Impact of Metabolic Associated Steatotic Liver Disease on Antiviral Therapy Outcomes on Chronic Hepatitis B Patients Receiving Antiviral Therapy

BACKGROUND AND AIM: Chronic hepatitis B (CHB) affects over 250 million people globally and is a major contributor to liver complications, including cirrhosis and hepatocellular carcinoma (HCC). Though antiviral therapies suppress HBV, the rising prevalence of metabolic-associated steatotic liver disease (MASLD) poses new challenges. This study assessed how MASLD influences liver-related outcomes, fibrosis progression, and survival in CHB patients undergoing nucleus(t)ide analogs (NAs) therapy, using large-scale data and clinical cohort analysis. METHODS: A retrospective study using the TriNetX US Collaborative Network, CHB patients receiving long-term NA therapy with undetectable serum HBV DNA and concomitant MASLD (CHB-MASLD-NA, n = 5600) were compared with those without MASLD (CHB-non MASLD-NA, n = 11 021), matched 1:1 by propensity scores (n = 4761 each after matching). Primary outcomes included 10-year incidence of HCC and cirrhosis, with survival assessed via Kaplan-Meier curves and hazard ratios (HRs) from Cox models. Separately, a clinical cohort of 64 CHB patients and 137 MASLD-only patients was assessed for steatosis (controlled attenuation parameter, CAP) and fibrosis (liver stiffness). RESULTS: Analysis revealed that co-existing MASLD significantly compromised clinical outcomes. CHB-MASLD-NA patients faced a substantially higher risk of developing cirrhosis or HCC (HR 1.75, 95% CI 1.53-2.00, p < 0.001) and demonstrated lower 10-year survival rates (61.5% vs. 79.3%, p < 0.001) compared to the non-MASLD group. These findings were corroborated by the clinical cohort, where CHB-MASLD-NA patients exhibited greater liver stiffness (9.85 vs. 4.95 kPa) and a higher prevalence of advanced fibrosis compared to CHB alone and MASLD-only groups (28.0% vs. 14.3% and 4.4%). HBV DNA load was not a significant predictor of outcomes in this population (HR 1.00). Notably, as steatosis worsened, the pro-inflammatory cytokine TNF-α increased more sharply (3.73-fold) than the antiviral cytokine IFN-γ (2.13-fold). CONCLUSIONS: MASLD drives fibrosis and mortality in NA-treated CHB patients, as metabolic inflammation overrides the benefits of viral suppression. Integrated management, combining antiviral therapy, metabolic intervention, and immune monitoring, is essential to accurately assess progression and improve long-term prognosis.