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Summary  Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)‐free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN‐free, RBV‐free therapy between cirrhotic and noncirrhotic subjects.  mRNA  and micro RNA  (miRNA) expression analyses were performed on paired pre‐ and post‐treatment liver biopsies from genotype‐1  HCV  subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks ( n  = 4, 3 cirrhotics) or SOF/LDV combined with  GS ‐9669 or  GS ‐9451 for 6 weeks ( n  = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN‐stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type  III  IFNs (  IFNL 1 ,   IFNL 3 ,   IFNL 4‐ ΔG) similarly decreased with treatment, while   IFNA 2  expression, undetectable in all subjects pretreatment, was detected post‐treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable   IFNL 4‐ ΔG expression in post‐treatment liver. Other IFNs had no change in gene expression (  IFNG  ,   IFNB 1 ,   IFNA 5 ) or could not be detected. Although expression of multiple hepatic mi RNA s changed with treatment, many mi RNA s previously implicated in  HCV  replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN‐free  HCV  therapy is associated with changes in the host IFN response regardless of cirrhosis.

journal of viral hepatitis

Achieving sustained virologic response after interferon‐free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis