Safety and Tolerability of Vaginal PRO 2000 Gel in Sexually Active HIV-Uninfected and Abstinent HIV-Infected Women

Because consistent condom use to prevent HIV infection requires cooperative partners, and because the development and distribution of an HIV vaccine will take many years, there is an urgent need for the development of efficacious, convenient and inexpensive microbicides. Unfortunately, despite in vitro activity against HIV, the most widely studied microbicide, nonoxynol-9, has not been shown to be protective in several large phase III trials; moreover, concerns have been raised about its toxicity.

One novel microbicidal agent under investigation is PRO 2000 (Interneuron Pharmaceuticals Inc.), a synthetic naphathalene sulfonate polymer. PRO 2000 Gel is an aqueous gel formulation containing the synthetic polymer, a pH 4.5 buffer system and common preservatives. Non-cytotoxic PRO 2000 concentrations of 0.01 percent or less have been shown to block HIV infection of T lymphocytes, macrophages and cervical explant tissue in vitro. Also, it has been show to protect against vaginal HIV transmission in non-human primate models. The compound binds to the HIV envelope glycoprotein (gp120) and interferes with one or more of the early events in the HIV-1 infection process. In vitro, the product is also active against herpesviruses, Chlamydia trachomatis and Neisseria gonorrhoeae, but not against Candida albicans or Lactobacillus spp. at concentrations up to 4 percent.

Because of promising in vitro and animal data and the safety and tolerability of PRO 2000 Gel in abstinent participants, a protocol team within the HIV Prevention Trial Network was established to assess the safety and tolerability of increasing concentrations and frequencies of PRO 2000 Gel in sexually active HIV-uninfected women and then to evaluate the highest tolerated dose for safety in HIV-infected, sexually abstinent women.

In the current study, 63 women (50 low-risk HIV-uninfected women and 13 HIV-infected women) from Providence, Philadelphia, Durban and Johannesburg were enrolled after being screened to exclude pre-existing illnesses and were instructed to use the product once or twice daily for 14 intermenstrual days. They underwent colposcopy prior to product use and after 14 days of product use, with a pelvic examination at day 7. Sixty of the 63 enrolled participants completed the study.

The researchers reported that PRO 200 Gel was safe and well tolerated when used once or twice daily at either 2 percent or 4 percent concentrations in low-risk sexually active HIV-uninfected women and at 4 percent twice daily in abstinent HIV-infected women. There were no serious adverse events. However, 73 percent of participants had at least one adverse experience: 82 percent of these were classified as mild, and over 90 percent of the findings and symptoms were localized to the genital tract. Women who used the 4 percent gel twice daily tended to have more adverse events than all the other groups.

"Although some women reported transient and limited vaginal discomfort or bleeding, or product leakage, none of them discontinued product use. Pelvic examination and colposcopy also detected discrete epithelial disruptions in 24 percent of the study participants; however, in the majority, the product itself did not appear to play a clear role in disrupting genital tract mucosa. Increased findings and symptoms noted among women who used the 4 percent concentration twice daily suggest the need to use lower concentrations and/or dosing frequencies in future trials. The product was also well tolerated by HIV-infected women. The results of this trial justify the evaluation of this product in large-scale efficacy trials to assess its possible role in limiting HIV transmission," the authors concluded.

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