Direct-acting antivirals and risk of hepatocellular carcinoma: from genetic signature to metabolic risk factors

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related death. Hepatitis C virus and mainly hepatitis C virus-related cirrhosis is the chief risk factor for HCC. Many direct-acting antivirals are available for the eradication of hepatitis C virus with remarkable results in terms of virological response and with optimal safety profile. Notably, some authors have suggested that viral eradication due to these new drugs might favor both occurrence and recurrence of HCC. The exact biological mechanisms of carcinogenesis in this specific setting have not been well identified, but it has been suggested that adjustments in immune surveillance and increase in vascular endothelial growth factor expression could have a chief role. Remarkably, after publication of many large studies and meta-analyses, we can affirm that there is no increased risk on a population basis. Nonetheless, on an individual basis, sustained virological response due to direct-acting antivirals may facilitate HCC onset in some specific subgroups of patients. Among them, we could point out patients with activated neoangiogenesis but also subjects with particularly severe metabolic imbalance.