STD Quarterly
Microbicide candidate found safe, but not effective — What's the next step in research?
Search continues for female-controlled HIV protection method
Bad news: Results of the first large-scale effectiveness trial for a microbicide indicate that while the candidate, Carraguard, is safe, it was not shown to be effective in preventing male-to-female transmission of HIV.1 There is good news, however: Other microbicide candidates are in the research pipeline, with three potential methods in advanced clinical trials.
Results released at the Microbicides 2008 conference in New Delhi, India, show that while Carraguard was safe and acceptable to women, it did not reduce their risk of acquiring HIV. The Population Council enrolled some 6,200 women in South Africa between 2004-2007 to test the product, which is an odorless, clear gel made from carrageenan, a derivative of seaweed.
"I think a product is certainly within our reach," says Anna Forbes, MSS, deputy director for the Global Campaign for Microbicides. "I think we don't know yet how long our reach is going to have to be."
While Carraguard did not prove effective as a microbicide, the completion of the trial serves as a "milestone" in HIV prevention research, says Peter Donaldson, PhD, Population Council president. "The trial has contributed significantly to the field's body of knowledge regarding product development, trial design, and women's and their partners' willingness to use a vaginal gel consistently," noted Donaldson in the Council's official statement. "The data from the trial will be used by the Population Council and others working on microbicides to improve future products and trials."
At the beginning of the Phase III trial, scientists were hopeful regarding Carraguard's protective qualities. The test product and similar carrageenan formulations had undergone extensive safety testing involving more than 850 women and men in earlier clinical trials in Australia, Chile, the Dominican Republic, Finland, South Africa, Thailand, and the United States.
To conduct the Phase III randomized, double-blind study, Population Council researchers enrolled 6,202 women at three sites: the Setshaba Research Centre, through the University of Limpopo/Medunsa campus; the Empilisweni Centre for Wellness Studies, through the University of Cape Town; and the Isipingo Clinic, through the Medical Research Council of South Africa. Half of the women were given Carraguard gel and condoms, while the other half received a placebo gel and condoms. All participants received HIV education, gynecological exams, risk-reduction, and safer-sex counseling, as well as testing and treatment for curable sexually transmitted infections. The Population Council funded medical and psychological services for women who were HIV- positive at screening or became HIV-positive during the course of the trial. Support for the study came from the U.S. Agency for International Development and the Bill & Melinda Gates Foundation.
At the conclusion of the study, there were 134 new infections in the Carraguard group, yielding an incidence rate of 3.3 infections per 100 woman-years, and 151 new infections in the placebo group, for an incidence rate of 3.7 per 100 woman-years.
An important finding
While the Population Council's research didn't initially turn up an effective candidate for HIV prevention, it did indicate there were no safety-related differences between women using Carraguard and women using the placebo, with few gel-related side effects. This finding is important because Carraguard is a key component of next-generation microbicide candidates being developed at the Population Council. Several of these candidates combine Carraguard with one or more ingredients that have been shown to be effective in preventing virus transmission in laboratory settings.
"Carraguard formulation has several unique rheological properties that yield homogenous and extremely stable formulations," says Robin Maguire, director of microbicides product development at the Population Council. "By either modifying the carrageenan or by adding other antiviral agents, we observe an additive anti-HIV effect in laboratory testing."
What lies ahead?
What has been gained from the Carraguard trial? Several things, says Forbes.
"We learned that this kind of trial can be done. While that seems fairly obvious, it hasn't been completely obvious until now," she observes. "The ability to retain over 6,000 women who are followed for up to two years in a trial that requires them to apply the intervention themselves is actually quite a feat, so that is encouraging."
Scientists now have a clearer road map when it comes to understanding what constitutes safety in a microbicidal product, notes Forbes. "We can look back at the biomarkers that were collected in the Carraguard trial and see how they differ, between the biomarkers among the women using the placebo and the biomarkers among the women using the gel," she explains. "That will tell us more about what indicates safety in a product."
Three microbicidal candidates are now in advanced clinical trials, says Forbes. They are BufferGel, developed by ReProtect of Baltimore; PRO 2000/5, developed by Indevus Pharmaceuticals of Lexington, MA; and tenofovir gel, developed by Gilead Sciences of Foster City, CA. In December 2006, Gilead Sciences assigned a royalty-free license for development of the tenofovir topical gel to the International Partnership for Microbicides in Silver Spring, MD, and CONRAD in Arlington, VA.
BufferGel's effectiveness lies in its ability to lower the pH of the vagina. By keeping the vaginal environment more acidic, HIV transmission may be inhibited, research indicates.2 PRO 2000/5 is a sulphonated polymer that acts as an entry inhibitor.3 The active ingredient in tenofovir gel is a class of antiretroviral drugs called nucleotide reverse transcriptase inhibitors, which act against HIV by blocking the virus' ability to replicate and grow inside the body.4
To test BufferGel and PRO2000/5, the two candidates are being analyzed in a four-arm, multicenter, Phase II/IIb randomized, controlled trial conducted by the Microbicide Trials Network, a worldwide collaborative clinical trials network funded by the National Institutes of Health.
Enrollment for the study began in February 2005, with recruitment completed in July 2007. About 3,100 sexually active HIV-negative women have been enrolled at seven sites in Malawi, South Africa, Zambia, Zimbabwe, and the United States; each study participant is followed for at least one year. Women are randomly assigned to one of four study groups: BufferGel, PRO 2000/5 gel, placebo gel, and no gel. Participants who are assigned to the three gel groups apply the gel up to one hour before sexual intercourse using pre-filled applicators. Results from the study are expected in 2009.
Phase II results for the tenofovir gel were reported at Microbicides 2008. The data suggest the gel is safe for women to use on a daily basis.5
If any of the three products prove effective, it is still possible women could see the first candidate microbicide introduced in at least the hardest-hit countries within the next three to four years, forecasts Forbes. If none of the products yield positive results, don't discount the advent of microbicides, she says. Microbicide development is no different from any other form of drug development; the only difference is that microbicide research is publicly funded and, therefore, the results of every trial are publicly available. Drugs developed with private funds from pharmaceutical companies face a similar road, with less public tracking, notes Forbes.
"The consensus I heard very strongly at Microbicides 2008 is that researchers still agree that while microbicide development is possible to do, it's turning out to be difficult to do," she notes. It isn't any different from drug development in any other area, Forbes says. "It's just since this is all being paid for by public money, it's all happening under public scrutiny; and with drug development done by the large pharmaceutical companies, there are many, many products that don't work out, and we just don't know about them."
References
- Johansson E. Population Council: Results of Phase III Carraguard trial.
- Neurath AR, Strick N, Li YY. Anti-HIV-1 activity of anionic polymers: A comparative study of candidate microbicides. BMC Infect Dis 2002; 2:27.
- Smita J, Soma D, Beverly B, et al. Phase I safety study of 0.5% PRO 2000 vaginal gel among HIV uninfected women in Pune, India. AIDS Res Ther 2006; 3:4.
- 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.
- Hillier S. Update from clinical trials of microbicide effectiveness. Presented at the Microbicides 2008 Conference. New Delhi, India; February 2008.
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