Vaginal microbiome modulates topical antiretroviral drug pharmacokinetics.

JCI Insight
Ekaterina TanevaBetsy C Herold

Abstract

Tenofovir gel and dapivirine ring provided variable HIV protection in clinical trials, reflecting poor adherence and possibly biological factors. We hypothesized that vaginal microbiota modulates pharmacokinetics and tested the effects of pH, individual bacteria, and vaginal swabs from women on pharmacokinetics and antiviral activity. Tenofovir, but not dapivirine, uptake by human cells was reduced as pH increased. Lactobacillus crispatus actively transported tenofovir leading to a loss in drug bioavailability and culture supernatants from Gardnerella vaginalis, but not Atopobium vaginae, blocked tenofovir endocytosis. The inhibition of endocytosis mapped to adenine. Adenine increased from 65.5 μM in broth to 246 μM in Gardnerella, but decreased to 9.5 μM in Atopobium supernatants. This translated into a decrease in anti-HIV activity when Gardnerella supernatants or adenine were added to cultures. Dapivirine was also impacted by microbiota, as drug bound irreversibly to bacteria, resulting in decreased antiviral activity. When drugs were incubated with vaginal swabs, 30.7% ± 5.7% of dapivirine and 63.9% ± 8.8% of tenofovir were recovered in supernatants after centrifugation of the bacterial cell pellet. In contrast, no impact o...Continue Reading

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Citations

Sep 11, 2018·Clinical Pharmacology and Therapeutics·Craig W Hendrix
Oct 16, 2019·Annual Review of Medicine·Jared M BaetenSharon L Hillier
Sep 5, 2020·The Journal of Obstetrics and Gynaecology Research·Xinyuan LiangXiaomin Xiao
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Feb 20, 2020·Nature Reviews. Urology·Paweł ŁaniewskiMelissa M Herbst-Kralovetz
Dec 15, 2020·Current Pharmacology Reports·Joseph L Dempsey, Julia Yue Cui
Mar 16, 2021·Current HIV/AIDS Reports·Marta Rodriguez-GarciaMimi Ghosh
Apr 18, 2021·Expert Review of Clinical Pharmacology·Carlo BastianelliGiuseppe Benagiano
Jul 20, 2021·Advanced Drug Delivery Reviews·José das NevesBruno Sarmento
Jan 13, 2022·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Ignacio Rodríguez-IzquierdoMa Ángeles Muñoz-Fernández

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Methods Mentioned

BETA
PCR

Software Mentioned

GraphPad Prism

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