Microbicide breakthroughs may signal new era in HIV prevention

'Researchers actually got a standing ovation, which is unheard of'

After a rocky decade, the microbicides field finally is seeing some success, opening up a promising future that should include a wider range of HIV prevention options for women as well as for men who have sex with men (MSM).

The CAPRISA 004 microbicide trial using tenofovir gel vaginally demonstrated positive results in reducing HIV infection, as well as preventing genital herpes infections. The results first were reported in July 2010, a decade after the field experienced its first disheartening news with results from the earliest vaginal microbicide trials.

"It's been quite a long road with lots of ups and downs," says Ian McGowan, MD, PhD, FRCP, professor of medicine in the division of gastroenterology, hepatology, and nutrition with a joint appointment in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh School of Medicine in Pennsylvania. "It's safe to say the microbicides field was greatly energized by the reporting of the CAPRISA 004 study," 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.

"This was the first study to show proof of principle for the development of a vaginal microbicides product that worked well," she says. "That was stunning and validated an approach that many people were skeptical about."

Researchers presented CAPRISA 004 data at the 18th International AIDS Conference, held July 18-23, 2010 in Vienna, Austria.

CAPRISA was the first study to show potential for using a specific antiretroviral (ART) as a pre-exposure prophylaxis (PrEP), Marrazzo says.

"This definitely is the beginning of the end, but it's also a new beginning," says Joseph Romano, PhD, senior scientific advisor of the International Partnership for Microbicides in Silver Spring, MD.

"I think people recognize the limitations that were associated with some of the early generation microbicide products, particularly in the context of true antiretroviral compounds," he says. "There are a lot of smart people involved, and there is enthusiasm around the notion of using antiretrovirals in microbicides."

The microbicide field also is taking a major step now in expanding to products for use rectally by both men and women, McGowan says.

"We need rectal microbicides because MSM are at risk from that route, and women around the world are having anal sex and are at risk," he adds.

McGowan has been long involved in microbicides research and currently is investigating the use of tenofovir gel when applied rectally. He's the co-principal investigator of the Microbicide Trials Network (MTN) based in Pittsburgh.

The first generation microbicide drugs were not effective and some created headlines when their use resulted in more HIV infections than placebo.

"As we moved into using antiretrovirals like tenofovir, we were first able to show effectiveness in the lab, and then, in July of this year, in humans," McGowan says. "For the first time the field demonstrated a proof of concept that tenofovir gel significantly reduced the HIV acquisition rate."

The CAPRISA 004 study, conducted by investigators with the Microbicide Trials Network (MTN) found a 39% fewer HIV infections among women who used tenofovir gel before and after sex than those who used placebo. The 39% effect was modest, rising to 40% effectiveness when investigators pulled out numbers for only the women who had been adherent 80% or greater, he says.

"For those who were less than 50% adherent we saw effectiveness rates of only 28%," he adds.

Despite this caveat and the study's 6% to 60% confidence interval, the HIV community welcomed this first bit of positive microbicide news with loud acclaim at the International AIDS Conference last July.

"The CAPRISA researchers actually got a standing ovation, which is unheard of," McGowan says. "It was a profound manifestation of all the frustration we've experienced over the years with studies that haven't worked out."

Will VOICE be loud?

McGowan and other investigators hope the next microbicide study news also will be positive when results from the VOICE – Vaginal and Oral Interventions to Control the Epidemic research is published. The VOICE study could have results early in 2013.

Study subjects in VOICE trials will use tenofovir gel daily as opposed to being used only around sex, as was the study design for the CAPRISA study. Daily use might improve its efficacy.

"I think that more frequent gel dosing in VOICE may well be associated with higher rates of effectiveness," McGowan says. "It's a very exciting potential."

Microbicide researchers quickly built on the July meeting's good news with international discussions held in the fall about what should happen next in product development.

"A couple of months after the July meeting, a number of us went to South Africa for a meeting sponsored by WHO and UNAIDS to discuss what additional steps were needed to get this product to women as quickly as possible," McGowan says. "We have a little bit of a pause before the next study findings come out, but we need that time to think about how we can move from the clinical trial setting to make the product available in the community."

When pharmaceutical products are sponsored by pharmaceutical companies the product development work is well underway by the time final results are published. However, the microbicide field has no major pharmaceutical sponsors. Academic researchers and non-profit organizations are taking the lead in new product development, and they have less experience in transitioning a study drug to market, McGowan explains.

"We need to talk about what's needed to get this product licensed for HIV prevention in women," he says. "When we went to the FDA [Food and Drug Administration], they said they'd consider an application with CAPRISA and VOICE results."

This means the tenofovir gel's earliest potential marketing date will be after 2013, which is the earliest VOICE results will be available.

"Usually, you need to have two, well-controlled studies showing effectiveness and safety," McGowan says. "We don't want to license this product until we have results from two studies moving into the same direction."

So it's possible the world's first vaginal microbicide for prevention of HIV will be on the market in 2014.

"Our hope is that by then there might be quite a lot of drug available to move into communities if the planets align, and everything shows this strategy is safe and effective," McGowan says.