Differential efficacy of immunotherapy in hepatocellular carcinoma (HCC) based on etiology: A systematic review and meta-analysis in viral vs. non-viral HCC.

Abstract

542 Background: The tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) varies significantly by etiology, potentially influencing responses to immune checkpoint inhibitors (ICIs). While viral-associated HCCs (HBV/HCV) are thought to be more immunogenic, clinical evidence from trials on the comparative efficacy of ICIs across etiologies remains inconsistent. This meta-analysis aims to compare treatment outcomes of ICI-based therapy in patients with viral versus non-viral HCC. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, Embase, Web of Science, and Cochrane Library was performed for studies published up to June 2025. We included randomized controlled trials and cohort studies that reported overall survival (OS) or progression-free survival (PFS) outcomes stratified by HCC etiology (viral vs. non-viral). Pooled hazard ratios (HRs) were calculated using random-effects models with Stata software (version 18.0). Results: A total of 26 studies comprising data from both RCTs and cohort studies were included. In the indirect comparison (ICI vs. non-ICI controls), the survival benefit was most pronounced in HBV-HCC (OS HR 0.67, 95% CI 0.58-0.77; PFS HR 0.58, 95% CI 0.51-0.67), intermediate in HCV-HCC (OS HR 0.84, 95% CI 0.71-0.99; PFS HR 0.75, 95% CI 0.60-0.94), and most attenuated in non-viral HCC (OS HR 0.88, 95% CI 0.78-1.00; PFS HR 0.71, 95% CI 0.60-0.83). In the direct comparison among patients receiving ICIs, viral HCC showed significantly better PFS (HR 0.84, 95% CI 0.74-0.96) and a strong trend toward improved OS (HR 0.91, 95% CI 0.79-1.05) compared to non-viral HCC. Substantial heterogeneity was observed in HBV and HCV direct comparisons, partially explained by geographic variations and lines of therapy. Conclusions: This meta-analysis demonstrates a clear efficacy gradient for immunotherapy in HCC based on etiology, with the greatest benefit observed in HBV-related HCC, intermediate in HCV-related HCC, and most modest in non-viral HCC. These findings underscore the importance of etiology as a key determinant of immunotherapy response and support its incorporation as a stratification factor in both clinical practice and future trial design.