In Japan, an estimated 100-150 million people are persistently infected with hepatitis C virus (HCV). The present standard-of-care (SOC) therapy for patients infected with HCV of genotype 1b, the most prevalent genotype in Japan, is peginterferon (PEG-IFN) combined with ribavirin (RBV) for 48 weeks. However, sustained virological response (SVR), judged by the loss of detectable HCV RNA from serum 24 weeks after the completion of therapy, can be achieved in only 42-52% of the patients. To cope with this grim situation, a number of direct acting antivirals (DAAs) have been designed and developed, represented by NS3/4A protease inhibitors and NS5B polymerase or NS5A inhibitors. Among them, telaprevir (TVR) has shown promising results, when combined with PEG-IFN and RBV, in the phase 2 and 3 clinical trials, by improving SVR to ~70% in patients infected with HCV-1. Moreover, the triple therapy with TVR, PEG-IFN, and RBV for 12 weeks, followed by PEG-IFN and RBV for an additional 12 weeks (T12PR24) were reimbursed since November 2011 in Japan. In Japanese clinical studies (phase III, T12PR24), the SVR rates of naive, relapse and non-responder were 73% (92/126), 88% (96/109) and 35% (11/32). We investigate the predictive factors of SVR to a 12-week or 24-week regimen of triple therapy in 81 Japanese patients infected with HCV genotype 1. SVR was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of SVR. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished SVR (85%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high SVR (57%), and SVR (17%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70). Important adverse events were anemia and shin disorder (mainly rash, drug eruptions, and erythema). Next, dual oral therapy with the NS5A inhibitor (daclatasvir) and NS3 protease inhibitor (asunaprevir) in HCV genotype 1b-infected null responders or patients ineligible or intolerant to peginterferon/ribavirin were done (phase II) in Japan. This study (AI447-017) enrolled two populations infected with HCV genotype 1, including null responders and patients intolerant or medically ineligible to PEG-IFN and RBV. The overall SVR rate was 77%. A higher SVR rate was observed in the null responders (91%) compared to the ineligible and intolerant patients (64%). The overall response to therapy was not influenced by IL28B genotype. Potential association between virologic failure and pre-existing NS5A polymorphisms and low plasma concentrations of asunaprevir and daclatasvir requires further study.