MAFLD is linked to lower HBV DNA levels in chronic hepatitis B: clinical and transcriptomic insights

Chronic hepatitis B (CHB) frequently coexists with metabolic dysfunction-associated fatty liver disease (MAFLD), yet the impact of MAFLD on hepatitis B virus (HBV) replication remains incompletely understood. We aimed to investigate the association between MAFLD and HBV DNA levels and to provide biological context through integrative transcriptomic analyses.

We analyzed a large retrospective cohort of patients with CHB and assessed the association between MAFLD and serum HBV DNA levels using linear regression models. HBV DNA was analyzed as a continuous outcome after log10 transformation. To provide molecular context for the clinical findings, weighted gene co-expression network analysis (WGCNA) was performed in an independent HBV liver transcriptomic dataset to identify HBV-associated host co-expression modules. These modules were subsequently characterized in independent liver transcriptomic datasets representing distinct metabolic and histological liver contexts using single-sample gene set enrichment analysis (ssGSEA).

MAFLD was independently associated with lower circulating HBV DNA levels. This association varied across MAFLD phenotypes, with the lowest HBV DNA levels observed in overweight- or obesity-related MAFLD. Transcriptomic analyses identified HBV-associated host co-expression programs linked to lipid and cholesterol metabolism, inflammatory signaling, and antiviral responses. Cross-cohort analyses further showed that selected modules varied across distinct metabolic and fibrotic liver contexts.

MAFLD is associated with reduced HBV DNA levels in patients with CHB, especially in overweight- or obesity-related MAFLD. The transcriptomic findings provide complementary biological context for this clinical association and highlight metabolic and immune pathways that warrant further mechanistic investigation.