Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel

Abstract

Background: Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex.

Methods: Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity.

Results: Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P < .001) in CVL, 75% and 71% (P < .001) in vaginal tissue, and 75% (P = .06) and 55% (P < .001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration.

Conclusions: Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis.

Keywords: HIV; MTN-011; pharmacokinetics; post-coital; tenofovir gel.

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Tenofovir (TFV) drug levels are reduced in cervicovaginal lavage (CVL) samples following unprotected sex. The concentration of TFV in CVL at each visit was measured (ng/mL); samples with drug levels below the lower limits of quantification (LLOQ) were set at the LLOQ (n = 2 at each visit). The line indicates the median, and the percentage change in drug levels in paired samples is shown (−1 hour gel/no sex vs −1 hour gel/sex; −24 hour gel/no sex vs −24 hour gel/sex, and −1 hour gel/sex vs 1 dose before and 1 dose after sex). **P < .01; ***P < .001; Wilcoxon rank sum adjusted for multiple comparisons. Abbreviation: BAT, 1 dose before and 1 dose after.

Figure 2.

Tenofovir (TFV) drug levels are reduced in vaginal and cervical tissue following unprotected sex. The concentrations of TFV in vaginal (A) and cervical (B) tissue at each visit were measured (ng/mg tissue). Biopsies with drug levels below the lower limits of quantification (LLOQ) were set at the LLOQ. The line indicates the median, and the percentage change in drug levels in paired samples is shown (−1 hour gel/no sex vs −1 hour gel/ sex; −24 hour gel/no sex vs −24 hour gel/sex; and −1 hour gel/sex vs 1 dose before and 1 dose after sex). *P < .05; **P < .01; ***P < .001; Wilcoxon rank sum adjusted for multiple comparisons. Abbreviation: BAT, 1 dose before and 1 dose after.

Figure 3.

Tenofovir–diphosphate (TFV–DP) levels are reduced in cervical tissue following unprotected sex. The concentrations of the active metabolite, TFV–DP, were measured in cervical (A) and vaginal (B) tissue at each visit (fmol/mg tissue). Biopsies with drug levels below the lower limits of quantification are shown (−1 hour gel/no sex vs −1 hour gel/ sex; −1 hour gel/sex vs 1 dose before and 1 dose after sex). *P < .05; **P < .01; Wilcoxon rank sum adjusted for multiple comparisons. Abbreviation: BAT, 1 dose before and 1 dose after.

Figure 4.

Inhibitory activity of cervicovaginal lavage (CVL) against human immunodeficiency virus (HIV) infection in vitro. The percentage inhibition of HIV infection by CVL at each visit was determined. The lines indicate the median for the group, and values below zero indicate enhancement. The anti-HIV activity is compared between the paired no gel baseline visits (no gel/no sex vs no gel/sex) and between post-coital gel applications and no gel/sex visits. *P < .05; ***P < .001; Wilcoxon rank sum adjusted for multiple comparisons. Abbreviation: BAT, 1 dose before and 1 dose after.

Figure 5.

Inhibitory activity of cervicovaginal lavage (CVL) against herpes simplex virus type 2 (HSV-2) infection in vitro. The percentage inhibition of HSV-2 infection by CVL at each visit was determined. The lines indicate the median for the group. The anti-HSV activity is compared between the paired no gel baseline visits (no gel/no sex vs no gel/sex) and between post-coital gel applications and no gel/sex visits. **P < .01; ***P < .001; Wilcoxon rank sum adjusted for multiple comparisons. Abbreviation: BAT, 1 dose before and 1 dose after.