Current advances and future directions in the management of HBV-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a major driver of global cancer mortality, with HCC incidence projected to rise in the coming decades and chronic hepatitis B virus (HBV) continuing to account for a substantial proportion of cases worldwide. HBV-related HCC is distinguished by dual carcinogenic pathways: direct oncogenic effects mediated by viral persistence and genomic integration, and indirect carcinogenesis arising from chronic inflammation, fibrosis, and cirrhosis. Despite the success of nucleos(t)ide analogue (NA) therapy in suppressing HBV replication and reducing HCC incidence, residual risk persists, mandating risk-stratified surveillance even during long-term viral suppression. In parallel, advances in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combinations, have established immunotherapy-based regimens as preferred first-line options for unresectable disease. Emerging data have suggested a possible role for ICIs for select patients in earlier lines of disease, including the perioperative setting or in combination with transarterial chemoembolization for patients with intermediate-stage disease. This review synthesizes clinically relevant advances across the HBV-HCC continuum: molecular pathogenesis and risk stratification tools, antiviral strategies spanning curative and palliative settings, contemporary locoregional modalities, systemic regimens including ICI-based combinations, tyrosine kinase inhibitors, and biomarker-directed agents, and special clinical scenarios, such as portal vein tumor thrombus, high viral load, pregnancy, and viral coinfections. We emphasize HBV-specific safety considerations, including rigorous mitigation of reactivation risk with NA prophylaxis and standardized HBV DNA monitoring, and highlight future directions, such as validated composite biomarkers (e.g. circulating tumor DNA-based minimal residual disease assays), optimization of immuno-oncology locoregional therapy sequencing, and the potential influence of next-generation functional-cure HBV therapeutics on long-term HCC incidence and recurrence.