Abstract
The introduction of small molecules targeting viral functions has caused a paradigm shift in hepatitis C virus (HCV) treatment. Administration of these direct-acting antivirals (DAAs) achieves a complete cure in almost all treated patients with short-duration therapy and minimal side effects. Although this is a major improvement over the previous pegylated interferon plus ribavirin (PEG-IFNα/RBV) standard-of-care treatment for HCV, remaining questions address several aspects of the long-term benefits of DAA therapy. Interferon (IFN)-based treatment with successful outcome was associated with substantial reduction in liver disease-related mortality. However, emerging data suggest a complex picture and several confounding factors that influence the effect of both IFN-based and DAA therapies on immune restoration and limiting liver disease progression. We review current knowledge of restoration of innate and HCV-specific immune responses in DAA-mediated viral elimination in chronic HCV infection, and we identify future research directions to achieve long-term benefits in all cured patients and reduce HCV-related liver disease morbidity and mortality.