The path to cancer, and back: Immune modulation during hepatitis C virus infection, progression to fibrosis and cancer, and unexpected roles of new antivirals

Hepatitis C virus (HCV) infection affects over 130 million individuals worldwide, and it is the number 1 reason for liver transplantation in the United States. HCV infection progresses in a slow chronic fashion eliciting a strong but ineffective immune response, mainly characterized by NK cell dysfunction and T cell exhaustion. The chronic hepatic inflammation leads to liver fibrosis, cirrhosis and cancer in a significant number of patients. In recent years, groundbreaking research has led to the discovery of new HCV-specific direct acting antivirals (DAAs), which have an unprecedented efficacy to clear the virus, and establish a sustained virological response. Indeed, curing HCV infection with an oral medication is now reality. The effects of DAAs in mitigating the HCV-related complications of liver fibrosis and cancer are yet largely unknown. Nonetheless, recent controversial reports suggest a potential increase in liver cancer recurrence upon use of DAAs. In the current manuscript we review the most important immune-mediated mechanisms underlying HCV chronicity and the development of liver fibrosis and cancer. Furthermore, we discuss recent concern on use of the new agents.