Population Briefs | October 2007, Vol. 13, No. 2 | Tests Suggest New Microbicide Will Have Improved Efficacy

October 2007, Vol. 13, No. 2

Focus on: Microbicide Development
Tests Suggest New Microbicide Will Have Improved Efficacy

Petri-dish tests of a new candidate microbicide indicate that the formulation is likely to be more effective at preventing the sexual transmission of HIV than the first-generation candidates currently in clinical trials. The new compound, called PC-815, combines Carraguard®, the Population Council’s first generation candidate, with an anti-HIV drug called MIV-150. The drug stops HIV from reproducing by blocking the reverse transcriptase enzyme, which normally allows the virus to replicate and spread.

Microbicides
Vaginal microbicides would be products designed to reduce the male-to-female transmission of HIV when used during sex. Currently there are no microbicides on the market. In March 2007, the Population Council completed data collection for a large Phase 3 clinical trial in South Africa to test the efficacy and long-term safety of Carraguard vaginal gel. The trial is the first Phase 3 trial of a product designed as a microbicide completed anywhere in the world. Results are expected by early 2008.

Promising candidates
“While developing and testing Carraguard, we have continued investigating ways to improve the formulation,” says Robin A. Maguire, director of microbicides product development at the Population Council. “PC-815 is one of the most promising second-generation microbicide candidates being developed at the Council.” Candidate microbicides that combine two or more anti-HIV approaches represent a potentially more effective tactic for limiting HIV infection. PC-815 blocks virus attachment with Carraguard and directly targets virus replication with the reverse transcriptase inhibitor MIV-150.

Studies have shown that MIV-150 is not absorbed by the body, even when given orally in high doses. This characteristic may make it an ideal candidate for use in microbicides. “It is not desirable for the product to be absorbed by the body,” says Population Council immunologist Melissa Robbiani. If the drug were absorbed, it could contribute to the development of resistant strains of virus, interact adversely with other medications the person is taking, or cause unwanted side effects. Moreover, extensive toxicology studies have shown that MIV-150 appears to be safe and well tolerated.

Effective product
Drugs similar to MIV-150 generally act after virus enters susceptible immune system cells. Ideally, however, drugs used in microbicides would neutralize HIV before it enters and infects cells. In the recent Population Council experiments, researchers found that MIV-150 inactivates free virus—that is, virus that is not in cells—making it impossible for the virus to enter and infect cells.

Because sexual transmission of HIV occurs in the presence of semen, the researchers tested MIV-150 and Carraguard in the presence of human seminal fluid. Seminal fluid had no effect on the antiviral activity of either compound. Finally, PC-815 was approximately ten times stronger than Carraguard alone in blocking the varieties of HIV found in sub-Saharan Africa.

“This study shows that PC-815 is likely to be a more efficacious microbicide than Carraguard,” says Population Council virologist David M. Phillips, lead researcher on the study. Currently, the Council is conducting two-year stability studies on the product. Toxicological testing has established that PC-815 is not toxic to human vaginal cell samples outside the body or vaginal epithelial cells in rabbits. Additional testing has demonstrated that PC-815 appears to have no effect on the vaginal epithelia of rabbits and rats. Phase 1 safety trials in humans are expected to be completed later this year.

Source
Fernández-Romero, José A., Mitchell Thorn, Stuart G. Turville, Kanani Titchen, Kristin Sudol, Jifan Li, Todd Miller, Melissa Robbiani, Robin A. Maguire, Robert W. Buckheit Jr., Tracy L. Hartman, and David M. Phillips. 2007. “Carrageenan/MIV-150 (PC-815), a combination microbicide,” Sexually Transmitted Diseases 34(1): 9–14. (abstract)

Outside funding
National Institutes of Health, Swedish International Development Cooperation Agency, Swedish Ministry of Foreign Affairs, and United States Agency for International Development

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