Viral suppression continued through MAPK inhibitor 24 weeks for many patients, especially those initially assigned to therapy with RBV (arm 2) or Peg-IFN/RBV (arm 3). All patients (13 of 13) receiving tegobuvir/GS-9256/RBV initially and continuing on Peg-IFN/RBV had HCV RNA <25 IU/mL at week 24; 13 of 14 (94%) patients assigned to tegobuvir/GS-9256/Peg-IFN/RBV

and continuing on Peg-IFN/RBV maintained HCV RNA <25 IU/mL at week 24. Population sequence analysis was performed in 15 rebound patients whose HCV RNA was ≥1,000 IU/mL at the time of rebound. In 14 of 15 of these patients, mutations were detected in both the NS3 and NS5B genes (Table 4), and the mutations are known to cause lowered antiviral susceptibility to GS-9256 and tegobuvir in vitro. The remaining patient had only the NS3 R155K mutation detected. The dual-therapy arm with tegobuvir/GS-9256 had the highest rate of detected mutations. In HCV genotype 1a patients, NS3 R155K and NS5B Y448H were the most common mutations selected; in HCV genotype 1b patients, NS3 D168E/V and NS5B Y448H were the most common. In 4 of 5 patients with HCV genotype 1b with either NS5B C316N or C445F at baseline, viral rebound was associated with the emergence of NS3 D168E/V/H/L mutations without the selection of additional NS5B mutations. Tegobuvir/GS-9256 was well tolerated, and most adverse events were mild to moderate AZD2281 nmr in severity. Adverse events were more common in the tegobuvir/GS-9256/Peg-IFN/RBV

treatment arm, with events consistent

with those reported for IFNs (Table 5). Two serious MCE adverse events were reported during the study: infective bursitis and vasovagal collapse. Both were considered by the investigator to be unrelated to study drug. One patient, in the tegobuvir/GS-9256 arm, discontinued tegobuvir and GS-9256 on day 22 because of fatigue. This patient had initiated Peg-IFN and RBV on day 19, but continued with Peg-IFN/RBV after discontinuing tegobuvir and GS-9256. The patient completed study participation to week 6, but was later lost to follow-up. No grade 4 adverse events or lab abnormalities were observed. Reductions in hemoglobin and neutrophils were consistent with those associated with RBV and Peg-IFN alpha-2a administration. Transient bilirubin elevations, primarily grades 1 and 2, occurred in all treatment groups, but were generally indirect and not associated with elevations in ALT or AST. Overall, while taking assigned therapy, 9 patients experienced grade 1 elevations in total bilirubin, 4 had grade 2 elevations, and 2 had grade 3 elevations (maximum, 3.2 mg/dL). Overall incidence of hyperbilirubinemia (grade 1 and above) in treated patients was 4 of 16 (25%), 5 of 15 (33%), and 6 of 15 (40%) in the tegobuvir/GS-9256, tegobuvir/GS-9256/RBV, and tegobuvir/GS-9256/Peg-IFN/RBV arms, respectively. No clinically significant effect on cardiac repolarization (i.e.