Vaginal microbiome, antiretroviral concentrations, and HIV genital shedding in the setting of hormonal contraception initiation in Malawi.

OBJECTIVE: The aim of this study was to understand how vaginal microbiota composition affects antiretroviral concentrations in the setting of hormonal contraception initiation. METHODS: Cervicovaginal fluid (CVF) concentrations of tenofovir, lamivudine, and efavirenz from 73 Malawian women with HIV were compared before and after initiation of depot-medroxyprogesterone acetate (DMPA) or levonorgestrel implant. We evaluated antiretroviral concentrations and vaginal microbiota composition/structure in the context of contraception initiation and predicted genital shedding using multivariable repeated measurements models fit by generalized estimating equations. RESULTS: Mean lamivudine CVF concentrations decreased 37% 1 month after contraception initiation. Subgroup analyses revealed a 41% decrease in women 1 month after initiating levonorgestrel implant, but no significant difference was observed in DMPA group alone. Tenofovir, lamivudine, and efavirenz CVF concentrations were positively correlated with anaerobic bacteria associated with nonoptimal vaginal microbiota. Risk of genital HIV shedding was not significantly associated with tenofovir or lamivudine CVF concentrations [tenofovir relative risk (RR): 0.098, P = 0.75; lamivudine RR: 0.142, P = 0.54]. Lack of association between genital HIV shedding and efavirenz CVF concentrations did not change when adjusting for vaginal microbiota composition and lamivudine/tenofovir CVF concentrations (RR: 1.33, P = 0.531). CONCLUSION: No effect of hormone initiation on genital shedding provides confidence that women with HIV on either DMPA or levonorgestrel implant contraception will not have compromised ART efficacy. The unexpected positive correlation between antiretroviral CVF concentrations and certain bacterial taxa relative abundance requires further work to understand the mechanism and clinical relevance.

Translational Models to Predict Target Concentrations for Pre-Exposure Prophylaxis in Women.

The HIV epidemic remains a significant public health burden. Women represent half of the global HIV epidemic, yet there is an urgent need for a variety of prevention options to meet the needs of more women. Pre-exposure prophylaxis (PrEP) is a valuable prevention tool that uses antiretrovirals before a potential HIV exposure to prevent virus transmission. Development of effective preventive drug regimens for women is dependent on convenient dosing schedules and routes of administration, and on identifying defined target concentrations in mucosal tissues that provide complete protection against HIV transmission. There is a critical need for a translational model that can accurately predict in vivo target concentrations that are completely protective against HIV infection. There is no gold-standard preclinical model to predict PrEP efficacy. In this study, we review the strengths and limitations of three different preclinical models and their utility in predicting target concentrations in the female genital tract: humanized mice, non-human primates, and the ex vivo tissue model.