Ongoing microbicide studies may lead to more options

Daily doses and a vaginal ring are being tried

The HIV community has waited a long time but there might finally be some rewards when the first microbicide options become available worldwide. Among these options are an intravaginal ring that delivers dapivirine and the daily use of tenofovir vaginal gel.

Investigators with the International Partnership for Microbicides now are studying an advanced version of dapivirine gel that is delivered via a vaginal ring.

"This ring for dapivirine is similar to the NuvaRing®, a contraceptive ring, that women wear for 28 days," says Joseph Romano, PhD, senior scientific advisor of the International Partnership for Microbicides in Silver Spring, MD. It's more convenient and cheaper than daily doses of an antiretroviral gel, he notes.

"Women do not have to worry about dosing it every day or at the time of sex, and they don't have to worry about applicators for gel products," Romano says. "It's cheaper to make a ring than 30 doses of gel," he adds. "And there is a presumed assumption that since women will only have to put it in once and not worry about it, then you'll get a higher rate of product compliance."

A phase I study published in 2009 found that intravaginal rings were safe and well tolerated with similar adverse events reported in the placebo and dapivirine groups.1

"Clinical findings with the ring have shown it to be safe and well tolerated in women; it's like the placebo," Romano says.

There will be a phase III, placebo-controlled study of the intravaginal ring with dapivirine beginning in 2011, he says.

"Investigators will look for how well the ring with dapivirine inhibits against HIV versus placebo," Romano says. "We hope to see a statistically significant difference."

The study will recruit thousands of women and last 33 months, he adds.

The Microbicides Trial Network (MTN) based in Pittsburgh, PA, recently announced the successful completion of its CAPRISA 004 trial which evaluated tenofovir gel in preventing heterosexual HIV transmission in 889 women in South Africa. MTN has moved ahead with its VOICE — Vaginal and Oral Interventions to Control the Epidemic study, which also will begin next year.

CAPRISA had women use the vaginal microbicide gel within 12 hours before having sex and up to 12 hours after having sex. The VOICE study, which will enroll 5,000 heterosexual women in sub-Saharan Africa, will study daily use of a microbicide, says Jeanne Marrazzo, MD, MPH, professor of medicine in the division of allergy and infectious diseases at the University of Washington in Seattle, WA. Marrazzo also is an associate professor of medicine at Harborview Medical Center in Seattle. She's a lead investigator with VOICE.

"We were interested in our study in looking at daily dosing so women have a steady state of whatever product they are taking," Marrazzo says. "Some women don't have control over when sexual activity will occur."

A critical difference

Women enrolled in VOICE will be randomized to one of five arms of the double-blind, placebo-controlled trial. For each arm they will be expected to adhere to the daily treatment for the duration of the trial, which is expected to last two years:

  • One group of women will receive a daily tablet of tenofovir for about two years;
  • A second group of women will take a daily tablet of the combination drug tenofovir disoproxil fumarate and emtricitabine (Truvada®);
  • A third group will take a daily placebo tablet;
  • A fourth group will administer a tenofovir vaginal gel each day;
  • A fifth group will administer a placebo gel each day.

"Everybody is asked to use whatever they were randomized to once a day regardless of sexual activity," Marrazzo says. "That's the critical difference from the CAPRISA study, which looked at whether using the gel before or after sex reduced risk of HIV."

The women will receive ongoing HIV risk-reduction counseling, condoms, and HIV testing and treatment of sexually-transmitted diseases (STDs).

The oral and topical formulations of tenofovir and Truvada were developed by Gilead Sciences Inc. of Foster City, CA. The company assigned a royalty-free license for the topical gel to IPM and CONRAD of Arlington, VA, four years ago.

"The beautiful thing about VOICE is it reflects our feeling that these products — even if incredibly biologically effective — will only work if women use them," Marrazzo says. "With this design of randomly putting women in five arms, we could get a sense of whether women liked the product and whether they were adherent to the product they are assigned to use."

Researchers will ask women enrolled in VOICE what their perception is of the gel or tablet. For some women the fact that the gel is noticeable to partners will be a concern, and for others it might be positive, Marrazzo says.

"Those issues are going to be very important as we look through data and get information from women," she says. "We want to know if there are concerns or advantages to these approaches and what they are."

Investigators also will ask women about how their partners perceived the gel.

"Male partner involvement is something that these big studies of prevention in women are increasingly paying attention to," Marrazzo says.

A lot of options needed

In addition to the VOICE study and the intravaginal ring research, microbicide studies are looking at a variety of options, including some involving rectal microbicides. At the same time some studies will find out whether oral antiretrovirals given as pre-exposure prophylaxis (PrEP) are effective.

All of these approaches are important, Marrazzo and Romano say.

"I'm a strong believer in the use of antiretrovirals in a topical manner both rectally and vaginally," Romano says. "With the proper development of formulations and product and proper clinical evaluation, I do believe there will be products in various configurations."

When microbicide and PrEP products come to the market, some people will prefer rings, some gels, some tablets, and some will prefer microbicides that don't require an applicator, he adds.

"People are going to want to have different products," he says. "You truly need a lot of options to manage the growth of the epidemic."

HIV researchers and others have put a great deal of time and effort into developing microbicides largely because they realized early on that the magic bullet of an HIV vaccine will not happen as quickly as needed.

"Ideally, we needed an HIV vaccine 20 years ago," Marrazzo says. "So the next thing is to explore, validate new tools that people can use to help them stay uninfected."

For instance, the PrEP approach could be effective across multiple exposures.

"If you have a pill that people could take to reduce their daily risk that's a pretty powerful thing," Marrazzo says. "The next best thing on top of that is to give people choices of a gel or maybe even a vaginal ring that is a next generation delivery platform that people are excited about."

Reference

  1. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr. 2009;51(4):416-423.