Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-a-2b (PEG-IFN-a-2b) to HCV genotype 1infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naı ¨ve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-a-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-a-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatmentexperienced and treatment-naı ¨ve patients during period 1, with a mean viral load decline of at least 4 log 10 in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naı ¨ve (!60%) patients had undetectable HCV-RNA (<25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naı ¨ve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-a-2b was safe and well tolerated. Conclusion: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naı ¨ve HCV genotype 1-infected patients. (HEPATOLOGY 2010;52:1590-1599) C hronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV-related end-stage liver disease is now the main indication for liver transplantation in North America and western Europe. 1 Estimates suggest that there are 170 million HCV-infected patients worldwide and that 3 to 4 million people are newly infected each year. 2 Approximately 80% of patients who become infected with HCV develop chronic hepatitis C. 3 The current standard of care (SOC), combination therapy of pegylated interferon-a (PEG-IFN-a) and ribavirin (RBV), achieves a sustained virological response (SVR) in only approximately 40% of patients infected with HCV genotype 1. 4,5 The HCV nonstructural protein 3 (NS3) gene encodes a serine protease critical for viral replication and