Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women

Abstract

Background: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women.

Methods: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report.

Results: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR.

Conclusions: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women.

Clinical trials registration: NCT02010593.

Keywords: dapivirine; menopause; microbicide; pre-exposure prophylaxis; vaginal rings.

© The Author(s) 2018. 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.

Flowchart of study participants.

Figure 2.

Anti-HIV activity in cervicovaginal lavage by study arm. A, dapivirine; B, placebo. Abbreviation: HIV, human immunodeficiency virus.

Figure 3.

Pharmacokinetic and pharmacodynamic correlations from cervicovaginal lavage. The fitted curves are the arcsine of % anti-HIV-1 activity vs log10 of drug concentrations. Week 4: Hill slope 1.12, EC50 2.5 ng/mL. Week 12: Hill slope 0.80, EC50 1.44 ng/mL. Overall: Hill slope 1.03, EC50 2.03 ng/mL. Abbbreviation: DPV, dapivirine.

Figure 4.

Distribution of the difference in percent cells between week 12 and baseline (week 0) in each treatment arm, faceted by cell subset and parent. Abbreviations: NA, not applicable; VR, vaginal ring.