Repeated rectal application of a hyperosmolar lubricant is associated with microbiota shifts but does not affect PrEP drug concentrations: results from a randomized trial in men who have sex with men

Abstract

Introduction: Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is highly effective in preventing HIV infection among men who have sex with men (MSM). The effects of consistent personal lubricant use in the rectum on tissue PrEP drug concentrations and the rectal microbiota are unknown. We investigated rectal PrEP drug concentrations and the microbiota in MSM before and after repeated rectal application of a hyperosmolar lubricant.

Methods: We randomized 60 HIV-negative MSM to apply 4 mL of hyperosmolar rectal lubricant daily (n = 20), take daily oral TDF/FTC (n = 19), or both (n = 21) for seven days. Blood, rectal biopsies and rectal secretions were collected via rigid sigmoidoscopy before and on day 8 after product use. Tenofovir (TFV) and FTC as well as their intracellular metabolites tenofovir-diphosphate (TFV-DP), FTC-triphosphate (FTC-TP) were measured by HPLC-mass spectrometry. Rectal mucosal microbiota was sequenced with 16S rRNA sequencing using Illumina MiSeq.

Results: Seven days of lubricant application was not associated with differences in PrEP drug concentrations in rectal tissue or secretions. Lubricant use was associated with a decrease in the relative abundance of the Bacteroides genus (p = 0.01) and a non-significant increase in the Prevotella genus (p = 0.09) in the rectum. PrEP drug concentrations in rectal tissue and secretions were not associated with microbiota composition or diversity either before or after lubricant use.

Conclusions: Repeated rectal application of a hyperosmolar lubricant does not affect mucosal PrEP drug concentrations but is associated with changes in the rectal microbiome.

Keywords: HIV; anti-retroviral agents; gut microbiota; lubricant; men who have sex with men; pre-exposure prophylaxis.

Figure 1

PrEP drug concentrations in rectal secretions, rectal tissue and PBMC in study participants who took oral PrEP stratified by lubricant use. TFV and FTC concentrations were measured by HPLC‐mass spectrometry and are presented in ng/swab for rectal secretions. Intracellular metabolites tenofovir‐diphosphate (TFV‐DP) and emtricitabine‐triphosphate (FTC‐TP) in biopsies and PBMCs were also measured by HPLC‐mass spectrometry and were normalized to concentrations per mg of tissue and per 10⁶ cells respectively. All p‐values for median differences between study arms by Wilcoxon rank sum test >0.25. Drug levels below the limit of quantification are displayed at 10°. FTC, emtricitabine; PBMC, peripheral blood mononuclear cell; PrEP, pre‐exposure prophylaxis; TFV, tenofovir; TFV‐DP, tenofovir‐diphosphate.

Figure 2

Lubricant use is associated with shifts in rectal microbiota composition. Mean relative abundance of the top 10 most abundant genera in the rectal mucosa before and after study product use stratified by study arm: Lube only, PrEP only, or PrEP and Lube use for seven days (a). Change in mean relative abundance before and after study product use in terms of lubricant and PrEP use for the top 10 genera were examined by linear regression modelling (b). PrEP, pre‐exposure prophylaxis.

Figure 3

Microbiota species are not associated with differences in tissue PrEP drug concentrations. Associations by Spearman correlation between gut microbial diversity (Shannon index), the relative abundance of Bacteroides, Prevotella or an unspecified genus of Prevotellaceae as measured before study product use, and PrEP drug concentrations in rectal tissues following seven days of oral TDF/FTC dosing. All p‐values for correlations >0.25. Similar results were seen for PBMC and rectal secretions specimens. FTC, emtricitabine; PBMC, peripheral blood mononuclear cell; PrEP, pre‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.

Figure 4

Microbiota composition are not associated with changes in PrEP drug concentrations. Representative data for TFV‐DP and FTC‐TP drug concentrations in rectal tissues following seven days of oral TDF/FTC dosing were stratified at the median into low (blue circles) and high (red circles) drug level groups. Bray–Curtis and Jaccard distance‐based principal coordinates analysis (PCoA) plots are shown for rectal tissues demonstrating no separation between specimens with low and high drug levels. Similar results were seen for PBMC and rectal secretions specimens. FTC, emtricitabine; PBMC, peripheral blood mononuclear cell; PrEP, pre‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TFV‐DP, tenofovir‐diphosphate.