The initial daily dose of TVR (1500 or 2250 mg/day) and administration intervals (q8h or q12h) Cetuximab were determined by each attending physician according to age, sex,

bodyweight and hemoglobin level. Peginterferon-α-2b (PEG-Intron; MSD, Tokyo, Japan) was injected s.c. at a median dose of 1.5 μg/kg per week. Ribavirin (Rebetol; MSD) dose was adjusted according to bodyweight (600, 800 and 1000 mg for <60, ≥60 to <80, and ≥80 kg, respectively). In patients with hemoglobin level of less than 13 g/dL at the start of therapy, ribavirin dose was reduced by 200 mg in accordance with the general consensus statements.[28] Triple therapy was administrated for 12 weeks, followed by an additional 12 weeks of peginterferon-α-2b and ribavirin combination therapy (T12PR24) or 36 weeks of peginterferon-α-2b and ribavirin (T12PR48) in patients who agreed to the extended therapy. The administration of each drug was appropriately reduced or withdrawn if a serious adverse event occurred or was suspected to be developing during the course of treatment. Treatment was stopped for patients with HCV RNA of more than 3 log10 IU/mL at week 4, detectable HCV RNA at week 12 or a more

than 2 log10 IU/mL increase in HCV RNA levels from the lowest level during therapy irrespective of adverse events because of the low likelihood of achieving Cabozantinib an SVR and high likelihood of developing antiviral resistance. Virological response was analyzed on an intent-to-treat basis. The successful end-point of treatment was SVR for patients showing find more undetectable HCV RNA for 24 weeks after treatment cessation. Relapse was defined as when HCV RNA levels became undetectable by the end-of-treatment but became positive during the follow-up period. Viral breakthrough (VBT) was defined as when HCV RNA

became undetectable during the treatment period but then became positive before the end of the treatment period. Non-response was defined as when HCV RNA was detectable throughout the treatment period. Extended rapid virological response (eRVR) was defined as undetectable HCV RNA at both weeks 4 and 12 after starting treatment. All patients provided written informed consent. The study protocol conformed to ethics guidelines established in adherence with the 2008 Declaration of Helsinki and was approved by the ethics committee of each participating institution. Hepatitis C virus genotype was determined by direct sequencing followed by phylogenic analysis of the NS5B region.[29] The antiviral effects of therapy on HCV were assessed by measuring serum HCV RNA levels during treatment at least once every 4 weeks before, during and after therapy. HCV RNA levels were determined using the COBAS AmpliPrep/CABAS TaqMan HCV Test (Roche Diagnostics). The linear dynamic range of the assay was 1.2–7.8 log10 IU/mL, and undetectable samples were defined as negative. Core amino acid substitution at position 70 was determined as described previously.