Controversies of Direct-Acting Antivirals in Hepatocellular Carcinoma

Therapy for chronic hepatitis C virus infection with direct-acting antiviral agents (DAAs) has been highly successful in achieving sustained virological response (SVR) with associated improvements in liver dysfunction, liver-related mortality, and transplant-free survival. There is a high risk of hepatocellular carcinoma (HCC) with an annual incidence of 2% to 4% in patients with cirrhosis. Following DAAs treatment and achievement of SVR, the risk of incident and recurrent HCC drops significantly over time, with risk associated with demographic and liver disease-related factors. Several risk factors have been described including age, male, diabetes comorbidities, alcohol abuse, hepatitis B virus or human immunodeficiency virus-coinfection, and advanced liver disease or increased liver fibrosis. Recurrence risk after DAA therapy has been associated with baseline tumor burden, with increased risk with larger lesion(s), multifocal disease, elevated alpha-fetoprotein level, treatment type (curative vs palliative), and shorter interval between HCC complete response and DAA initiation. Overall, due to the heterogeneity among individual patient data and lack of adequately controlled data, there are no conclusive statements that can be drawn that DAAs exposure is directly associated with HCC occurrence or recurrence. However, the best available data suggest a decreased risk of incident HCC with DAA therapy and no increased risk of recurrence with DAAs after complete tumor response.