Check advances made in microbicide development

While no microbicide has yet moved from the research pipeline to the pharmacy shelf, progress is going forward on several fronts to develop female-controlled physical and chemical barrier methods to prevent HIV and other sexually transmitted diseases (STDs).

Findings from a new study conducted by infectious disease researchers at the Miriam Hospital and Brown Medical School in Providence, RI, indicate that tenofovir, a drug already given orally to treat HIV, also is safe when applied as a vaginal microbicide gel.1 Results from the multi-site study suggest that tenofovir, when used in a vaginal gel, produces mild or no side effects in HIV-positive and HIV-negative women.1

What is the next step in research? The National Institutes of Health is funding a Phase II study of 200 women in the United States and India to evaluate longer-term safety in a cohort of at-risk women, says Kenneth Mayer, MD, professor of medicine and community health at Brown University/Miriam Hospital. If that trial is successful, an efficacy trial will follow, says Mayer.

Tenofovir, a nucleotide reverse-transcriptase inhibitor, is the active ingredient found in the antiretroviral drug Viread made by Gilead Sciences in Foster City, CA. Viread was approved for treatment of HIV infection by the Food and Drug Administration in 2001.

Scientists are interested in tenofovir, a nucleotide analogue, because it is easily activated and has a high barrier to resistance, compared with other reverse-transcriptase inhibitors.2 A phase I study that looked at vaginal application of tenofovir gel demonstrated that it was well tolerated among sexually active women; pharmacokinetic data indicated minimal product absorption.3 Results of animal studies in monkeys have demonstrated tenofovir’s potential to prevent transmission of simian immunodeficiency virus in female rhesus macaques.2

To conduct the currently published study, investigators enrolled 84 women, ages 18-45; 24 of the participants were HIV-positive. All participants used the study product for 14 consecutive days, with research sites located at the Miriam Hospital in Providence, the Hospital of the University of Pennsylvania in Philadelphia, and Harlem Hospital and Bronx-Lebanon Hospital Center, both in New York City. The most common adverse effects reported by women in the study group included itching and increased vaginal discharge.1

Scientists also evaluated a subgroup of women in the study to determine whether the active ingredient in tenofovir gel was absorbed into their bloodstream. About half of the women were found to have low tenofovir levels in their plasma at one or more times during the 14-day study. More research is needed to see if absorption of tenofovir into the bloodstream could be beneficial or harmful, scientists note.1

Another vaginal gel formulation in research is Carraguard, from the Population Council in New York City. A sulfated polymer derived from carrageenan, Carraguard has been found to prevent HIV-infected mononuclear cells from binding to vaginal epithelia.4

Preliminary data from a Phase I clinical trial found that men who applied Carraguard before sex over three months did not experience significantly more irritation than a control group of men using a placebo.5 According to the Population Council, early research on female use of Carraguard indicates it does not cause significant irritation of the female reproductive tract and that the gel is generally acceptable for use.

A randomized, placebo-controlled Phase III trial of Carraguard is under way in South Africa, says Diane Rubino, Population Council spokeswoman. The trial is being conducted through collaborations with the University of Cape Town in Gugulethu, the Medical University of Southern Africa in Soshanguve, and the Medical Research Council in Isipingo. As of February 2006, 5,343 women had enrolled in the study, reports Rubino. The study is designed to determine the efficacy of Carraguard gel in preventing male-to-female vaginal transmission of HIV when applied prior to vaginal sex, and to evaluate its safety when used for up to two years, states Rubino. (Editor’s note: Look for upcoming coverage of microbicide development following the Microbicides 2006 conference, scheduled for April 23-26 in Cape Town, South Africa. The biannual international conference offers updates on recent microbicide research and provides a forum for the discussion of new developments in microbicide research, including behavioral, clinical, social science, community, basic science, and advocacy issues. See the conference lineup at the event’s web site, www.microbicides2006.org.)

References

  1. Mayer KH, Maslankowski LA, Gai F, et al. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS 2006; 20: 543-551.
  2. Dhawan D, Mayer KH. Microbicides to prevent HIV transmission: Overcoming obstacles to chemical barrier protection. J Infect Dis 2006; 193:36-44.
  3. Maslankowski L, Mayer K, El-Sadr W, et al. Vaginal tenofovir gel tolerability in HIV-uninfected women and abstinent HIV-infected women: HPTN 050. Presented at the Microbicides 2004 conference. London; 2004.
  4. Perotti ME, Pirovano A, Phillips DM. Carrageenan formulation prevents macrophage trafficking from vagina: Implications for microbicide development. Biol Reprod 2003; 69:933-939.
  5. Kilmarx P, Wankrairoj M, Achalapong J, et al. Safety of Carraguard use by heterosexual men in a six month clinical trial in Thailand. Presented at the Microbicides 2004 Conference. London; 2004.