Hepatitis C and hepatocellular carcinoma: Implications for pathogenesis and treatment

Infection with hepatitis C virus (HCV) is the second commonest cause of hepatocellular carcinoma (HCC) worldwide, the number one cause in Japan and a major reason for increasing HCC incidence in North America and Australia. HCV is an RNA virus whose genome does not enter the host nucleus to damage DNA directly. In chronic HCV infection, viral persistence is related to suppression of host innate immunity and dampening of the adaptive immune response. Conversely, immunosuppression facilitates viral replication and progression of chronic hepatitis C (CHC). In cell culture and transgenic mice, HCV proteins, such as core, NS3 and NS5A produce multiple effects on transcriptional regulation of gene expression and cell signaling of potential relevance to inflammatory recruitment, cell death and proliferation of hepatocytes. This has led many authors to conclude that HCV has direct hepatocarcinogenic properties, but there are potential flaws in this interpretation related to the experimental systems used. Instead, clinicopathological correlations indicate that the HCV pathway to liver cancer proceeds via chronic liver inflammation (CHC) and cirrhosis, and this takes decades to unfold. Other host determinants of HCC risk in HCV-infected patients include older age, male gender, genetic factors/ethnicity, previous heavy alcohol intake, hepatitis B virus (HBV) infection, obesity, type 2 diabetes and cigarette smoking. While interactions between viral proteins, alcohol and hepatic lipid metabolism or insulin receptor signaling are evident experimentally, these co-morbid environmental factors are likely to operate principally by worsening the inflammatory activity and rate of fibrotic progression of CHC to cirrhosis. Conversely, effective antiviral therapy abolishes liver inflammation and injury when sustained virus response (SVR) is obtained, and this reduces incidence of HCC by over 80%, even when cirrhosis is established. Continuous interferon therapy does not diminish HCC risk when SVR is not obtained. After resection of HCC, antiviral treatment reduces late recurrence related to development of new cancers rather than residual disease, and this improves patient survival. The approach to treatment of HCV genotype 1 is changing. “Triple therapy” with pegylated interferon, ribavirin and a direct antiviral, such as telaprevir or boceprevir, improves efficacy during first treatment and retreatment of non-SVR cases. Since hepatocarcinogenesis with HCV is intimately related to continuing hepatic necroinflammatory activity and cirrhosis, it is likely this will further reduce HCC rates by eradicating liver inflammation and preventing cirrhosis.