Metabolic dysfunction and cancer in HCV: shared pathways and mutual interactions

Hepatitis C virus hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, CHC natural history is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression as well as a precancerous niche to promote cancer development, and the role of HCV in these processes. We also highlight the therapeutic implications of sustained metabolic dysfunction in CHC post SVR as well as considerations for patients who develop HCC on the background of metabolic dysfunction.