LAUSR

Simple Summary Hepatitis viruses are key actors in the development of hepatocellular carcinoma (HCC), one of the leading causes of death in cancer. From the discovery of hepatitis viruses, many steps in this research field have been made. In this expert narrative review, the pathway leading to the actual public health figures is put in a historical perspective, and future scenarios are imagined for the coming years based on new technology and biological knowledge. Understanding the historical context of the role of hepatitis viruses in the development of HCC is important for improving our comprehension of the mechanisms by which these viruses contribute to cancer development, expanding strategies for prevention and treatment, and improving public health policies to reduce the burden of HCC in populations with high rates of viral hepatitis. Abstract Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading cause of hepatocellular carcinoma (HCC) worldwide. Currently, HBV-related HCC predominates in Sub-Saharan Africa and South-East-Asia, while HCV-related HCC predominates in northern Africa and in the western world. Liver cirrhosis is the underlying condition in most HBV cases and in nearly all HCV cases. Several cofactors, viral and non-viral, play a role in the progression toward HCC: dual HBV/HCV infection, HDV, HIV, alcohol intake, smoking, diabetes mellitus, obesity, and NAFLD/NASH. HBV vaccine is effective in preventing both infection and HCC; antiviral drugs may suppress HBV replication and eradicate HCV infection, halting progression to HCC. Inequalities exist between high- and low-income countries with respect to vaccine availability and access to antivirals. These factors represent barriers to the control of HCC incidence. Lack of an effective vaccine against HCV is also a serious barrier to HCV elimination and HCC prevention. The most crucial steps and knowledge that have arisen over time on the association between the two major hepatotropic viruses and HCC are discussed in this historical review.