Study of tenofovir vaginal gel shows daily dosing ineffective due to lack of adherence

(Press-News.org) ARLINGTON, VIRGINIA (12:15 EST MARCH 4, 2013) — Researchers with the Microbicide Trials Network (MTN) today announced results of the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study at the Conference for Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia. The VOICE study tested oral and vaginal antiretroviral-based approaches as HIV prevention methods in 5,029 women in South Africa, Uganda, and Zimbabwe. Funded by the U.S. National Institutes of Health and managed by the MTN, the VOICE study was a major undertaking, which has provided important data regarding drug safety, effectiveness, acceptability and adherence.

"The principal investigators of the study, Drs. Jeanne Marazzo and Zvavahera Mike Chirenje, and the entire VOICE team have done an outstanding job," said CONRAD Executive Director Gustavo Doncel, M.D., Ph.D.

VOICE launched in September 2009 as a Phase IIB safety and effectiveness study to compare 3 different once-daily HIV prevention strategies: 1) a pill of combination emtricitabine and tenofovir (Truvada®), 2) a pill containing only tenofovir (Viread®), and 3) tenofovir 1% vaginal gel. Study participants received ongoing HIV risk-reduction counseling, condoms, and diagnosis and treatment of sexually transmitted infections throughout the trial. They were tested monthly for HIV and quarterly for drug levels.

In an evaluation of plasma samples in a subset of the women, drug was detected on average in 28% of participants taking oral tenofovir, 29% of participants taking oral Truvada, and 23% of participants in the vaginal gel study arm. Unfortunately, due to the low adherence, none of the products were deemed effective in reducing HIV acquisition in this particular trial. The estimates of effectiveness for both oral tenofovir and Truvada were less than zero. The study showed a 14.7% reduction of HIV infection in the tenofovir gel arm, when compared to placebo gel. This level of protection, however, was not statistically significant.

Some of the previous studies using the same antiretrovirals in tablet or gel form for HIV prevention showed effectiveness. In particular, CAPRISA 004, a study completed in 2010 using the same tenofovir vaginal gel used in the VOICE trial, showed an average of a 39% reduction in HIV infections and a 54% reduction in women who used it at least 80% of the time. Additionally, tenofovir gel reduced the risk of herpes genital infections by 51%. The dosing regimen was different than the daily dosing used in the VOICE study – women in CAPRISA 004 were required to insert 1 dose before sex and 1 dose after sex, not to exceed 2 doses in 24 hours (a regimen dubbed BAT24). CAPRISA 004 was the first trial to show that a topical product containing tenofovir could reduce HIV infection and suggests that a dosing method that requires women to use the product around the time of sex, versus daily dosing, may be preferable to women.

To that end, FACTS 001, a study sponsored by CONRAD, funded by USAID, the Bill & Melinda Gates Foundation and the South African government, and co-chaired by the South African scientists, Drs. Helen Rees and Glenda Gray, is currently being conducted at 9 sites in South Africa. The trial replicates the dosing regimen used in CAPRISA 004 (i.e., BAT 24). FACTS 001 is using a variety of methods to collect information about gel use, condom use, and sexual behavior in order to measure adherence. The study has enrolled close to 1,900 participants and is expected to be complete at the end of 2014. FACTS 001 is an important study as it is designed to confirm the results obtained in CAPRISA 004 and contribute to the approval of tenofovir gel as a pericoital method for prevention of HIV infection in women.

The VOICE study also found that single women under 25 were the least likely to use the product and the most likely to acquire HIV. "The VOICE results highlight the gravity of the epidemic, especially in young, unmarried women, and the importance of developing products that appeal to them. At CONRAD, we remain committed to designing HIV prevention products based on innovation and sound product development strategies," said Dr. Doncel.

"The results of the CAPRISA 004 and VOICE trials illustrate that there are some women who may only want to use a product when they know they are having sex and the FACTS 001 study plays a very important role in testing that hypothesis. We need more information on the type of products that women who are at the highest risk level want and will use," said Dr. Jill Schwartz, CONRAD's Medical Director.

### CONRAD, who has a royalty-free license to tenofovir gel from Gilead Sciences, manufactured and supplied the gel for these trials. CONRAD also holds the public sector licensing rights in developing countries for the prevention of genital herpes, a common sexually transmitted infection, through the use of tenofovir gel.

CONRAD was established in 1986 and is a Division of the Department of Obstetrics and Gynecology at Eastern Virginia Medical School (EVMS) in Norfolk, VA, where it has laboratories and a clinical research center. Thanks to our funders, which include the U.S. Agency for International Development and the Bill and Melinda Gates Foundation, CONRAD is a leader in researching and developing new contraceptive options and products to prevent HIV and STIs. The main office is located in Arlington, VA and we collaborate with academic and research institutions around the world.