Absence of steatosis combined with cardiometabolic risk factors confers the highest hepatocellular carcinoma risk in treated chronic hepatitis B.

[BACKGROUND] Chronic hepatitis B (CHB) is a major cause of hepatocellular carcinoma (HCC). In patients receiving CHB treatment, coexistence of steatotic liver disease (SLD) and cardiometabolic risk factors (CMRFs) markedly influence HCC risk. This study explored hepatic and metabolic profiles, HCC predictors, and the modifying roles of SLD and CMRFs in CHB.

[METHODS] This study included 1012 patients receiving nucleos(t)ide analogs between 2004 and 2022. They were stratified into SLD ( = 702) or non-SLD ( = 310) groups.

[RESULTS] Over a 5.5-year follow-up period, 73 patients developed HCC. At baseline, the SLD group had younger age, higher body mass index values, lower fibrosis indices, and more severe metabolic dysregulation than did the non-SLD group. SLD conferred protection against HCC (adjusted hazard ratio: 0.43;  = 0.001). However, the presence of ≥2 CMRFs significantly increased HCC risk (adjusted hazard ratio: 1.93;  = 0.009). The highest HCC risk was observed in patients without SLD having ≥2 CMRFs (5-year incidence rate: 21.4%). The protective effect of SLD persisted after inverse probability of treatment weighting. It was most pronounced in older, cirrhotic, and high-metabolic-risk subgroups. Hepatitis B virus DNA suppression, hepatitis B surface antigen decline, and fibrosis score improvement during treatment were similar between the two groups.

[CONCLUSIONS] Among patients with CHB receiving nucleos(t)ide analogs, those without SLD having ≥2 CMRFs had the highest risk of HCC. Thus, steatosis and metabolic burden should be incorporated into precision risk stratification.