CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

872 Safety and Pharmacokinetics of Dapivirine Vaginal Rings in Postmenopausal US Women Beatrice A. Chen 1 ; Craig Hoesley 2 ; Robert A. Salata 3 ; Jingyang Zhang 4 ; Lydia E. Soto-Torres 5 ; Annalene Nel 6 ; Sherri Johnson 7 ; Charlene S. Dezzutti 1 ; Mark A. Marzinke 8 ; for the MTN-024/IPM 031 ProtocolTeam for the MicrobicideTrials Network 1 Univ of Pittsburgh, Pittsburgh, PA, USA; 2 Univ of Alabama at Birmingham, Birmingham, AL, USA; 3 Case Western Reserve Univ, Cleveland, OH, USA; 4 SCHARP, Seattle, WA, USA; 5 NIAID, NIH, Bethesda, MD, USA; 6 Intl Partnership for Microbicides, Paarl, South Africa; 7 FHI 360, Washington DC, DC, USA; 8 Johns Hopkins Univ, Baltimore, MD, USA Background: 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. Methods: 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. Results: 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. Conclusions: 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.

873 Adherence and Acceptability of a Dapivirine Vaginal Ring in Postmenopausal US Women Ariane van der Straten 1 ; Nicole Laborde 1 ; Helen Cheng 1 ; Craig Hoesley 2 ; Robert A. Salata 3 ; Sherri Johnson 4 ; Annalene Nel 5 ; Lydia E. Soto-Torres 6 ; Beatrice A. Chen 7 ; for the MTN-024/ IPM 031 ProtocolTeam for the MicrobicideTrials Network 1 RTI, San Francisco, CA, USA; 2 Univ of Alabama at Birmingham, Birmingham, AL, USA; 3 Case Western Reserve Univ, Cleveland, OH, USA; 4 FHI 360, Washington DC, DC, USA; 5 Intl Partnership for Microbicides, Paarl, South Africa; 6 NIAID, NIH, Bethesda, MD, USA; 7 Univ of Pittsburgh, Pittsburgh, PA, USA Background: Microbicide vaginal rings (VR) provide sustained release of the NNRTI dapivirine (DPV). In a Phase 2a trial, we evaluated the adherence and acceptability of DPV VRs among postmenopausal U.S. women, a population with high biological, behavioral and social risks, in which 12% of new HIV infections occur. Methods: We enrolled 96 HIV-uninfected postmenopausal women in MTN-024/IPM 03, a 2-arm, double-blinded, multi-site, randomized trial (3:1) of a monthly silicone VR containing 25 mg DPV or placebo, used continuously for 12 weeks. Adherence was assessed by case reports and computer-assisted self-interviewing (CASI) at monthly follow ups; and acceptability by CASI at the final visit, and by in-depth-interviews (IDIs) in a random subset (n=24). Analysis was blinded and behavioral data were combined across Study Groups. Results: Mean age was 56.8 years (range 46-65); 61% had a main partner, and 66%were currently sexually active. Study retention was 97%; 73% reportedly had the ring in place during the entire 12 weeks of use; 91% never had the ring out for more than 12 hours. Ever reporting the VR out decreased from 17% (week 4) to 5% (week 12). Six women reported full expulsions and 26 partial slippage, primarily due to bowel movements; 18 reported removals due to physical discomfort, worries, or to clean the VR. Most (99%) said the VR was very easy/easy to use; 96% indicated it never interfered with daily activities, 91% very much liked/liked the VR, 83%were never worried about it, and 65% preferred VR to condoms while 24% liked both equally. Thirty six percent reported vaginal changes with the VR, including wetness (21%) or dryness (10%). Of those sexually active, 49% did not feel the VR during sex, 82% said it did not change her sexual pleasure and 10% said her pleasure increased. Only 2 disliked wearing the VR during sex because their partners had sexual dysfunctions. During IDIs, women typically said the ring was empowering, “super-easy” to use, and preferred over condoms, as VR do not break, impact male performance, or interrupt sex. Side effects like vaginal wetness were perceived as beneficial and none had complaints about the VR interfering with other postmenopausal bodily changes. A few women had challenges with VR insertions and removals and needed staff assistance, for example due to obesity. Conclusions: Participants reported high adherence, found VRs acceptable and preferred it to condoms. VR are a promising microbicide approach for HIV prevention in postmenopausal women. 874 Distinct Pharmacodynamic Activity of Rilpivirine in Mucosal Explant Tissue Charlene S. Dezzutti 1 ; Laura J. Else 2 ; Sarah E.Yandura 3 ; Cory Shelter 3 ; Julie Russo 3 ; David J. Back 2 ; Ian McGowan 4 1 Univ of Pittsburgh, Pittsburgh, PA, USA; 2 Univ of Liverpool, Liverpool, UK; 3 Magee-Womens Hosp of the Univ of Pittsburgh Med Cntr, Pittsburgh, PA, USA; 4 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA Background: A long-acting injectable form of rilpivirine (RPV) is being evaluated in clinical trials for HIV prevention. Preclinical testing was done to define pharmacokinetic (PK) and pharmacodynamic (PD) activity of RPV in ectocervical and colonic tissues treated in vitro and to help inform PK data obtained from clinical trials. Methods: In vitro 99% effective dose (ED 99 ) and cytotoxic dose (CD 99 ) of RPV against HIV-1 BaL was defined using a TZM-bl assay. RPV was evaluated for potency using polarized ectocervical and colonic explant tissues. Ten-fold dilutions of RPV, starting at 100 µM, were applied either to the apical tissue surface with HIV or in the basolateral medium, 24 hours prior to HIV being applied to the apical tissue surface. Supernatants were collected over the culture period and assessed for HIV replication using a p24 ELISA. RPV was quantified in mucosal tissue using a validated liquid chromatography-mass spectrometry assay. PK/PD correlations were determined using GraphPad Prism. Non-linear Emax model with variable slope was used to evaluate concentration-response relationships using SigmaPlot.

Poster Abstracts

367

CROI 2016