicide gel may prevent male-to-female sexual transmission of HIV infection. The study investigators, including Drs. Benoit Masse and Barbra Richardson, statisticians in the Vaccine and Infectious Disease Institute, presented the findings at the recent Conference on Retroviruses and Opportunistic Infections in Montreal.

The investigators found the microbicide gel—known as PRO 2000 (0.5 percent dose)—to be safe and 30 percent effective. While less than the 33 percent effectiveness that would have been considered "statistically significant,” the findings are very important because they offer the first evidence that a microbicide—of which there are many different classes—could actually work.

"This is a huge boost to the field of HIV prevention research, and it provides hope that a female-controlled method of HIV prevention could be available in the not too distant future," Richardson said.

"Although at face value, 30 percent effectiveness is somewhat modest, any proven concept can be improved upon leading to the development of microbicides with much higher effectiveness," Masse said. "This is great news for the millions of women around the world for whom this represents one step toward empowerment."

Microbicides are substances (such as a gel, cream or film) intended to reduce or prevent the sexual transmission of HIV and other sexually transmitted infections when applied topically inside the vagina or rectum. Several candidate microbicides are being tested in clinical trials, although none is yet approved or available for use. Earlier trials have yielded disappointing results or were stopped prematurely.

HPTN 035 differs from other microbicide trials
Unlike any other microbicide trial to date, HPTN 035 evaluated in the same study two candidate microbicides for their safety and ability to prevent HIV infection—each with a different mechanism of action. PRO 2000 inhibits the entry of HIV into cells; BufferGel boosts the natural acidity of the vagina in the presence of seminal fluid, which can help to inactivate HIV and other pathogens.

Another unique feature of HPTN 035, which began in 2005, is its inclusion of two control (comparison) groups: one in which women used a placebo gel (with no active ingredient) and one in which women used no gel. While a placebo control group is standard in clinical trials, a control group in which no product is used represents a departure from other microbicide studies. This unique feature of the trial has enabled the evaluation of the inertness of the placebo gel, which has been questioned in the past.

All participants received counseling on safe sex practices, condoms and detailed information about the possible risks and benefits of trial participation before enrollment, they were also monitored monthly and treated for sexually transmitted infections throughout the study.

Results of the HPTN 035 study
In the final analysis, 194 women in the study became infected with HIV. Of these 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 gel. Based on these data, PRO 2000 was 30 percent effective compared with the placebo gel (33 percent effective compared with no gel). Statistical significance was reached when both control groups were pooled. PRO 2000 was particularly effective among the volunteers who reported low condom use and high gel use. 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. HPTN 035 successfully retained a majority of its enrollees, with 94 percent completing their participation with an average follow-up of 20 months.

The UK Microbicides Development Programme is conducting another study of the PRO 2000 gel that will conclude later this year. Known as MDP 301, the phase 3 trial should provide more information regarding the gel’s effectiveness.

Currently, women comprise half of all people worldwide living with HIV. In sub-Saharan Africa, women represent nearly 60 percent of adults living with HIV, and in several southern African countries young women are at least three times more likely to be HIV-positive than young men. In most cases, women become infected with HIV through sexual intercourse with an infected male partner. Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot negotiate condom use with their male partners. An effective microbicide could provide women with an HIV prevention method they initiate.

The multi-center HPTN 035 trial was led by the U.S.-based Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health—all are components of the National Institutes of Health. Prior to the establishment of the MTN, the study was led by the NIAID-funded HIV Prevention Trials Network (HPTN), from which the study gets its name. The phase 2/2b trial is the NIH’s first large clinical study of a microbicide.

For more information about the HPTN 035 clinical study, see http://www3.niaid.nih.gov or  http://www.mtnstopshiv.org/news/studies/17.

[Adapted from news releases from the National Institutes of Health and the Microbicide Trials Network.]