Global Underutilization of Antiviral Therapy and Survival Outcomes in Hepatitis B Virus-Related Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of 78 Studies and 68,243 Patients

Antiviral therapy with nucleos(t)ide analogues is recommended for patients with viremic hepatitis B virus (HBV)-related cirrhosis regardless of levels of viremia or liver enzymes. However, hepatocellular carcinoma (HCC) is not an antiviral treatment criterion in the U.S. HBV treatment guidelines, though prior studies have reported improved survival with antiviral treatment in HBV-related HCC. To inform guidelines, we estimated antiviral treatment rates and their association with survival and HCC recurrence rates in HBV-related HCC. We conducted a systematic review and meta-analysis of studies published between 2006 and 2024 that reported antiviral treatment, survival, and/or HCC recurrence rates in adults with HBV-related HCC, following PRISMA guidelines. Random-effects models pooled study estimates. Of the initial 4556 studies, 178 underwent full-text review, and 78 (68,243 patients) were analysed. The pooled antiviral treatment rate (52 studies, 41,345 patients) was 53.1%. In studies reporting pre-HCC antiviral initiation, 17.2% of HBV-related HCC patients received therapy before diagnosis. Treated (vs untreated) patients had higher 3- and 5-year OS (80.4% vs. 59.2% and 72.1% vs. 46.8%, both p < 0.01). Five-year OS was 78.0% vs. 56.4% in inactive HCC (p < 0.01) and 48.2% vs. 22.6% in active HCC (p = 0.14). Antiviral therapy remained independently associated with improved 5-year OS in multivariable meta-regression. There was no significant difference in HCC recurrence rates. Antiviral therapy is associated with improved long-term survival but remains underutilized in HBV-related HCC. These findings highlight a critical gap in care and underscore the need for earlier and more consistent antiviral initiation in patients with HBV-related HCC.