Abstract Body

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’ AUCtau, Cmax and Ctau 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.

Conclusions: Study treatments were generally well tolerated. LDV/SOF increases TFV exposure within RTV-boosted ATV- or DRV-based regimens. The safety of higher TFV concentrations in this setting has not been established. Consider alternative HCV or ARV therapy to avoid increases in TFV. Patients should be monitored for TFV-associated adverse reactions if coadministered.