By Liz Highleyman

Following disappointing early study results, researchers announced on January 31 the discontinuation of a study of UsherCell, an experimental vaginal microbicide intended to prevent sexual transmission of HIV.

Ushercell is a cellulose sulfate gel produced by Polydex Pharmaceuticals of Toronto, Canada, which was being developed by the non-profit health agency CONRAD with funding from the U.S. Agency for International Development and the Bill & Melinda Gates Foundation.

Among the products furthest along in the microbicide clinical development pipeline, Ushercell had advanced through 11 Phase I and II trials since 1999 involving more than 500 women and about 50 men, with no evidence of safety problems.

However, preliminary results from a Phase III study of more than 1300 women in Benin, South Africa, Uganda, and India showed that women using Ushercell had a higher rate of new HIV infections compared with women using a placebo gel. Based on these results, the trial's Independent Data Monitoring Committee decided to stop the study. Researchers have not yet released incidence rates or other specific data.

As a precaution, Family Health International (FHI) also halted a similar trial of Ushercell involving nearly 1700 women in Nigeria, although a higher rate of HIV infection has not been observed in that study to date (nor has any benefit been seen).

"While the findings are unexpected and disappointing, we will learn scientifically important information from this trial that will inform future HIV prevention research," said Dr. Lut Van Damme, principal investigator of the CONRAD study.

It is not yet known why women using Ushercell had a higher rate of HIV infection, but the product may somehow increase vulnerability to the virus. Previously, this was shown to be the case with nonoxynol-9 -- a spermicidal gel used as a contraceptive and condom lubricant -- which was found to irritate vaginal and rectal linings, thereby facilitating HIV entry.

In the wake of this disappointing turn of events, researchers and advocates remain committed to further microbicide research.

"Of course we wish the results had been different, but learning what doesn't work can be just as important to progress as learning what does work," said Lori Heise of the Global Campaign for Microbicides. "It is essential to build on what has been learned here and proceed with the research as rapidly as possible. Millions of women's lives are at stake."

"While extremely disappointing, this setback is also an opportunity to learn why some women who used Ushercell were found to be at increased risk of HIV infection," added International AIDS Society president Dr. Pedro Cahn. "This will strengthen future microbicide research and increase our overall knowledge of how such compounds work."

Three other microbicides are currently in advanced clinical development. Data from a Phase III study of Carraguard (a non-specific entry inhibitor derived from seaweed) are expected later this year. Results from studies of PRO2000 (another non-specific entry inhibitor) and BufferGel (a vaginal defense enhancer) are due in 2008 and 2009. But this past August, FHI halted a trial of Savvy (a surfactant gel) after a review of interim data suggested that the study was not likely to provide convincing evidence of efficacy.

"Getting a negative result for one product certainly doesn't signal failure for the microbicide field or broader biomedical HIV prevention research effort as a whole," said Mitchell Warren of the AIDS Vaccine Advocacy Coalition. "Each trial result is a puzzle piece and, together, they make up the complex picture that will show us how to develop successful new HIV prevention tools."

02/06/07

Sources

CONRAD. Phase III Trials of Cellulose Sulfate Microbicide for HIV Prevention Closed. Press release. January 31, 2007.

Family Health International. FHI Closes Phase III Trial of Cellulose Sulfate for HIV Prevention. Press release. January 31, 2007.

Polydex Pharmaceuticals Limited. Polydex Pharmaceuticals Reports Phase III Trial of Ushercell for HIV Prevention Halted. Press release. January 31, 2007.

World Health Organization/UNAIDS. Cellulose Sulfate Microbicide Trial Stopped. Press release. January 31, 2007.

Global Campaign for Microbicides/African Microbicides Advocacy Group/AIDS Vaccine Advocacy Coalition. Leading Advocates Express Support for Microbicide Research, Despite Disappointing Clinical Trial Results. Press release. January 31, 2007.

International AIDS Society. Statement on Announcement that Two Phase III Trials of HIV Microbicide Candidate Ushercell Have Been Halted. Press release. February 1, 2007.

M Marchione. Studies of AIDS Microbicide Gels Halted. Associated Press. January 31, 2007.