The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma

Hepatitis delta virus (HDV) infection requires the presence of hepatitis B virus (HBV), and chronic HBV-HDV coinfection is considered the most severe form of viral hepatitis. When compared with HBV mono-infection, HBV-HDV coinfection is associated with higher rates of liver cirrhosis and hepatocellular carcinoma (HCC). In this review, we aim to elucidate the complex relationship between HDV infection and the development of HCC. The exact mechanisms underlying the carcinogenic potential of HDV remain to be fully elucidated. Evidence suggests that HDV has both indirect and direct oncogenic effects. Indirect effects promote accelerated progression to liver cirrhosis, which results in a different tumor microenvironment. Direct oncogenic effects are suggested by a distinct molecular signature. The recent epidemiological data regarding HBV-HDV coinfection should make us reconsider the HCC screening strategy, with special focus in younger non-cirrhotic patients. Finally, treating HCC in patients with chronic HDV poses unique challenges due to the complex interplay between HBV and HDV and the severity of liver disease. An in-depth understanding of the epidemiology and pathophysiology of HDV infection and carcinogenesis is essential to improve disease management in this high-risk population.