Failure of HIV microbicide raises concerns

Researchers shut down an HIV microbicide clinical trial last month in Africa and India after early data indicated microbicide users had a higher rate of infection than women using a placebo. The discouraging results have surprised and disappointed researchers, and may ultimately have a negative impact on the future role of microbicides in preventing the spread of the virus.

Several other microbicides are in the pipeline for testing and development, but this trial failure may push some researchers in the direction of other HIV prevention options, predicted Daniel Kuritzkes, director of AIDS research at Brigham and Women's Hospital. "The field is moving towards more specific approaches -- use of topical applications of antiviral drugs, as opposed to true microbicides," he told The Scientist. "The [closed trial's] results would make me less enthusiastic about pursuing other [microbicides]. I would be a bit leery about getting into microbicide studies."

Enrollment for the phase III trial for the cellulose-sulfate compound, called Ushercell, began in 2005. When it was stopped, the trial's preliminary analysis included 1,333 women in India, Uganda, Benin, and South Africa. Initial results showed that 35 women had contracted HIV while using the compound, a higher rate of infection than that seen in women using a placebo. CONRAD, the Arlington, Va.-based nonprofit reproductive health organization that funded the development and testing of Ushercell, halted the trial immediately.

The results were met with shock by researchers involved in the study. "We have no idea at all how to explain the mechanism in which there was an increase in infection," Lut Van Damme, who led the trial, told The Scientist. "Nothing went wrong, the trial went according to all rules and regulations."

Ushercell, originally created by Polydex Pharmaceuticals, had successfully completed 11 safety and contraceptive trials involving more than 500 patients before entering the HIV-prevention trial.

CONRAD has invested nearly $40 million to date on developing and testing Ushercell, estimated Executive Director Henry Gabelnick. The agency will continue to sponsor the investigation into what went wrong with Ushercell, but may re-direct funding to several other compounds still in development, Gabelnick said.

He added that he was very disappointed by the failed trial. "It was totally unexpected," Gabelnick told The Scientist. "You invest so much time and effort. You plan for success."

The compound, in gel form, is inserted vaginally or anally one hour before intercourse. A previous trial suggested Ushercell could also work as a contraceptive.

Researchers involved in the trial will spend the remainder of the year collecting, cleaning, and analyzing the trial's data set. Still, Van Damme said she already anticipates that exploration into Ushercell as an HIV microbicide is over.

Polydex spokesperson Linda Hughes said that if further tests show Ushercell was not the cause of increased HIV infection, it could still have a life as a second generation microbicide or as an inert addition to an antiviral treatment. "It could be reconsidered," she told The Scientist, "but it wouldn't be what we'd hoped for."

Van Damme was also the head researcher of a study that tested nonoxynol-9, the controversial spermicide, as a microbicide against HIV. Results from that study also showed an increased rate of HIV infection among gel users, in that case due to lesions created by the gel. According to Van Damme, the current mystery surrounding Ushercell's failure is nothing like the trial of nonoxynol-9, which showed signs during preclinical experiments that it might not work as an HIV microbicide.

Population Council, a New York-based non-profit research organization that is also testing a microbicide against HIV, is already feeling some negative effects from the Ushercell trial, according to spokesperson Melissa May. She noted that sites that are set to finish the microbicide phase III trial at the end of March have received several concerned phone calls from trial participants about the safety of the compound following the news about Ushercell. "The fallout that has come, and the confusion as a result of the announcement [of the Ushercell trial closing], is piling on the disappointment," May told The Scientist. While results of the trial of the microbicide, called Carraguard, won't be available at least until the end of the year, an independent data monitoring committee evaluated the trial three times, and each time declared the compound was safe.

For now, Van Damme and her colleagues are left to sleuth out how Ushercell was associated with more cases of HIV in their trial subjects. But she said she believes that microbicides will continue to be a viable product for HIV prevention, and characterized the Ushercell episode as a learning experience. "Every trial which comes to an end, so to speak, always has some positive things," she said. "Maybe we'll learn something down the line. All in all, science will be served."

Andrea Gawrylewski
mail@the-scientist.com

Links in this article:

Daniel Kuritzkes
http://www.hms.harvard.edu/aids/programs/oip/faculty/kuritzkes.htm

R. Walgate, "HIV microbicide by 2010?" The Scientist, July 16, 2004
http://www.the-scientist.com/article/display/22293

CONRAD
http://www.conrad.org/

J. Yajnik, "Getting your Gates," The Scientist, November 2006.
http://www.the-scientist.com/article/display/25259

Henry Gabelnick
http://www.conrad.org/bios/gabelnick.htm

RA Anderson et al, "Contraception by Ushercell (cellulose sulfate) in formulation: duration of effect and dose effectiveness," Contraception 70: 415-22, November 2004.
http://www.the-scientist.com/pubmed/15504382

ME Watanabe, "Topical control of HIV transmission possible," The Scientist, November 11, 2002.
http://www.the-scientist.com/article/display/13372/

Population Council
http://www.popcouncil.org/

Carraguard
http://www.popcouncil.org/microbicides/index.html