Anti-HIV gel proven safe, tolerable for women

Phase II study results set the stage for larger trials to see if tenofovir prevents HIV infection

BIRMINGHAM, Ala. - An experimental anti-HIV gel is safe for women to use on a daily basis, according to researchers at the University of Alabama at Birmingham (UAB) and the University of Pittsburgh School of Medicine.

Testing showed the gel, called tenofovir, was favorably self-applied and tolerable to non-HIV-infected women, a significant boost to HIV and AIDS prevention efforts focused on next-generation microbicides to reduce infection rates, the researchers said.

The women study participants said if tenofovir gel is approved for the prevention of HIV infection, they would be willing to apply the gel to themselves daily or before sex, whichever is determined the best use.

"The gel is safe to use, and well tolerated by HIV-negative women. That's a key message in our findings," said Craig Hoesley, MD, associate professor in the UAB Division of Infectious Diseases and author on the initial Phase II results. "This sets the stage for larger studies to see if tenofovir can prevent HIV infection."

The tenofovir Phase II trial results were presented Monday, Feb. 25 at an international microbicides meeting in New Delhi, India. The researchers are part of the U.S. National Institutes of Health-funded Microbicide Trials Network, an international team of researchers devoted to exploring and evaluating anti-HIV microbicides.

"Based on what we have learned we can proceed with greater confidence on a path that will answer whether tenofovir gel and other gels with HIV-specific compounds will be able to prevent sexual transmission of HIV in women when other approaches have failed to do so," said Sharon L. Hillier, PhD, director of reproductive infectious disease research at the University of Pittsburgh School of Medicine and principal investigator on the Phase II study.

Researchers evaluated if tenofovir was safe to use every day for six months, or safe to use prior to each act of intercourse. They found both approaches equally safe. Women in the study were asked to use condoms in addition to the gel.

The researchers found no disruption of liver, blood or kidney function in each group of women using a different gel regimen, including those given a placebo gel that looked and felt identical to the tenofovir gel.

The study included 200 sexually active HIV-negative women enrolled at UAB, Bronx-Lebanon Hospital Center in New York and the National AIDS Research Institute in Pune, India. Participants were age 19 to 50, and 64 percent were married.

In addition to the safety findings, the researchers found a significant willingness by women to follow the anti-HIV treatment guidelines. Eighty percent of the women instructed to use the gel within two hours of having sex said they followed instructions, and 83 percent instructed to use the gel daily said they had done so in the week prior.

Hoesley said if the gel were approved to help prevent HIV infection, more than 90 percent of the study volunteers said they would seriously consider using it, regardless of the regimen, to protect their sexual health.

"We asked women 'How acceptable is this as a prevention option, is it too messy, is it a nuisance, and will you use it?' Our study showed they will use it and they're not bothered by the gel," Hoesley said.

The active ingredient in tenofovir gel is a class of anti-retroviral drugs called nucleotide reverse transcriptase inhibitors, which act against HIV by blocking the virus' ability to replicate and grow inside the body.

Trial finds tenofovir gel safe for daily use and most women adhered to study regimens

Results of Phase II study of ARV-based microbicide presented at international meeting in India bolster interest in latest approach

NEW DELHI, Feb. 25, 2008 - A vaginal microbicide that incorporates an antiretroviral (ARV) drug normally used to treat people with HIV is safe for sexually active HIV-negative women to use every day over an extended period, suggest results of a clinical trial of tenofovir topical gel. Moreover, most of the women who participated in the study conducted in India and the United States adhered to a regimen involving either daily or sex-dependent use of the gel, report researchers from the U.S. National Institutes of Health-funded Microbicide Trials Network (MTN) at Microbicides 2008, an international meeting taking place Feb. 24-26 at the Hotel Ashok in New Delhi.

The findings, presented today for the first time, are a significant boost to HIV prevention efforts focused on the potential of "next-generation" microbicides to curb infection rates in women. Globally, nearly half of those living with HIV/AIDS are women, and between 70 and 90 percent of all HIV infections in women are due to heterosexual intercourse. In India and many other parts of the world, even married women and women with steady partners are at risk.

In this Phase II study, called HPTN 059, researchers wanted to understand if tenofovir was safe to use every day for six months compared to its use prior to each act of sex, and if women were able to adhere, or follow, each regimen. Researchers found both approaches equally safe and women's adherence to product use similar. Interestingly, most participants also said they would be willing to apply gel, including daily, if one were found effective to prevent against getting HIV from their sexual partners.

Microbicides are products designed to prevent the sexual transmission of HIV when applied topically on the inside of the vagina or rectum. Tenofovir gel is among a newer class of candidate microbicides that differ from early types because they have specific action against HIV. In addition, because tenofovir gel and similar products are longer acting, their use may not be required before each act of sex, which is not always practical or desirable for some women.

"Finding that daily use is both safe and feasible is important because we believe a daily approach may provide more sustainable protection against the virus in women who can't always predict when they will have sex. Based on what we have learned we can proceed with greater confidence on a path that will answer whether tenofovir gel and other gels with HIV-specific compounds will be able to prevent sexual transmission of HIV in women when other approaches have failed to do so. It is a critical time for all of us engaged in HIV prevention, and I truly believe we are turning a corner," said Sharon L. Hillier, PhD, professor and vice chair for faculty affairs, and director of reproductive infectious disease research in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, who is MTN principal investigator and led the study.

According to UNAIDS, women represent nearly half, or 46 percent, of the 33.2 million people living with HIV/AIDS worldwide, and they are more than twice as likely as men to acquire HIV through sexual intercourse, due to both biological and cultural factors. Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot successfully negotiate condom use with their male partners.

HPTN 059 involved 200 sexually active HIV-negative women: 52 were enrolled at the University of Alabama at Birmingham (UAB) in Birmingham, Alabama; 48 at Bronx-Lebanon Hospital Center, Bronx, New York; and 100 women entered the study at the National AIDS Research Institute in Pune, India. The mean age was 32 and 64 percent of the women were married. All but one of the women at the Indian site were married compared to 28 percent of the women at the two U.S. sites.

Once enrolled, women were randomly assigned to one of four groups: tenofovir gel applied daily; tenofovir gel applied up to two hours before sex; placebo gel (without an active drug) used every day; or placebo gel applied prior to sex. Because the tenofovir and placebo gels look the same, neither researchers nor participants knew who had been assigned to use which gel during the six-month study period. Women were assessed at one month, three months and six months. Throughout the study, participants received free condoms and HIV risk-reduction counseling as well as routine testing and treatment for sexually transmitted infections.

The study found no differences in liver, blood and kidney function between the groups of women using either regimen of tenofovir gel and the groups assigned to use placebo, nor were there differences in these safety measures between groups using daily gel and groups using gel with sex. Likewise, researchers report no statistical differences in the development of genital symptoms such as itching and burning, which are considered minor. One woman became pregnant and stopped gel use. No participants acquired HIV during the study.

Adherence to treatment was also similar. According to structured interviews, 80 percent of the women instructed to use gel within two hours of having sex said they complied with the regimen. Of the women in the daily-use groups, an average of 83 percent reported study gel use in the past week. The two most cited reasons women gave for not using gel was menstruation (41 percent) and forgetting (23 percent).
Overall, 41 percent of the women indicated there was nothing they disliked about using the gel and 39 percent said it was easy to use. Other attributes of the gel women identified included its potential for protecting against HIV (19 percent), its smell and appearance (14 percent) and that it made sex more pleasurable (12 percent). Thirty-two percent didn't like that the gel was messy, but none of the women said sex was made less pleasurable because of the gel.

Importantly, when asked if they would use the gel if it were found to help prevent people from getting HIV, 90 percent of the women who had been assigned to use the gel at the time of sex and 96 percent of the women who had been asked to use gel daily said yes.

"Women are definitely willing to use a gel to protect against sexual transmission of HIV. That's very encouraging," Dr. Hillier commented.

HPTN 059 also evaluated how the active ingredient in the gel was absorbed from the vagina into the blood and vaginal tissue; and looked at the effects of prolonged use on vaginal flora, the vagina's naturally protective population of microorganisms; and whether the activity of certain immune system molecules called cytokines could serve as a useful measure, or marker, for assessing the safety of microbicides. Results of these evaluations are not yet available.

HPTN 059 was conducted by the Microbicide Trials Network (MTN), a clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). Prior to the establishment of the MTN, HPTN 059 study was led by the NIAID-funded HIV Prevention Trials Network (HPTN), from which the study gets its name.

At the site level, HPTN 059 was led by Smita Joshi, MBBS, in Pune, India; Jessica Justman, M.D., at Bronx-Lebanon Hospital; and Craig Hoesley, M.D., UAB.

In its pill form, tenofovir is a mainstay of one of the most widely used regimens for treating HIV. The active ingredient in tenofovir gel belongs to a class of anti-retroviral drugs called nucleotide reverse transcriptase inhibitors, which act against HIV by targeting a key enzyme the virus needs to copy itself before taking over a host cell. The topical gel form of tenofovir was not developed as treatment for HIV but as an approach to prevent the sexual transmission of HIV. Both oral and topical formulations were developed by Gilead Sciences, Inc., of Foster City, California, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia, in December 2006.

MTN will launch a series of other trials that will further evaluate the safety and adherence of tenofovir gel as well as look at its effectiveness for preventing HIV. Researchers will soon begin enrolling participants into MTN-002, the first trial of a candidate microbicide in pregnant women that seeks to understand the extent of drug absorption during pregnancy and the degree to which the active ingredient in tenofovir gel can be transferred to the fetus. Another trial, MTN-001, will be the first direct comparison of oral and vaginal gel preparations of tenofovir - looking at differences in drug absorption (systemically and locally) and adherence and acceptability of each approach separately and in combination. Finally, the VOICE Study (Vaginal and Oral Interventions to Control the Epidemic) will be the first effectiveness trial of a microbicide that women use every day instead of at the time of sexual intercourse. Moreover, VOICE will be the only trial evaluating two promising HIV prevention approaches in the same study: tenofovir gel and pre-exposure prophylaxis, or PrEP, an HIV prevention approach that involves daily use of oral anti-retrovirals.

Currently, tenofovir gel is being evaluated in a Phase IIb study being conducted at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban. The study, known as CAPRISA 004, will enroll 980 women. Unlike VOICE, researchers are evaluating a dosing strategy timed around sexual intercourse.

Other microbicide products have been or are currently being tested in clinical trials, although none is yet approved or available for use by women.