Microbiome Composition and Female Genital Tract Compartmental Antiretroviral Drug Exposure in HIV-Infected Women Pubblico

Abstract

Background: Optimal female genital tract (FGT) antiretroviral exposure is essential for genital virologic suppression and relevant to HIV prevention methods utilizing antiretroviral therapy in women. Changes in FGT microbiota are common and occur with bacterial vaginosis (BV), sexually transmitted infections (STIs), and certain hygienic practices, and may alter genital pH and other factors that influence compartmental drug penetration. We therefore characterized the FGT microbiome serially over a menstrual cycle in HIV-infected women and examined the relationship between FGT microbiota and antiretroviral concentrations.

Methods: Virologically suppressed HIV-infected women on tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and atazanavir/ritonavir (ATV/RTV) without clinical BV/STIs were prospectively enrolled. Twenty participants underwent 6 twice-weekly visits (N=117) over one menstrual cycle where paired samples for plasma and cervicovaginal trough antiretroviral concentrations, and cervicovaginal lavage (CVL) were collected. Antiretroviral concentrations were measured using high-performance liquid chromatography-tandem mass spectroscopy. Illumina MiSeq 16S rRNA gene sequencing of CVL samples, with analysis using Dirichlet Multinomial Mixtures, clustered each participant-visit into a unique microbiome community type (CT) based on similar bacterial taxa abundances. Generalized mixed models were used to evaluate predictors of microbiome CT and to estimate the association between CT and FGT antiretroviral concentrations controlling for significant predictors.

Results: Participants were 95% African American with median age 38 (range, 24-48) years. High-quality sequencing data (N=109) lead to 3 unique microbiome CTs: a low-diversity CT dominated by Lactobacillus (N=40), and intermediate- (N=28) and high-diversity (N=41) CTs with increased abundance of multiple anaerobic taxa. In multivariable models, controlling for plasma antiretroviral concentrations, body mass index, recent sexual activity and CVL blood contamination, low- and high-diversity CTs were associated with 52% (95% Confidence Interval (CI), 31-88%) and 46% (CI, 23-92%) of the ATV concentrations (P=0.03), and 51% (CI, 28-91%) and 54% (CI, 23-127%) of the TDF concentrations (P=0.06) in the FGT, respectively, compared to intermediate-diversity CTs. FTC concentrations were not significantly associated with CT (P=0.27).

Conclusions: We demonstrate in this proof-of-concept study that certain microbiome CTs are associated with decreased FGT antiretroviral drug concentrations. Validation of these findings in larger studies and with additional antiretrovirals could influence antiretroviral drug choice for biomedical HIV prevention in women.

Table of Contents

Introduction. 1

Background. 4

Methods. 11

Results. 19

Discussion/Conclusions. 23

References. 31

Tables and Figures. 41

1. Table 1. Baseline demographic and clinical characteristics of study participants. 41

2. Figure 1. Alpha-diversity by Shannon Diversity Index of microbiome community groups. 42

3. Figure 2. Relative abundance of bacterial taxa by microbiome community group. 43

4. Figure 3. Timeline of female genital tract microbiome community types by menstrual cycle phase over a single menstrual cycle for 20 HIV-infected women on antiretroviral therapy. 44

5. Table 2. Distribution of clinical factors and C24 antiretroviral drug concentrations by FGT microbiome community type over the menstrual cycle in 20 HIV-infected women. 45

6. Table 3. Univariate pairwise associations between FGT microbiome community types and clinical predictors among 20 HIV-infected women over the menstrual cycle. 47

7. Table 4. Univariate associations between clinical predictors and genital antiretroviral drug concentrations among 20 HIV-infected women over the menstrual cycle. 49

8. Table 5. Association between the female genital tract microbiome and the female genital tract concentrations of TDF, FTC and RTV-boosted ATV among 20 HIV-infected women. 51

9. Figure 4. Estimated geometric mean female genital tract antiretroviral drug concentrations by microbiome community type from multivariable models. 52

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Medicine and Surgery
Parola chiave	antiretroviral therapy vaginal microbiome HIV/AIDS pharmacology
Committee Chair / Thesis Advisor	Ofotokun, Igho, Emory University
Committee Members	Qayed, Muna , Emory University Klein, Mitchel, Emory University

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