CROI 2016 Abstract eBook

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Oral Abstracts

99 Lower Ribavirin Exposures in HIV+ Patients That Relapsed to Acute HCV Treatment Christine E. MacBrayne 1 ; Michael Hughes 2 ; Kimberly M. Hollabaugh 2 ; Jhoanna C. Roa 3 ; Xinhui Chen 4 ; Diana M. Brainard 5 ; RaymondT. Chung 6 ; Susanna Naggie 7 ; Jennifer Kiser 1 ; for the A5327 StudyTeam 1 Univ of Colorado, Denver, CO, USA; 2 Harvard Sch of PH, Boston, MA, USA; 3 Social & Scientific Systems, Inc., Silver Spring, MD, USA; 4 Univ of Colorado, Aurora, CO, USA; 5 Gilead Scis, Inc, Foster City, CA, USA; 6 Harvard Med Sch, Boston, MA, USA; 7 Duke Univ Sch of Med, Durham, NC, USA Background: ACTG 5327 (SWIFT-C) Cohort I determined the efficacy of sofosbuvir (SOF) and weight-based ribavirin (RBV; 1000 or 1200mg daily) in 17 HIV-1 infected individuals with acute hepatitis C virus (HCV). The rate of relapse following 12 weeks of treatment was 41% in this Cohort. The objective of this analysis was to determine the contribution of RBV pharmacokinetics to viral relapse. Methods: RBV plasma concentrations were determined using a validated LC/MS-MS method. RBV concentrations at weeks 4, 8, and 12 of treatment, RBV dose, IL28B genotype, ITPA phenotype, race, and antiretroviral (ARV) regimen were compared in those who achieved sustained virologic response (SVR) vs. relapse using the Mann-Whitney U test. Self- reported adherence was measured using a written four-day recall at each visit. Results: Seventeen HIV-infected males (11 Hispanic, 6 Caucasian, mean + SD age 42.8+10.6yrs, weight 75.9+10.3kg, and CrCl 120.2+27.3 mL/min, 11/2/1/3 HCV genotype 1a/1b/2b/indeterminate, 4/10/3 IL28B CC/CT/TT, 12/3/2 with 100%/60%/30% ITPA activity) received 12 weeks of SOF/RBV for acute HCV. No patient required a RBV dose reduction. Self-reported adherence to SOF/RBV was >95%. RBV concentrations are shown in the table. Median RBV exposures were 34% lower (p=0.01) at week 12 in those that relapsed vs. those that achieved SVR. The other variables tested were not significantly associated with relapse. Conclusions: RBV exposures were lower at end of treatment in HIV-infected patients that relapsed to SOF/RBV therapy for acute HCV compared to those that achieved SVR. The cause of this discrepancy in exposures is unclear, but could relate to pharmacokinetic variability, a chance imbalance between groups, or differences in adherence despite the high levels of self-reported adherence.

100 Drug Interaction Studies Between Sofosbuvir/Velpatasvir and Boosted HIV ARV Regimens Erik Mogalian ; Luisa M. Stamm; Anuoluwapo Osinusi; Gong Shen; Karim Sajwani; John McNally; John Ling; Anita Mathias Gilead Scis, Inc, Foster City, CA, USA

Background: A once-daily fixed-dose combination tablet composed of sofosbuvir (SOF; nucleotide analog NS5B inhibitor) and velpatasvir (VEL, GS-5816; pangenotypic NS5A inhibitor) is in clinical development for the treatment of chronic HCV infection. Phase 1 studies were conducted in healthy volunteers to evaluate potential drug-drug interactions (DDIs) between SOF/VEL and HIV antiretroviral (ARV) regimens containing a pharmacokinetic “booster” (RTV or COBI) to support their use together in HIV/HCV co-infected patients. Methods: These were multiple-dose, randomized, cross-over DDI studies. Subjects received SOF/VEL and ARV regimens (EVG/COBI/FTC/TDF, FTC/TDF+DRV/r, FTC/TDF+ATV/r, FTC/TDF+LPV/r, and EVG/COBI/FTC/TAF) alone and in combination. Steady-state plasma concentrations of SOF, its predominant circulating nucleoside metabolite GS-331007, VEL, and ARVs were analyzed on the last day of dosing for each treatment and PK parameters were calculated. Geometric least-squares means ratios and 90% confidence intervals (combination vs. alone) for SOF, GS-331007, VEL, and ARV AUC tau , C max and C tau were estimated and compared against lack of PK alteration boundaries of 70-143% for all analytes. Safety assessments were conducted throughout the study. Results: 123 of 129 enrolled subjects completed the studies; 5 subjects withdrew consent and 1 discontinued due to pregnancy. The majority of adverse events (AEs) were Grade 1 and there were no discontinuations due to AEs and no serious AEs. SOF AUC increased 37%with EVG/COBI/FTC/TAF, decreased ~30%with FTC/TDF+DRV/r or LPV/r, and was unchanged with other regimens. GS-331007 AUC increased 48%with EVG/COBI/FTC/TAF and was unchanged with other regimens. VEL AUC increased 58%with EVG/COBI/FTC/ TAF, increased 142%with FTC/TDF+ATV/r, and was unchanged with other regimens. No clinically significant changes in the PK of EVG, COBI, DRV, ATV, LPV, RTV, FTC, and TAF were observed when administered with SOF/VEL. Increased TFV exposure (~40%) was observed with SOF/VEL when administered as TDF. No increase in TFV exposure was observed when administered as TAF. Conclusions: Study treatments were generally well tolerated. Results from this study demonstrate that SOF/VEL may be administered with EVG, COBI, DRV/r, ATV/r, and LPV/r with a backbone of FTC/TDF or FTC/TAF. The safety and efficacy of SOF/VEL and ARVs will be evaluated in clinical studies of HIV/HCV coinfected subjects. 101 EFV Reduced PK of Piperaquine for Malaria Prevention in HIV+ Ugandan Pregnant Women Richard Kajubi 1 ; Liusheng Huang 2 ; Norah Mwebaza 3 ; Abel Kakuru 4 ; Prasanna Jagannathan 2 ; Philip Rosenthal 2 ; Moses R. Kamya 5 ; Grant Dorsey 2 ; DianeV. Havlir 2 ; Francesca Aweeka 2 1 Makerere Univ, Kampala,, Uganda; 2 Univ of California San Francisco, San Francisco, CA, USA; 3 Infectious Diseases Rsr Collab and Makerere Univ, Kampala,, Uganda; 4 Infectious Diseases Rsr Collab and Makerere Univ, Kampala, Uganda; 5 Makerere Univ Coll of Hlth Scis, Kampala, Uganda Background: Improving health of HIV+ pregnant women living in sub-Saharan Africa requires strategies combating both HIV and comorbidities including placental malaria. Monthly chemoprevention for malaria with dihydroartemisinin(DHA)-piperaquine(PQ) is currently under study. For HIV+ pregnant women, DHA-PQ is administered with combination ART (cART), primarily EFV-cART as per 2013 WHO ART guidelines, without prior data on drug interactions, even though PQ is cytochrome p450 metabolized. We have included pharmacokinetic (PK) into our trials in Tororo, Uganda and report PK results for PQ with EFV cART to inform dosing guidelines. Methods: PROMOTE includes double blind, placebo controlled studies investigating DHA-PQ for malaria prevention in HIV– and HIV+ pregnant women (NCT02163447 and NCT02282293, respectively). Women are enrolled from 12-20 (HIV-) or 12-28 (HIV+) wks gestation. Those randomized to DHA-PQ receive a standard regimen (qd x 3d) either monthly or bimonthly (HIV-) or monthly only (HIV+). PK of DHA-PQ was studied using an intensive design in a subset of women at 28 wks gestation with comparisons made between HIV- (no cART) and HIV+ (EFV-cART). The area under the concentration-time curve (AUC) was measured over 21d via venous (0-8 hr) and capillary plasma on Day 3,4,7,14 and 21 with correlation studies allowing conversion of all PK to venous plasma. Samples were measured by LC tandemMS. EKGs were performed at baseline and at time of peak (C max ) levels. Results: 30 HIV– women (13 DHA-PQ monthly; 17 DHA-PQ bimonthly), median age 23 yrs, and 17 HIV+ women (all DHA-PQ monthly), median age 28 yrs, provided PK results. We found highly significant decreases for HIV+ women compared to HIV- women in PQ AUC (GMR:0.62-0.68) and Day 7,14 and 21 levels (GMR:0.21-0.40). Limiting the comparison to

Oral Abstracts

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CROI 2016