Entry inhibitors and future treatment of hepatitis C

•HCV entry inhibitors have a complementary mechanism of action to DAAs.•Entry inhibitors inhibit cell–cell transmission – a key factor for persistence.•Entry inhibitors are of interest for liver transplantation and difficult-to-treat-patients.•Most entry inhibitors are in preclinical development or early clinical stages.•Clinical trials are required to evaluate the role of entry inhibitors in patient management.

Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Furthermore, HCV-induced liver disease is the leading indication for liver transplantation. The recent introduction of direct-acting antivirals (DAAs) has revolutionized HCV treatment by making possible the cure of the majority of patients. However, their efficacy and safety in difficult-to-treat patients such as patients receiving immunosuppression, those with advanced liver disease, co-morbidity and HIV/HCV-co-infection remain to be determined. Furthermore, prevention of liver graft infection remains a pressing issue. HCV entry inhibitors target the very first step of the HCV life cycle and efficiently inhibit cell–cell transmission – a key prerequisite for viral spread. Because of their unique mechanism of action on cell–cell transmission they may provide a promising and simple perspective for prevention of liver graft infection. A high genetic barrier to resistance and complementary mechanism of action compared to DAAs makes entry inhibitors attractive as a new strategy for treatment of multi-resistant or difficult-to-treat patients. Clinical studies are needed to determine the future role of entry inhibitors in the arsenal of antivirals to combat HCV infection. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”