Abstract / Summary
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major but biologically distinct causes of hepatocellular carcinoma (HCC).This systematic review synthesized virological, histopathological, genomic, and molecular evidence linking HBV and HCV infections with HCC and compared their dominant pathways of hepatocarcinogenesis.The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.PubMed/MEDLINE was searched from inception through June 30, 2026, supplemented by backward citation searching.Human primary studies evaluating HBV-or HCV-associated HCC using virological, histopathological, genomic, epigenetic, or molecular outcomes were eligible.Of 310 records identified, 278 were screened after duplicate removal, 60 full-text reports were assessed, and 25 studies were included in the qualitative synthesis.Meta-analysis was not undertaken because of substantial clinical and methodological heterogeneity.Prospective HBV studies demonstrated strong virological risk gradients.Combined hepatitis B surface antigen and hepatitis B e antigen positivity was associated with an adjusted relative risk of 60.2 (95% confidence interval: 35.5-102.1)for HCC, while HCC incidence increased from 108 to 1,152 per 100,000 person-years across increasing HBV DNA categories.Molecular studies consistently demonstrated enrichment of HBV DNA integration in tumor tissue, with recurrent involvement of telomerase reverse transcriptase and other cancer-associated loci, together with insertional mutagenesis and structural genomic alterations.In HCV infection, cumulative HCC risk increased from 1.1% among HCV RNA-negative individuals to 6.4% and 14.7% among low-and high-viremia groups, respectively.HCV-associated HCC was more closely linked to chronic necroinflammation, oxidative injury, fibrosis, cirrhosis, viral proteinmediated signaling, and persistent epigenetic alterations rather than viral genome integration.Histopathological evidence generally demonstrated greater background necroinflammation and cirrhosis in HCV-associated HCC, whereas HBV-associated HCC could occur in less fibrotic or noncirrhotic liver.HBV and HCV therefore converge on hepatocarcinogenesis through chronic liver injury but differ in their dominant mechanisms.HBV has a prominent direct oncogenic component involving viral DNA integration and genomic instability, whereas HCV-associated HCC is predominantly driven by inflammation-, fibrosis-, and cirrhosis-associated carcinogenesis with additional molecular and epigenetic effects.Viral suppression or eradication reduces but does not completely eliminate HCC risk after advanced hepatic or persistent molecular injury has developed.