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Safety and Pharmacokinetics of Dapivirine Vaginal Rings in Postmenopausal US Women
Beatrice A. Chen1; Craig Hoesley2; Robert A. Salata3; Jingyang Zhang4; Lydia E. Soto-Torres5; Annalene Nel6; Sherri Johnson7; Charlene S. Dezzutti1; Mark A. Marzinke8; for the on behalf of the MTN-024/IPM 031 Protocol Team for the Microbicide Trials Network
1Univ of Pittsburgh, Pittsburgh, PA, USA;2Univ of Alabama at Birmingham, Birmingham, AL, USA;3Case Western Reserve Univ, Cleveland, OH, USA;4SCHARP, Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA;5NIAID, NIH, Bethesda, MD, USA;6Intl Partnership for Microbicides, Paarl, South Africa;7FHI 360, Washington, DC, USA;8Johns Hopkins Univ, Baltimore, MD, USA
Microbicide studies have not been conducted among postmenopausal women although this age group may be at higher risk for HIV than reproductive-age women due to vaginal atrophy and reduced innate antiviral activity. This study evaluated the safety and pharmacokinetics of a vaginal ring (VR) containing dapivirine (DPV), an NNRTI, compared to placebo in postmenopausal women.
We enrolled 96 HIV-negative postmenopausal U.S. women in a Phase 2a multi-site, double-blind, randomized (3:1) trial to evaluate monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. Menopause was defined as amenorrhea for >12 months, or >6 months status post-bilateral oophorectomy, and a follicle-stimulating hormone level >40 mIU/mL. Safety was assessed by adverse events (AE). DPV was quantified in plasma for all women and in vaginal fluid (VF) for 47 women. Cervical biopsies were obtained in 10 women after DPV VR removal at week 12. Steady-state DPV concentrations at 4, 8, and 12 weeks were analyzed using repeated measures ANOVA. Used rings were analyzed for residual DPV levels.
Mean age was 56.8 years (range 46-65); 66% were white, 31% were black, and 3% were of other race. Retention was 97%. There was no difference in the number of women with related Grade 2 or higher reproductive system AEs in the DPV vs placebo arms (6/72 (8%) vs 3/24 (13%), p=.68), and no difference in Grade 3 or higher AEs in the DPV vs placebo arms (4/72 (6%) vs 0/24 (0%), p=.57). One grade 3 AE, vaginal pain, was deemed related to study product. There were 6 protocol-required product holds for 5 women, all due to AEs which resolved; 2 women in the DPV arm declined to restart product. Median DPV concentrations in plasma and VF showed no change over 12 weeks. DPV was detectable in cervical tissue in only 5/10 women though median biopsy weights were 36% lower in women with undetectable levels. The median residual drug level for returned VRs across all visits was 21.1 mg, consistent with adherence to VR use.
DPV VRs were safe and well tolerated in postmenopausal women; only 2/96 women chose not to continue VR use due to AEs. Plasma and VF DPV concentrations remained constant over 12 weeks of use. Compared to published data on DPV VR use in reproductive-age women that found mean plasma DPV levels of 217.5 pg/mL, plasma DPV levels were not lower in postmenopausal women. Further studies are needed to assess biological differences in the postmenopausal genital tract.