ABSTRACT Background Despite achieving undetectable hepatitis B virus (HBV) DNA levels with nucleos(t)ide analogue (NA) therapy, patients with chronic hepatitis B (CHB) remain at risk of hepatocellular carcinoma (HCC). Novel covalently closed circular DNA activity biomarkers may improve risk stratification. Aims To comprehensively assess the association between serum HBV RNA and hepatitis B core‐related antigen (HBcrAg) levels, measured upon achieving undetectable HBV DNA levels, and subsequent HCC development in NA‐treated patients with CHB. Methods We retrospectively analysed 311 patients with CHB who achieved undetectable HBV DNA levels during NA therapy between 2000 and 2024. Serum HBV RNA (≥ 10 copies/mL) and HBcrAg (≥ 2.1 log U/mL) were measured in stored samples collected when HBV DNA first became undetectable. Cox regression analysis was performed to identify the factors associated with HCC development. Results During a median follow‐up of 11.0 years, 31 (10.0%) patients developed HCC. At viral suppression, 132 (42.4%) patients had HBV RNA ≥ 10 copies/mL. HCC incidence was significantly higher in patients with quantifiable HBV RNA than in those with unquantifiable HBV RNA (15‐year incidence, 17.8% vs. 8.8%, p = 0.026). Quantifiable HBV RNA independently predicted HCC (adjusted hazard ratio aHR, 3.313; 95% confidence interval CI: 1.154–9.507; p = 0.026). HBcrAg showed no association (aHR, 0.821; 95% CI: 0.253–2.669; p = 0.743). Patients with quantifiable HBV RNA and albumin‐bilirubin score ≥ −2.60 had the highest risk (5‐year incidence: 15.8%). Conclusions HBV RNA levels at viral suppression predict HCC development in NA‐treated patients with CHB, outperforming HBcrAg. Incorporating HBV RNA assessment can improve risk‐stratified HCC surveillance strategies.
Kumada et al. (2025) studied this question.