By Liz Highleyman

In order to be safe and effective, microbicides must protect against HIV infection without disrupting the mucosal linings of the vagina and/or rectum.

Development of one microbicide candidate, nonoxynol-9 (also widely used in over-the-counter contraceptive products and as a condom lubricant), was discontinued after studies in 2000-2001 showed that the compound damaged vaginal and rectal linings, potentially increasing susceptibility to HIV infection.

More recently, studies of cellulose sulfate (UsherCell) were halted in January 2007 after interim data showed that women who used the product were more likely to become infected with HIV -- although why this happens is not yet clear.

In the February 19, 2007 issue of AIDS, researchers reported results from a trial of another microbicide candidate, PRO 2000. In this prospective, randomized, double-blind study, 24 HIV negative, sexually abstinent women vaginally applied either a gel containing 5% PRO 2000 or an inactive placebo gel for 14 days.

Levels of cytokines, chemokines, defensins, and other protective factors, as well as intrinsic antimicrobial activity, were assessed in cervicovaginal fluid samples collected on days 0, 7, 14, and 21.

Results

• No increase in pro-inflammatory cytokines was observed.

• Instead, levels of cytokines and protective factors including interleukin-1 (IL-1) receptor antagonist, immunoglobulins, and human beta-defensin 2 were lower in the PRO 2000 arm compared with the placebo group.

• Levels of all immune mediators returned towards baseline by day 21.

• Women who underwent menstrual cycling had lower levels of most immune proteins on study days 7 and/or 14 compared with women using oral contraceptives.

• The magnitude of decline was greater among women who received PRO 2000 compared with the placebo gel.

• The reduction in protective factors was not associated with a loss of intrinsic antiviral activity against HIV or herpes simplex virus, or antibacterial activity against Escherichia coli or Staphylococcus aureus.

Conclusion
"In contrast to experience with nonoxynol-9, PRO 2000 did not trigger an inflammatory response in cervicovaginal secretions," the authors concluded. "There was a modest reduction in mucosal immune mediators, but this loss was not associated with a reduction in intrinsic antimicrobial activity."

02/23/07

Reference
M J Keller, E Guzman, E Hazrati, and others. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 21(4): 467-476. February 19, 2007.