MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Craig W Hendrix,Sharavi Gandham,Kailazarid Gomez,Lydia Soto-Torres,Namandje N Bumpus,Barbra A Richardson,Jessica Justman,Clemensia Nakabiito,Karen Patterson,Craig Hoesley,Beatrice A Chen,Vijayanand Guddera,Alexandra M Minnis,Robert Salata

doi:10.1371/journal.pone.0055013

Abstract

BackgroundOral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.ObjectiveMTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.Methods and FindingsWe enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).ConclusionsCompared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy.Trial RegistrationClinicalTrials.gov NCT00592124

Highlights

Four recently completed clinical trials demonstrated the effectiveness of both vaginal and oral tenofovir (TFV)-containing regimens as pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) infection in susceptible men, women, and partners of HIV-infected individuals [1,2,3,4]
Bridging data that connects drug concentrations in these more distant sites – blood and cervicovaginal fluid - to vaginal and rectal tissue in association with seroconversion events is needed to identify target drug concentrations in the mucosal tissue sites associated with protection of HIV infection
We report the results of such a PK bridging study, Microbicide Trials Network (MTN)-001, which directly compares vaginal TFV gel and oral tenofovir disoproxil fumarate (TDF) tablets in a cross-over design removing inter-individual variation to provide more precise paired comparisons

Summary

Introduction

Four recently completed clinical trials demonstrated the effectiveness of both vaginal and oral tenofovir (TFV)-containing regimens as pre-exposure prophylaxis (PrEP) to prevent HIV infection in susceptible men, women, and partners of HIV-infected individuals [1,2,3,4]. Knowledge of active drug at the site of action, arguably the vaginal tissue in women, linked with seroconversion events in these clinical trials could provide critical information for interpreting outcomes and guiding dose and frequency decisions for future clinical trials by indicating the critical concentration needed to prevent infection. Bridging data that connects drug concentrations in these more distant sites – blood and cervicovaginal fluid - to vaginal and rectal tissue in association with seroconversion events is needed to identify target drug concentrations in the mucosal tissue sites associated with protection of HIV infection. This knowledge would be of substantial benefit to future PrEP drug development. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development

Results

Discussion

Conclusion