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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients With Chronic Hepatitis C Virus Infection


Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients With Chronic Hepatitis C Virus Infection

C Nelson Hayes et al. Viruses.


Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.

Keywords: direct-acting antiviral agents; fibrogenesis; hepatitis C virus; hepatocellular carcinoma; interferon; reactive oxygen species; recurrence; sustained virological response.

Conflict of interest statement

Kazuaki Chayama has received honoraria from Bristol-Myers Squibb and MSD K.K. and research funding from Dainippon Sumitomo Pharma and AbbVie.


Figure 1
Figure 1
The hepatitis C virus life cycle and targets of interferon and direct-acting antiviral therapies. (1) cell entry, (2) uncoating, (3) HCV RNA translation and cleavage of the polyprotein, (4) RNA replication, (5) assembly, and (6) release.
Figure 2
Figure 2
Hepatitis C virus-induced hepatocarcinogenesis. (A) HCV-induced hepatocarcinogenesis proceeds slowly over a span of 20–40 years accompanied by progressive fibrogenesis and eventually cirrhosis. (B) Both structural (Core, E1, E2) and non-structural proteins (NS2, NS3, NS5A, NS5B) play direct or indirect roles in hepatocarcinogenesis through oxidative stress, proliferation, apoptosis, chronic inflammation, dysregulated lipid metabolism, and angiogenesis. DAA targets are indicated using lightning symbols. ROS: reactive oxygen species; EMT: epithelial/mesenchymal transition.

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