June 2, 2017

Pharmaceutics lab team learns why HIV prevention drug is not as effective in some women

Klatt lab team’s findings published in Science offer solutions to increase efficacy

UW Pharmaceutics Klatt Lab's graduate student Ryan Cheu, Associate Professor Nichole Klatt, and post-doc Alex Zevin

UW Pharmaceutics Klatt Lab’s graduate student Ryan Cheu, Associate Professor Nichole Klatt, and post-doc Alex Zevin

More than 1 million women are infected with HIV annually, and the majority of these new infections occur in young women in sub-Saharan Africa, with South Africa having among the highest incidence rates. Tenofovir is an antiretroviral drug that is used to prevent HIV infection (pre-exposure prophylaxis, “PrEP”). In clinical trials, tenofovir was effective for men, efficacy was highly variable in women.

In an article published in Science, UW School of Pharmacy Associate Professor of Pharmaceutics Nichole Klatt, along with UW graduate student Ryan Cheu, post-doc Alex Zevin, and Adam Burgener’s lab at the Public Health Agency of Canada found that tenofovir used as a topical vaginal gel for HIV prevention was more efficacious in women with healthy vaginal bacteria than bacteria associated with vaginosis, such as Gardnerella vaginosis. Furthermore, the team went on to determine that the reason tenofovir is less effective in women with G. vaginalis is because this bacteria can metabolize, or break down, the drug.

Their findings suggest that women with non–Lactobacillus-dominant vaginal bacteria may be more sensitive to the timing of gel application and adherence, whereas bacterial communities with Lactobacillus dominance may facilitate an environment more conducive to the topical PrEP efficacy.

The international team studied 688 women and investigated whether vaginal microbiota modulated tenofovir gel PrEP efficacy. It turned out that tenofovir reduced HIV infection by a 61% in women who were Lactobacillus-dominant—a staggering three-fold difference over women whose systems were non-Lactobacillus dominant. In non-Lactobacillus dominant systems, Tenofovir only reduced HIV incidency by 18%. Both groups had similar adherence to applying the gel.

The rapid depletion of tenofovir by G. vaginalis and other bacterial vaginosis (BV)-associated anaerobic bacteria by metabolism provides a biological mechanism likely contributing to a multifactorial process, including increased vaginal inflammation and adherence, leading to varying levels of HIV prevention efficacy observed across topical microbicide trials. Their data indicate that G. vaginalis is capable of decreasing the active drug by metabolizing tenofovir before drug uptake by target cells.

These findings provide evidence about the importance of vaginal microbial communities on prevention efficacy, which could help improve this HIV specific prevention strategy for women.

Because Lactobacillus dominance corresponds with a relatively low vaginal pH, typically below 4.5, vaginal pH testing may be a pragmatic approach to identify women most likely to benefit from topical tenofovir-containing microbicides and potentially other prevention strategies.

However, current treatment strategies for BV may not be sufficiently efficacious and better strategies that can both deplete anaerobic bacteria and support recolonization with Lactobacillus may be required. If validated in other trials, this could be a compelling reason for integrating topical microbicide implementation with sexual and reproductive health services so that vaginal health becomes an integral component of HIV prevention approaches.

Related: A microbiome variable in the HIV-prevention equation: Vaginal microbes thwart an antiretroviral microbicide

Associated Press Coverage: Women’s bacteria thwarted attempt at anti-HIV vaginal gel

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