Viral hepatitis and immunotherapy outcome in advanced hepatocellular carcinoma: A comprehensive umbrella review of 15 meta-analyses

Background First-line systemic therapy for unresectable/advanced hepatocellular carcinoma (HCC) now prioritizes immune checkpoint inhibitor (ICI)–based combinations, but whether viral hepatitis etiology modifies benefit remains clinically uncertain. Objective To synthesize meta-analytic evidence for first-line systemic therapy in unresectable/advanced HCC, assessing hepatitis B (HBV), hepatitis C (HCV), and nonviral etiology as effect modifiers. This umbrella review uniquely quantifies overlap across meta-analyses and applies credibility grading to clarify the strength of evidence for etiology-stratified outcomes. Design Umbrella-style systematic review of systematic reviews with pairwise meta-analyses (network meta-analyses excluded). PubMed/MEDLINE, EMBASE, and the Cochrane Library were searched from inception to 1 December 2025. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), etiology-stratified/interaction analyses were extracted, and overlap was quantified using corrected covered area (CCA). Results Fifteen meta-analyses/quantitative syntheses (2021–2025) were included. Across phase III RCT meta-analyses, immune-based combinations improved OS and PFS versus sorafenib/lenvatinib (ICI+targeted therapy: OS HR 0.71, 95% CI 0.62–0.82; PFS HR 0.62, 95% CI 0.54–0.71; PD-(L)1 inhibitor+antiangiogenic therapy: OS HR 0.69, 95% CI 0.53–0.89; PFS HR 0.60, 95% CI 0.53–0.67). In etiology-stratified PD-(L)1 inhibitor+antiangiogenic RCT meta-analyses, OS benefit was larger in HBV (HR 0.64, 0.55–0.74) than in nonviral etiology (HR 0.91, 0.75–1.11); a predictor meta-analysis supported effect modification (interaction P = 0.02 for OS; P ' 0.01 for PFS). Real-world head-to-head meta-analyses comparing atezolizumab–bevacizumab versus lenvatinib were inconsistent. Overlap across meta-analyses was very high (CCA 44.4% among RCT meta-analyses; 52.4% among real-world syntheses). Conclusion ICI-based combinations are effective first-line therapy for unresectable/advanced HCC. Viral hepatitis status, particularly HBV, may be associated with larger relative benefit than nonviral etiology, but subgroup and real-world findings require cautious interpretation. This synthesis clarifies the strength and limitations of current evidence and identifies priority areas for prospective validation, with direct implications for treatment selection as nonviral HCC becomes more prevalent.