Hypo-osmolar rectal douche tenofovir formulation prevents simian/human immunodeficiency virus acquisition in macaques

Abstract

In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques. Single TFV HOsm high-dose douches achieved peak plasma TFV levels similar to daily oral PrEP, while other formulations yielded lower concentrations. Rectal tissue TFV-diphosphate (TFV-DP) concentrations at the portal of virus entry, however, were markedly higher after HOsm douching than daily oral PrEP. Repeated douches led to significantly higher plasma TFV and higher TFV-DP concentrations in rectal tissue at 24 hours compared with single douches, without detectable mucosal or systemic toxicity. Using stringent repeated intrarectal SHIV exposures, single HOsm high-dose douches delivered greater protection from virus acquisition for more than 24 hours compared with oral PrEP. Our results demonstrate a rapid delivery of protective TFV doses to the rectal portal of virus entry as a potential low-cost and safe PrEP alternative.

Topical Microbicides in HIV Prevention: State of the Promise

“…A phase I dose escalation study of a tenofovir douche demonstrated excellent acceptability, no toxicity, full explant suppression, and colorectal tissue cell concentrations of tenofovir diphosphate from 1 h through 72 h after a single dose that exceeded concentrations achieved with the on-demand douche or oral TDF/FTC (48,49). Macaque studies indicate superior SHIV (simian/human immunodeficiency virus) protection with a single weekly tenofovir douche when compared to daily oral TDF/FTC dosing (50). The PREVENT Program has recently begun phase I studies of a douche formulation of griffithsin, a red algae-derived lectin that is a highly potent viral entry inhibitor with broad activity against HIV, HSV-2, HCV (hepatitis C virus), and other enveloped viruses.…”