[1, 2] The approval of the first HCV NS3/4A protease inhibitors (PIs), boceprevir and telaprevir, has established a new era of direct-acting antiviral (DAA) therapy for CHC.[3] Most importantly, the combination of a PI and Peg-IFN/RBV increases SVR rates in both treatment-naïve and previously treated patients with HCV genotype (G) 1 infection.[4] Furthermore, response-guided therapy (RGT) is possible with both of these PIs, which decreases treatment duration for many patients. These benefits have established PI-based triple therapy as the new standard of care for HCV G1 patients.[3, 9] Although boceprevir PLX4032 molecular weight and telaprevir

have efficacy advantages over Peg-IFNα-2a/RBV therapy, new issues include cost, an increased side-effect burden, potential for rapid emergence of resistance, potential for numerous drug-drug interactions and the inconvenience of thrice-daily dosing.[3] High rates of anemia were observed

in clinical trials of both telaprevir and boceprevir, and rash was prevalent in studies of telaprevir.[4] These adverse effects were associated with treatment discontinuation in clinical trials and have negative implications for patient acceptability and treatment compliance in practice.[4] Mericitabine is an investigational nucleoside analog polymerase inhibitor that terminates viral RNA chain elongation by inhibition of the HCV NS5B RNA GSK126 chemical structure Ibrutinib datasheet polymerase.[10] The active site of the NS5B polymerase is highly conserved across all HCV genotypes, offering the potential of broad cross-genotype activity.[11] This phase IIb clinical trial (PROPEL) was conducted to evaluate the efficacy and safety of mericitabine, together with standard doses of Peg-IFNα-2a (40 kD)/RBV for 8 or 12 weeks, followed by Peg-IFNα-2a/RBV for up to 40 weeks, in treatment-naïve patients infected with HCV G1 or G4. PROPEL, a phase IIb randomized, double-blind, active-controlled, parallel-group study, took place at 65 sites in North America, Europe, and Australia (http://www.clinicaltrials.gov. NCT00869661; funded

by F. Hoffmann-La Roche Ltd). The study was conducted in accord with the Declaration of Helsinki, the protocol was approved by all institutional review boards at participating sites, and each patient provided informed consent. Eligible participants were treatment-naïve males and females 18-65 years of age with HCV G1 or G4 infection of at least 6 months’ duration, serum HCV RNA level of at least 50,000 IU/mL, liver biopsy consistent with CHC within 24 calendar months of first dose (36 months for patients with cirrhosis or incomplete/transition to cirrhosis, fibrosis stage 3-4), and no concomitant infection with hepatitis A or B viruses or human immunodeficiency virus. (Further details on eligibility and exclusion criteria provided in the Supporting Information.