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

Background: Oral 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. Objective: MTN-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 Findings: We 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). Conclusions: Compared 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 Registration: ClinicalTrials.gov NCT00592124

A Randomized Trial to Assess Anti-HIV Activity in Female Genital Tract Secretions and Soluble Mucosal Immunity Following Application of 1% Tenofovir Gel

Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.ClinicalTrials.gov NCT00594373

Varieties of living things: Life at the intersection of lineage and metabolism

publication-status: Publishedtypes: Articl

Concentration ratios between dosing period by anatomic location.

<p>Pairs are included if at least one is above the limit of assay quantitation and the other is above the limit of assay detection. Other pairs are excluded. Serum and PBMC ratios are based on pooled values for data pairs from all times with research participants contributing more than one pair.</p

Ratio of unphosphorylated TFV to phosphorylated TFV-DP by anatomic sampling sites.

<p>Pairs are included if at least one value in the pair is above the limit of assay quantitation and the other is above the limit of assay detection. “N” is the number of pairs available meeting the inclusion criteria above. “Maximum N” is the number of possible pairs if all subjects at all visits provided a sample. C_max only includes US participants where multiple serum samples were available; the pair is defined by serum C_max matched with the corresponding PBMC TFV-DP concentration which is not necessarily peak TFV-DP after the same dose. Subscript “all” indicates that all PBMC-Serum pairs from each sample times are included, with participants contributing multiple pairs. All p<0.001 Wilcoxon signed rank test for TFV fmol/gm vs. TFV-DP fmol/gm. *Insufficient samples above the limit of assay quantitation and detection to estimate reliable medians given the inevaluable excluded pairs.</p

Accounting of research participants from screening to data analysis.

<p>Accounting of research participants from screening to data analysis.</p

Boxplots of TFV and TFV-DP concentrations by anatomic site.

<p>Side-by-side boxplots of end-of-period visit data for all participants by anatomic site and dosing regimen are shown. Each box indicates the interquartile range with center bar as median and whiskers 1.5 times the quartile. *Lower quartile (LQ) is below the limit of quantitation (LOQ), only median and above are shown. **Median is below LOQ, so the median of values above the LOQ are shown as a single bar. X-axis key: <i>anatomic location</i>, PBMC peripheral blood mononuclear cells, CVL cervicovaginal lavage, ECC endocervical cytobrush; <i>drug moiety</i>, TFV tenofovir, TFV-DP tenofovir diphosphate; <i>sample timing</i>, C_max peak concentration following dose at clinic visit, C_pre-dose concentration prior to dose at clinic visit, C_all pools values from all participants regardless of scheduled time relative to dose.</p