Unraveling the Mechanisms of Non-Response in Patients With and Without Cirrhosis Due to Chronic Hepatitis C

Up to 70 patients with chronic hepatitis C, genotype 1, who were partial or null responders to optimal therapy with the combination of peginterferon and ribavirin will be enrolled into this pilot study on the use of asunaprevir and daclatasvir together or in combination with peginterferon alfa-2a and ribavirin to improve response to antiviral therapy. Two separate studies will be conducted based upon HCV genotype 1 subtype. For patients with HCV genotype 1b: Will undergo baseline testing for NS5A RAVs known to confer resistance to daclatasvir (L31/Y93). Subjects who harbor these NS5A resistance associated variants will be excluded from receiving dual therapy but would be offered quad therapy and managed as a HCV genotype 1a subject. After medical evaluation and liver biopsy, 30 HCV genotype 1b patients will receive combination therapy with asunaprevir and daclatasvir alone for 24 weeks and undergo paired liver biopsies, pre-treatment and either at 2 or 4 weeks after starting therapy. Patients in whom HCV RNA is greater than or equal to LLOQ at 8 weeks will either discontinue therapy at that point (early stopping rule for futility) or may have rescue therapy instituted at the discretion of the investigator with a QUAD regimen (asunaprevir and daclatasvir plus peginterferon and ribavirin) provided they meet pre-specified inclusion criteria. For patients with HCV genotype 1a: After medical evaluation and liver biopsy 40 (15 with cirrhosis and 15 with Ishak fibrosis 0-2; the remaining 10 slots will be allocated for individuals who do not meet the histological entry requirement i.e. Ishak 3-4) HCV genotype 1a patients will be started on combination therapy with asunaprevir, daclatasvir, peginterferon alfa-2a and ribavirin for 24 weeks. Patients will be randomized to undergo a second liver biopsy at study week 4 after starting therapy either before or 6 hours after the next scheduled peginterferon dose to assess intrahepatic interferon stimulated gene expression. Intrahepatic drug concentrations of asunaprevir and daclatasvir will be measured as part of an ancillary study. Patients in whom HCV RNA is greater than or euqal to LLOQ at 8 weeks will discontinue therapy (early stopping rule for futility). Routine serum chemistries, complete blood counts and HCV RNA levels will be monitored more frequently for the initial 4 days and then at standard intervals during the period of antiviral therapy. The major endpoints will be changes in interferon stimulated gene and protein expression in the liver and changes in HCV RNA levels in liver and serum between baseline and 4 weeks. Secondary endpoints will be rates of sustained virologic response 12 and 24 weeks off therapy.