Baseline Viral Load and On-Treatment Hepatocellular Carcinoma Risk in Chronic Hepatitis B: A Multinational Cohort Study

Background & Aims: Hepatocellular carcinoma (HCC) risk persists in patients with chronic hepatitis B (CHB) despite antiviral therapy. The relationship between pre-treatment baseline hepatitis B virus (HBV) viral load and HCC risk during antiviral treatment remains uncertain. Methods: This multinational cohort study aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in 20,826 noncirrhotic, hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with baseline HBV DNA levels ≥2000 IU/mL (3.30 log₁₀ IU/mL) who initiated entecavir or tenofovir treatment. The primary outcome was on-treatment HCC incidence, stratified by baseline HBV viral load as a categorical variable. Results: In total, 663 patients developed HCC over a median follow-up of 4.1 years, with an incidence rate of 0.81 per 100 person-years (95% confidence interval [CI], 0.75–0.87). Baseline HBV viral load was significantly associated with HCC risk in a non-linear parabolic pattern, independent of other factors. Patients with baseline viral load between 6.00 and 7.00 log₁₀ IU/mL had the highest on-treatment HCC risk (adjusted hazard ratio, 4.28; 95% CI, 2.15–8.52; P < .0001) compared with those with baseline viral load ≥8.00 log₁₀ IU/mL, who exhibited the lowest HCC risk. Conclusion: Baseline viral load showed a significant, non-linear, parabolic association with HCC risk during antiviral treatment in noncirrhotic patients with CHB. Early initiation of antiviral treatment based on HBV viral load may help prevent irreversible HCC risk accumulation in patients with CHB.