Reversal, maintenance or progression: What happens to the liver after a virologic cure of hepatitis C?

• Sustained virologic response leads to improvement in hepatic inflammation and fibrosis in CHC patients.
• Stellate cells and monocyte-derived macrophages play key roles in fibrosis regression.
• A subset of patients maintains inflammation and fibrosis years post-SVR.
• Advanced fibrosis pretreatment is a risk factor for HCC post-SVR.
• The mechanisms for persistent liver disease post-SVR remain unclear.

A sustained virological response (SVR) from HCV (synonymous with virological cure) leads to decreased mortality, morbidity and improved quality of life, as well as a reduced incidence of liver disease progression, including liver failure, cirrhosis and hepatocellular carcinoma. Large clinical trials comparing pre- and post-treatment liver biopsies demonstrate improvements in inflammation as well as fibrosis score following SVR. However, a small subset of patients display persistent hepatic inflammation and/or progress to cirrhosis despite SVR. In addition to conferring a risk of fibrosis progression, advanced fibrosis pre-treatment is a major risk factor for post-SVR hepatocellular carcinoma. In this review, we discuss the mechanisms of fibrosis regression uncovered using experimental fibrosis models and highlight potential mechanisms in those few patients with fibrosis progression despite SVR. We also introduce current concepts of fibrosis-dependent tumorigenesis post-SVR in patients with advanced disease. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”