SUMMARY. , an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistanceassociated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log 10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.Keywords: GS-9857, hepatitis C virus, NS3/4A protease inhibitor.Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC 0-24 , area under the plasma concentration vs time curve up to 24 h; AUC inf , area under the plasma concentration vs time curve extrapolated to infinity; AUC last , area under the plasma concentration vs time curve from zero to the last quantifiable concentration; BMI, body mass index; C 24 , observed plasma concentration at 24 h postdose; C last , last observed quantifiable plasma drug concentration; CL/F, apparent oral clearance of drug following administration; C max , maximum plasma concentration; DAA, direct-acting antiviral; ECG, electrocardiogram; EC 50 , dose or systemic exposure required to produce 50% of the maximal drug induced anti-HCV activity; E max , maximal anti-HCV activity; HCV, hepatitis C virus; LC/MS/MS, liquid chromatography tandem mass spectroscopy; LLOQ, lower limit of quantification; MedDRA, Medical Dictionary for Regulatory Activities; NS, nonstructural protein; PK, pharmacokinetics; PD, pharmacodynamics; RAV, resistance-associated variant; RNA, ribonucleic acid; t 1/2 , elimination half-life; T last , time of last observed quantifiable plasma drug concentration; T max , time of maximum plasma concentration; ULN, upper limit of normal; k z , terminal elimination rate constant.Correspondence: Eric Lawitz, MD, The