MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments

Abstract

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.

Conflict of interest statement

Competing Interests: CONRAD provided regulatory support for the tenofovir gel IND given their ongoing management of tenofvoir gel development. However, NIH held the IND for the tenofovir gel in this study, not CONRAD, not Gilead. CONRAD did not provide financial support. Gilead had no role in this study - neither the design, drug supply, data collection and analysis, decision to publish, or preparation of the manuscript. MTN paid for the tenofovir gel. Finally, there are no restrictions to data from MTN-001 which is controlled by CONRAD or Gilead Sciences. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Accounting of research participants from screening to data analysis.

Figure 2. Serum TFV and TFV-DP concentration versus time.

Serum TFV (panel A) and PBMC TFV-DP (panel B) concentration versus time plots are shown for the observed 8 hour interval following a dose in clinic according to dosing regimen. Median with asymmetric upper and lower quartiles is shown. Values are only for the 70 US participants where all 6 PK samples were collected.

Figure 3. Boxplots of TFV and TFV-DP concentrations by anatomic site.

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: anatomic location, PBMC peripheral blood mononuclear cells, CVL cervicovaginal lavage, ECC endocervical cytobrush; drug moiety, TFV tenofovir, TFV-DP tenofovir diphosphate; sample timing, Cmax peak concentration following dose at clinic visit, Cpre-dose concentration prior to dose at clinic visit, Call pools values from all participants regardless of scheduled time relative to dose.