Vaginal Microbiome May Render HIV Tenofovir Microbicide Less Effective

Tenofovir is a common drug used as pre-exposure prophylaxis (PrEP) to prevent HIV infection. In clinical trials, tenofovir has demonstrated great efficacy in men, but not consistently in women. For example, the efficacy of antiretroviral drugs to prevent HIV infection ranged from −49% (VOICE trial; ClinicalTrials.gov identifier: NCT00705679)¹ to 62.2% (TDF2 trial; ClinicalTrials.gov identifier: NCT00448669)² for daily oral tenofovir, and from 0% (FACTS trial; ClinicalTrials.gov identifier: NCT01386294)³ to 39% (CAPRISA 004 trial; ClinicalTrials.gov identifier: NCT00441298)⁴ for daily or coital vaginally applied tenofovir gel. It is unknown whether these differences in efficacy are a consequence of poor adherence among women, there is a biological explanation, or both.

In a recent publication in Science, Nichole Klatt, PhD, associate professor in the department of pharmaceutics at the University of Washington in Seattle, and colleagues used stored samples from 688 women enrolled in the CAPRISA 004 clinical trial to investigate whether the composition of the vaginal microbiome might modulate the microbicide efficacy of tenofovir gel.⁵ In this study, cervicovaginal lavages from women who were assigned to either the tenofovir or the placebo-gel arm were analyzed by protein mass spectrometry and 16s ribosomal RNA sequencing.

Two major vaginal community groups were identified: one in which Lactobacillus was dominant (“healthy vaginal microbiome”) and the other dominated by non-Lactobacillus microbiota (typically associated with bacterial vaginosis).

Using these data, the investigators found that tenofovir gel was 3 times more effective in the 407 women with a Lactobacillus-dominant vaginal microbiome compared with 281 women whose vaginal microbiome had ≤50% Lactobacillus. Tenofovir gel reduced the incidence of HIV infection by 61% (P =.013) in women with Lactobacillus-dominant vaginal flora but only 18% (P =.644) in women with non-Lactobacillus bacteria. Gardnerella vaginalis tended to predominate in the women for whom tenofovir was less effective.

Mucosal levels of tenofovir were consistently lower in non-Lactobacillus women and negatively correlated with the presence of Gardnerella vaginalis and other anaerobic bacteria associated with bacterial vaginosis. Of note, the investigators found that Gardnerella vaginalis (and other bacterial vaginosis-associated bacteria) could rapidly metabolize and inactivate the drug in vitro. This observation provides a biological mechanism likely contributing to varying levels of HIV prevention efficacy across topical microbicide trials.

In an interview with Infectious Disease Advisor, Dr Klatt commented that “Our study suggest[s] that women with non-Lactobacillus-dominant vaginal flora might be more sensitive to the timing of tenofovir gel application and sub-optimal adherence. On the other hand, bacterial communities rich in Lactobacillus may improve efficacy of topical microbicide gels. Vaginal microbiota screening could be a useful tool to enhance efficacy of HIV prevention in women.”

“Further studies should evaluate if interventions aimed to manipulate the microbiome composition will be effective. We are also interested in investigating the role of the gut microbiome composition in pharmacokinetics of oral antiretrovirals and the role of the vaginal microbiome in affecting [the] efficacy of other candidate PrEP drugs,” Dr Klatt concluded.

References

1. Marrazzo JM, Ramjee G, Richardson BA, et al; VOICE Study Team. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509-518. doi:10.1056/NEJMoa1402269
2. Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434. doi:10.1056/NEJMoa1110711
3. Rees H, Delany-Moretlwe SA, Lombard C, et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. Presented at the: Conference on Retroviruses and Opportunistic Infections (CROI) 2017, February 13-16, 2017; Seattle, Washington. Abstract 26LB.
4. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168-1174. doi: 10.1126/science.1193748
5.  Klatt NR, Cheu R, Birse K, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356(6341):938-945. doi:10.1126/science.aai9383