CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

chronic virus infection. Our studies reveal specific nodes of the innate immune response that are subject to viral and host control, and whose actions impart control over the progression of acute to chronic infection transition. Targeting innate immune actions of the host should be formally considered in therapeutic strategies to interrupt persistence for clearance of chronic virus infection.

Session O-6 Oral Abstracts

Room 615

10:00 am– 12:00 pm Intracellular and Clinical Pharmacology, Drug Interactions, and Adherence 80 Scientific Overview: The Clinical Pharmacology of HIV Prevention Marta Boffito Chelsea and Westminster Hospital, NHS Foundation Trust/Imperial College, London, United Kingdom

The combination of tenofovir and emtricitabine is the only PrEP agent that was studied and showed efficacy in preventing HIV transmission, and its pharmacology in this context has been studied in depth. However, prospective randomized clinical trials have reported varying efficacy due to poor adherence to the drug. Importantly, this could be overcome by the introduction of long-acting injectable PrEP agents which may be administered monthly and ensure optimal and prolonged drug exposure in HIV target tissues. Pharmacological studies in the setting of HIV PrEP are fundamental to inform on different drug pharmacokinetics, pharmacodynamics and pharmacogenetics in view of the absence of easily measurable surrogate markers of efficacy, as they play a central role in interpreting drug concentration–responses and optimal drug exposure achievement. Existing strategies for the prevention of HIV infection and ways in which pharmacology may be a valuable resource for understanding drug pharmacokinetics, determining pharmacodynamic targets, identifying optimal drug combinations/doses, frequency of dosing, and designing clinical trials will be discussed. 81 Intracellular Pharmacokinetics of Sofosbuvir In Vivo Joseph Rower 1 ; Ariel Hodara 1 ; Jacob A. Langness 3 ; SarahTise 1 ; Greg Everson 1 ; AimeeTruesdale 2 ; Fafa Baouchi-Mokrane 2 ; Lane Bushman 1 ; Peter L. Anderson 1 ; Jennifer J. Kiser 1 1 University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, US; 2 Denver Health and Hospital Authority, Denver, CO, US; 3 University of Colorado Health, Aurora, CO, US; 4 University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, US Background: Sofosbuvir (SOF), an inhibitor of the Hepatitis C virus (HCV) NS5B polymerase, is a uridine nucleotide analog pro-drug. In cells, SOF is metabolized by host enzymes to GS-331007 (007) mono- (MP), di- (DP), and the pharmacologically active tri-phosphate (TP). There are limited data on the pharmacology of 007 TP in various cell types. We sought to characterize the pharmacology of SOF in peripheral blood mononuclear cells (PBMC). Methods: PBMC were collected from HCV-infected individuals receiving SOF-based HCV treatment during routine clinic visits. HCV treatment duration was extracted frommedical records and times of prior doses were by patient self-report. 007 MP, DP, and TP concentrations were determined using a validated LC-MS/MS assay linear in the range of 50-50000 fmol/sample, then normalized to a concentration per 10 6 cells (fmol/M). Log transformed data were naïve pooled to calculate 007 MP, DP and TP half-lives (t 1/2 ). Effects of clinical covariates on 007 phosphate concentrations were tested using unpaired t-tests for categorical covariates or Pearson correlation for continuous covariates. Results: PBMC were obtained from 45 individuals (29 genotype 1, 28 male, 5 African-American, 31 cirrhotic, 22 decompensated) receiving SOF plus ribavirin (RBV, n=27), simeprevir (SIM, n=7), or both (n=11) for a median (range) of 29 (19, 162) days of treatment and between 2.3 and 27 hours post-dose. All TP samples were quantifiable, while 2 MP and 16 DP were below the limit of assay detection. Median (range) concentrations were 220 (51.5, 846), 70.2 (25.8, 275), and 859 (54.5, 6756) fmol/M for PBMC 007 MP, DP, and TP, respectively. Estimates of t 1/2 were 13.8 (MP) and 26.0 (TP) hours. MP (203 vs. 375 fmol/M; p=0.03) and TP (970 vs. 2280 fmol/M; p=0.01) were significantly higher in subjects taking SIM. 007 phosphate concentrations did not differ by race, sex, presence of cirrhosis or decompensation and were not significantly correlated with age, weight or creatinine clearance. Conclusions: 007 phosphates are formed within PBMC, with the TP moiety representing the major anabolite. Higher MP than DP concentrations suggest that DP production may be a rate limiting step. 007 TP was predicted to have a long intracellular half-life in PBMC. SIM co-administration was associated with higher 007 MP and TP, possibly due P-glycoprotein inhibition by SIM. Additional well-controlled pharmacokinetic studies of intracellular SOF are needed, including an assessment of cell-specific pharmacology. Background: Use of some anti-HCV agents with antiretrovirals (ARVs) in coinfected patients may be complicated by drug-drug interactions (DDIs). A fixed-dose combination tablet composed of the NS5A inhibitor ledipasvir (LDV) 90 mg and NS5B inhibitor sofosbuvir (SOF) 400 mg is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. We conducted a Phase 1 study to evaluate the potential DDI between LDV/SOF and protease-inhibitor (PI)-containing ARV regimens: ritonavir [RTV, r] boosted atazanavir (ATV/r) or darunavir (DRV/r) plus emtricitabine/tenofovir DF (FTC/TDF; TVD). Methods: This was a multiple-dose, randomized, cross-over study in healthy volunteers. In Part A (simultaneous dosing), subjects received LDV/SOF, ARVs (Cohort [CH] 1: ATV/r (300 mg/100 mg)+TVD (200 mg/300 mg); CH 2: DRV/r (800 mg/100 mg)+TVD), and LDV/SOF+ARVs each for 10 days. In Part B (CH 3 and CH4), an evaluation of staggered (12 hour) dosing of LDV/SOF and ARVs was conducted. LDV, SOF, GS-331007 (predominant circulating metabolite of SOF), and ARV plasma concentrations were analyzed and PK parameters were calculated. 90% CIs for the geometric least squares means ratios (%; combination vs. alone) for analytes’ AUC tau , C max and C tau were estimated by a linear mixed effect model and compared to lack of PK alteration boundaries of 70-143%. Safety assessments were conducted during the study. Results: Ninety-five of 96 subjects (N=24/CH) completed the study; one CH 2 subject withdrew consent. Most adverse events (AEs) were Grade 1 or 2. Most commonly reported AEs were ocular icterus with ATV (22%, N=21; CH 1 and 3), headache (19%, N=18; all CH), and nausea (18%, N=17; all CH). One SAE of abdominal pain (Grade 3) was concluded related to ATV/r+TVD by the investigator. Modest increases in LDV and GS-331007 with ATV/r+TVD and a small reduction in SOF with DRV/r+TVD were observed. Increases in ATV and RTV were also observed, and TFV exposures were elevated with both ARV regimens, following either simultaneous or staggered administration of LDV/SOF. 82 Drug-Drug Interactions Between Anti-HCV Regimen Ledipasvir/Sofosbuvir and Antiretrovirals Polina German ; Kimberly Garrison; Phillip S. Pang; Luisa M. Stamm; Adrian S. Ray; Gong Shen; Marc Buacharern; Anita Mathias Gilead Sciences, Inc., Foster City, CA, US

Oral Abstracts

125

CROI 2015