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Background: A once-daily fixed-dose combination tablet composed of sofosbuvir (SOF; nucleotide analog NS5B inhibitor) and velpatasvir (VEL; pangenotypic NS5A inhibitor) is under regulatory review 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 to support coadministration in HIV/HCV co-infected patients.
Methods: These were multiple-dose, randomized, cross-over DDI studies. Subjects received SOF/VEL and ARVs EFV/FTC/TDF, RPV/FTC/TDF, DTG, RAL+FTC/TDF, EVG/COBI/FTC/TDF, DRV/r + FTC/TDF, ATV/r + FTC/TDF, LPV/r + FTC/TDF, or 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. PK parameters were calculated and geometric least-squares means ratios and 90% confidence intervals (combination vs. alone) for SOF, GS-331007, VEL, and ARV AUCtau, Cmax and Ctau were estimated and compared against lack of PK alteration boundaries of 70-143% for all analytes. Safety assessments were conducted throughout the study.
Results: 230 of 237 enrolled subjects completed the studies; 5 subjects withdrew consent, 1 discontinued due to Grade 1 urticaria and 1 discontinued due to pregnancy. The majority of adverse events (AEs) were Grade 1 and there were no serious AEs. Table 1 reports the effect of coadministration on HIV ARVs and SOF/VEL. No clinically significant changes in the PK of HIV ARVs, except TDF, were observed when administered with SOF/VEL. Increased TFV exposure (~40%) was observed with SOF/VEL when administered as TDF.
Conclusions: Study treatments were generally well tolerated. Results from these studies demonstrate that SOF/VEL may be administered safely with RPV, RAL, DTG, EVG, COBI, DRV/r, ATV/r, and LPV/r (but not EFV) with a backbone of FTC/TDF or FTC/TAF. The safety and efficacy of SOF/VEL and ARVs are being evaluated in clinical studies of HIV/HCV coinfected subjects.



ARV with SOF/VELEffect on SOF/VEL AUCEffect on ARV AUC
EFV/FTC/TDFSOF: « GS-331007: « VEL: ↓53%EFV: « FTC: « TFV: ↑81%
FTC/RPV/TDFSOF: « GS-331007: « VEL: «FTC: « RPV: « TFV: ↑40%
DTGSOF: « GS-331007: « VEL: «DTG: «
RAL + FTC/TDFSOF: « GS-331007: « VEL: «RAL: « FTC: « TFV: ↑40%
DRV/r + FTC/TDFSOF: ↓28% GS-331007: « VEL: «DRV: « RTV: « FTC: « TFV: ↑40%
ATV/r + FTC/TDFSOF: « GS-331007: « VEL: ↑142%ATV: « RTV: « FTC: « TFV: «
LPV/r + FTC/TDFSOF: ↓29% GS-331007: « VEL: «LPV: « RTV: « FTC: « TFV: «
EVG/COBI/FTC/TDFSOF: « GS-331007: « VEL: «EVG: « COBI: « FTC: « TFV: «
EVG/COBI/FTC/TAFSOF: ↑37% GS-331007: ↑48% VEL: ↑50%EVG: « COBI: « FTC: « TAF: « TFV: «
[Table 1. Effect of Coadministration on HIV ARVs and SOF/VEL]