CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: Better neurocognitive functioning was associated with higher 8-OH EFV but not EFV plasma concentrations. No correlation was observed with disturbed sleep or depression and exposure to EFV or the metabolite. These findings point to a need for greater understanding of the metabolic profile of EFV and 8-OH EFV in plasma and the CNS and relationships with antiviral effect and neurotoxicity. 85LB Levonorgestrel Implant + EFV-Based ART: Unintended Pregnancies and Associated PK Data Kimberly K. Scarsi 1 ; Kristin M. Darin 3 ; Shadia Nakalema 2 ; David Back 4 ; Pauline Byakika-Kibwika 2 ; Laura Else 4 ; Sujan Dilly-Penchala 4 ; Susan Cohn 3 ; Concepta Merry 5 ; Mohammed Lamorde 2 1 University of Nebraska Medical Center, Omaha, NE, US; 2 Infectious Diseases Institute, Kampala, Uganda; 3 Northwestern University, Feinberg School of Medicine, Chicago, IL, US; 4 University of Liverpool, Liverpool, United Kingdom; 5 Trinity College Dublin, Dublin, Ireland Background: The subdermal levonorgestrel (LNG) implant is recommended for long-acting, reversible contraception with high efficacy (expected failure rate <1%). Efavirenz (EFV)-based antiretroviral therapy (ART) may decrease LNG pharmacokinetic (PK) exposure via cytochrome P450 mediated drug-interactions. A priori, we hypothesized that over 1 year of combined use, EFV would reduce LNG exposure, but not below the proposed threshold for contraceptive efficacy (180 pg/mL). Methods: We present the final, 48-week results of a longitudinal, parallel group, PK evaluation of HIV-infected, Ugandan women desiring an implant for contraception. A standard dose LNG implant was inserted at entry in two groups: (1) subjects not yet eligible for ART (control group; n=17); (2) subjects with undetectable HIV-RNA on tenofovir/ emtricitabine/efavirenz (EFV group; n=20). At each visit, subjects were counseled on condom use and a pregnancy test was performed. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks after entry and plasma LNG concentrations were analyzed by a validated LC-MS/MS method, with an assay calibration range of 50-1500 pg/mL. Demographic data were analyzed with a T-test or chi-square, as appropriate. PK data were reported as geometric means (GM) and GM ratio. Results: All women were Black African with a mean age of 31 years. Subjects in the EFV group were on EFV for a median of 10 (range 5-66) months prior to entry. PK data are presented in the Table and reveal a 45-57% reduction in LNG concentrations beginning at week 1 and persisting through week 48. Unexpectedly, 3 women in the EFV group became pregnant between weeks 36 and 48. No pregnancy occurred in the control group. The LNG concentration prior to pregnancy in each subject was 122, 297, and 303 pg/mL, measured 2, 8, and 2 weeks, respectively, prior to conception. For subject safety, the EFV study armwas halted. At the last study visit, 15 subjects (75%) in the EFV group, but no subjects in the control group, had LNG concentrations below 303 pg/mL (the highest concentration at which a pregnancy was observed; p<0.001).

Oral Abstracts

Data presented as pg/mL and geometric mean (GM) with 90% confidence intervals, unless indicated. * n=11; excludes 3 pregnant patients and 6 subjects who did not reach the week 48 endpoint due to study arm closure.

Conclusions: Contraceptive failures (15%) were seen among HIV-infected women on EFV-based ART within a year of receiving an LNG implant, and LNG exposure was markedly reduced. In addition, the proposed threshold for LNG efficacy (180 pg/mL) was inadequate in our study population. Alternative contraception should be offered to women on EFV- based ART plus LNG implant, but studies of novel implant dosing strategies should be pursued. 86LB A Phase IV PrEP Study Reveals Limited Ex Vivo Potency of Oral Maraviroc Against HIV-1 Julie Fox 1 ; Carolina Herrera 2 ; Juan ManuelTiraboschi 1 ; Akil Jackson 3 ; Laura Else 4 ; Natalia Olejniczak 2 ; Saye Khoo 4 ; David Back 4 ; Robin Shattock 2 ; Marta Boffito 3 On behalf of KCL Infectious Diseases Biobank 1 Guys and St Thomas’ NHS Foundation Trust, London, United Kingdom; 2 Imperial College London, London, United Kingdom; 3 Chelsea and Westminster Hospital, NHS Foundation Trust, London, United Kingdom; 4 University of Liverpool, Liverpool, United Kingdom Background: Oral pre-exposure prophylaxis (PrEP) may be an effective prevention strategy against HIV-1 transmission. All completed PrEP clinical trials have tested ARV acting post-viral entry in the target cell. We present results of the first PrEP study evaluating the potential of an entry inhibitor, maraviroc, in a phase IV, multi-site, open-label, randomized controlled pharmacokinetic and ex vivo pharmacodynamic clinical trial. Methods: 56 healthy adult female (n=26) and male participants (n=30) were randomized to a control arm (Arm A n=6 who had tissue samples taken at two time points one month apart) or to one of 4 intervention arms (n=12 per arm) where a single oral maraviroc 300 mg dose was taken at two time points prior to sampling, one month apart (Arm B: first sampling 2 h post first dose and second sampling 24 h post second dose; Arm C: 4 h and 36 h; Arm D: 6 h and 48 h; Arm E: 12 h and 72 h). Sampling to determine maraviroc concentration included blood, oral fluid and rectal fluid for all. In addition, men provided a urethral swab and a rectal biopsy and women provided a cervico-vaginal aspirate and a vaginal biopsy. Anti-viral activity was assessed by ex vivo challenge with R5-tropic HIV-1 BaL of explants cut frommucosal tissue biopsies and measurement of p24 antigen levels in was significantly reduced (p=0.0005 two-tailed t -test) in vaginal biopsies harvested 2h post dosing with p24 levels in culture supernatant at day 15 of culture of 26.74 ± 17.27 pg/ml compared to 200.24 ± 45.89 pg/ml in untreated tissue. No significant reduction of p24 levels were detected at any other time point in vaginal tissue and at no dosing time point in rectal tissue. No Adverse events were reported. Conclusions: A transient inhibition of ex vivo HIV infection was demonstrated in vaginal tissue 2h after a single oral 300mg maraviroc dose. The lack of inhibition in rectal tissue, despite the ability of Maraviroc to penetrate into the rectum, reveals significant mucosal differences affecting the activity of maraviroc in vaginal and rectal transmission sites. Multi-dosing of maraviroc in humans should be investigated for HIV prevention. supernatants during 15 days of culture. Results: Viral replication capacity of HIV-1 BaL

127

CROI 2015