Hepatitis B Virus RNA Predicts Hepatocellular Carcinoma Despite Viral Suppression

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.

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.

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.

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%).

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.