Prevotella bivia Influences Antiretroviral Pharmacokinetics and Viral Replication in an Ex Vivo Vaginal Tissue Model.

The vaginal microbiome plays a complex role in tenofovir's mucosal pharmacology. While the relative contribution of systemic versus local concentrations to PrEP PK/PD is an ongoing debate, the development of effective HIV prevention requires an understanding of events at the site of transmission. Our objective was to further understand the relationship between tenofovir mucosal pharmacology and non-optimal vaginal microbiota using the ex vivo vaginal tissue model. Vaginal and cervical explants were produced from cadaver tissue using a biopsy punch. Explants were incubated with Prevotella bivia (103-105 colony forming units/ml) with and without tenofovir for 24 h. TFVdp and endogenous adenosine triphosphate (dATP) were quantified using liquid chromatography tandem mass spectroscopy. Explants were then challenged with 106 TCID50 the viral concentration where 50% of tissue cultures are infected, of HIVJR-CSF for 3 h. Explants were cultured on gel-foam rafts for 48 h then collected for HIV RNA quantification using RT-qPCR. TFVdp formation in vaginal tissue was approximately 76% lower in anaerobic conditions (p = 0.2) compared to aerobic. While dATP concentrations did not significantly differ between any Prevotella bivia concentrations and the Prevotella-free control, TFVdp and TFVdp:dATP ratio in vaginal tissue decreased as Prevotella bivia concentrations increased, although not statistically. Unexpectedly, tenofovir efficacy increased as Prevotella bivia concentrations increased. The ex vivo tissue model was successful in demonstrating the pharmacology of TFVdp is affected by Prevotella bivia. Viral replication was also affected by Prevotella bivia; therefore, further work is needed to fully understand effects on tenofovir pharmacodynamics.