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Antiretroviral (ARV) drugs have transformed HIV infection from a death sentence to a manageable chronic illness for millions worldwide. Now, scientists are testing whether ARVs can be used as microbicides, taken orally or applied vaginally as a gel or foam to prevent the transmission of the AIDS-causing human immunodeficiency virus.

If ARVs are proved as effective as microbicides, they have the potential to dramatically curb HIV infection rates. This is especially true in sub-Saharan Africa where women, who comprise nearly 61 percent of the adults living with HIV there, are eager for products besides condoms that they can use to protect themselves against the disease.

"I think it is very exciting to be integrating microbicides with drugs that have proven to work for treatment," says Roberta Black, chief of the Microbicide Research Branch at the National Institute for Allergy and Infectious Disease (NIAID) in Bethesda, Md. "This really jump-starts research efforts."

Microbicide research is at a crossroads as scientists begin testing the next generation of these drugs in the wake of a series of high-profile failures, including three late-stage clinical trials that were halted in the past year because the tested drug was found to be ineffective and, in one case, actually raised the risk of HIV transmission.

The latter trial, involving nearly 1,400 women in Durban, South Africa; Kampala, Uganda; Cotonou, Benin; Chennai, India; and Karnataka, India, was stopped last year when researchers realized the microbicide gel, made up of cellulose sulfate, not only failed to prevent HIV infection, but upped participants' risk of acquiring the virus. Forty-one women contracted HIV during the trial—25 in the cellulose sulfate gel group and 16 in the placebo gel group.

Carraguard, a seaweed-based microbicide tested by the Population Council, a nonprofit biomedical research group based in New York City, failed to show efficacy in a study carried out between 2004 and 2007 on 6,200 women. Carraguard is a polyanion, meaning that it carries a negative electrical charge that attracts HIV, whose surface is positively charged. The idea was that polyanions could prevent the virus from attaching to the host cell.

Almost simultaneously, last February in the U.K., the Microbicides Development Programme at Imperial College London announced that it was stopping one arm of a trial of another polyanion, PRO-2000, because the product was unlikely to show any benefit.

Two other compounds that showed early promise—nonoxynol-9 and Savvy—have also proved lackluster in recent years. Both are detergents, common agents used in spermicides, that disrupt HIV in test tubes, but in human microbicide trials they did not stop HIV transmission.

"It’s very easy to get depressed," says Polly Harrison, founder and director of the Alliance for Microbicide Development, a Silver Spring, Md.–based nonprofit that advocates for the worldwide development of the products. "But the field has rallied and dusted itself off."

The reason for the rally isARVs. Two classes are in development as microbicides: entry inhibitors that prevent the virus from attaching to target cell surfaces or stop it from entering the cell after attachment, and reverse transcriptase inhibitors (RTIs) that block virus from replicating itself if it succeeds in entering a cell.