Simultaneous L31M/V/F

and Y93H mutations were detected in four of the 110 patients (3.6%). When the clinical relevance of NS5A resistance was investigated, Y93H was significantly correlated with the IL28B major (TT) genotype of the host (P = 0.042). Y93H was detected frequently by deep sequencing in daclatasvir treatment-naïve patients. Importantly, it seems that the IL28B status of the patients may influence the presence of Y93H mutations, resulting in different treatment responses to daclatasvir. Recently, treatment of hepatitis C virus (HCV) infection has advanced markedly. Specifically, the advent of telaprevir (TPV) and BMS-777607 boceprevir (BPV), first-generation protease inhibitors, dramatically increased the sustained virological response (SVR) rate to as high as 60–80% by combination with pegylated (PEG) interferon (IFN)/ribavirin (RBV) therapy.[1] However, high SVR rates following SAR245409 mw combination therapy have not been seen in null-responders

to previous PEG IFN/RBV combination therapy.[2] Under these circumstances, development of more effective drug therapies with less serious adverse effects is anticipated. Daclatasvir (BMS-790052), a non-structural (NS)5A replication complex inhibitor, is a potent and promising direct antiviral agent (DAA) for HCV. Daclatasvir has anti-HCV activity with broad genotypic coverage, but is most effective for genotype 1b viruses.[3] Moreover, among all NS5A inhibitors, daclatasvir is most advanced in its development for clinical use.[4, 5] Drug-resistant mutations have been identified for daclatasvir, and resistance is acquired by Y93H, L31M/V/F or P32L substitutions in NS5A in genotype 1b HCV. In particular, simultaneous substitutions of Y93H and L31M/V/F produce more robust resistance.[6, 7] In Japan, a clinical phase II trial of 24-week combination therapy of two oral agents, GNAT2 the NS5A inhibitor daclatasvir and NS3 protease inhibitor asunaprevir (BMS-650032),

was carried out in 43 patients with genotype 1b HCV infection. The therapy achieved an SVR rate of 90.5% in patients with a null response to PEG IFN/RBV combination therapy and of 63.6% in patients considered ineligible or intolerant for IFN-based therapy.[8, 9] The result was that the SVR rate was markedly high, in particular, in patients with a null response to PEG IFN/RBV combination therapy, giving hope to these difficult to treat patients. The study also revealed that the presence of Y93H prior to treatment was significantly associated with non-SVR to the regimen of the two oral agents.[8-11] On the other hand, it remains unknown whether differences in clinical backgrounds, including previous history of IFN therapy and its response, are associated with the presence of Y93H in daclatasvir treatment-naïve genotype 1b patients.