Impact of vaginal microbiome communities on HIV antiretroviral-based pre-exposure prophylaxis (PrEP) drug metabolism.

Ryan K Cheu,Casey Kim,Adam D Burgener,Margaret Fischl,Avie Ha,Luca Schifanella,Violeta J Rodriguez,Charlene J Miller,Christina Lee,Andrew T Gustin,Maria L Alcaide,Kelly B Arnold,Nichole R Klatt,Daniel C Douek

doi:10.1371/journal.ppat.1009024

Abstract

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women.

Highlights

Women account for more than half of the 35 million people living with human immunodeficiency virus (HIV), and young women are among the most vulnerable to HIV acquisition worldwide
Lactobacillus spp. prevent the colonization of dysbiotic bacteria, which is associated with increased HIV transmission
We show that primary bacteria from women with dysbiosis impact pre-exposure prophylactics (PrEP) drug levels and kinetics

Summary

Introduction

Women account for more than half of the 35 million people living with human immunodeficiency virus (HIV), and young women are among the most vulnerable to HIV acquisition worldwide. While oral PrEP with Tenofovir/Emtricitabine (TDF/FTC) has demonstrated efficacy in men who have sex with men (MSM) [3], both oral and topical PrEP have yielded highly variable efficacy results for women [4]. This variability has been attributed to adherence or the presence of semen, other biological issues such as the vaginal microbiome can play a role. Recent studies have highlighted the role these microbes can play in diminishing the efficacy of HIV prevention for women [4]

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