Impact of direct-acting antiviral agents on the development of hepatocellular carcinoma: evidence and pathophysiological issues

Hepatitis C virus (HCV) infection is currently one of the main causes of cirrhosis and hepatocellular carcinoma (HCC) at a global level. Recently, a new generation of direct-acting antiviral agents (DAAs) has entered the HCV treatment landscape, providing impressively high rates of sustained virological response (SVR), and is expected to lead to an eventual decrease in HCV-related cirrhosis, liver transplantation and mortality. However, during the first years of their use, several studies reported a possible correlation between DAA treatment and an increased risk of HCC. Following the publication of larger prospective studies, the risk of de novo HCC occurrence has clearly been proven to be lower after the achievement of SVR, regardless of antiviral treatment. On the other hand, the risk of HCC recurrence following treatment with DAAs is debatable; existing data remain controversial, possibly because of the lack of large, well designed cohorts with more homogeneous patient populations. With regard to the pathophysiology behind the above observations, especially in patients with previous HCC history, HCC development could possibly be favored by the changes in the immunological milieu and the different cellular behavior after eradication of HCV infection with DAA treatment.