Some 40 microbicide products, including those whose active ingredient are ARVs, are currently in development around the world, according to the Alliance for Microbicide Development. Of these, 10 products have been shown to be safe and effective in animal trials and are being tested in humans in the U.S., Africa and India, according to the Center for AIDS Programme of Research (CAPRISA) in Congella, South Africa.
The ARV drug that holds the most promise is tenofovir, an RTI manufactured under the brand name Viread by Gilead Sciences. It is best known as the combination therapy pill, Truvada. The U.S. National Institutes of Health (NIH) and CAPRISA are set to conduct separate human trials of oral and topical tenofovir. NIH is currently recruiting up to 4,200 high-risk women (it hasn't yet said where) to test the gel and pill forms in a two-year trial set to begin in July. The CAPRISA trial of some 1,000 high-risk South African women began in May 2007 and is set to run through the end of next year.
There are about six ARV clinical trials underway in the United States, Africa and India. Among other drugs being tested: Dapivirine and Maraviroc, an RTI and an entry inhibitor, respectively. The International Partnership for Microbicides, a nonprofit drug development group in Silver Springs, Md., is conducting trials on Dapivirine gels and vaginal rings — thin, transparent rings inserted into the vagina that release medications over a month or more. (Vaginal rings are are already available as birth control, such as the product NuvaRing.)
The Partnership's CEO, microbiologist Zeda Rosenberg, says ARVs are promising because they last longer in the body than the compounds used in previous microbicides. The idea is that women could apply an ARV microbicide gel once a day or less and it would still be effective in preventing HIV transmission during a sexual encounter within 12 to 24 hours. To date, the gels tested had to be applied just before sex.
"Early-generation microbicides were coitally dependent, meaning they had to be used just prior to sex," Rosenberg says.
Divorcing microbicide use from sexual activity could help researchers sort out ineffective products from those that simply aren’t being used properly by trial participants. "You cannot watch people apply vaginal microbicide right before they have sex," Harrison says.
They can, however, supervise application in the clinic on a daily basis if the product is longer lasting. A crucial recent development has been production of a gel out of ARVs that could be applied once a day and retains effectiveness regardless of climate. The gels also need to be safe. Some earlier microbicides caused vaginal inflammation. So far, two promising tenofovir gels have been produced, Rosenberg says.
In September, the Contraceptive Research and Development program (CONRAD) in Arlington, Va., a not-for-profit drug research organization affiliated with Eastern Virginia Medical School received a five-year, $100-million grant from the U.S. Agency for International Development (USAID) to test a tenofovir gel, develop new biomarkers (which tell researchers that disease is present so they know if a preventative measure worked to block transmission), and refine mouse modeling for microbicides, which, like most other drugs, are tested on mice and other animals before human trials. But many researchers say these need to be improved.
"Currently there are no markers or models that allow us to predict the safety and efficacy of a microbicide candidate with accuracy," says Henry Gabelnick, executive director of CONRAD. Some scientists are concerned that using ARVs for prevention could increase the spread of HIV resistance, because their use might boost transmission of naturally resistant variants of the disease. For instance, the use of the ARV drug nevirapine to prevent mother-to-child HIV transmission carries the risk of promoting drug-resistant virus.