PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B

Recent studies reported that moderate hepatitis B virus (HBV) DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed at developing and validating a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in twenty-three tertiary university-affiliated hospitals of South Korea (2012–2020). A new HCC risk score (PAGED-B) was developed (training cohort, n=2,367) based on multivariable Cox models. Bootstrap for internal validation and external validation (validation cohort, n=1,218) were performed. Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00–7.99 log10 IU/mL) were independently associated with HCC development. PAGED-B score with five predictors for HCC development (platelets, age, gender, diabetes, and moderate HBV DNA) showed a time-dependent area under the receiver operating characteristics curve (AUROC) of 0.81 for 5-year HCC development. In the validation cohort, the AUROC of PAGED-B at 5-years was 0.85, significantly higher than the other scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio= 8.43 in the training and 11.59 in the validation cohorts, all P