Non-linear association between liver fibrosis scores and viral load in patients with chronic hepatitis B

Background/Aims: Serum hepatitis B virus (HBV) DNA levels and non-invasive liver fibrosis scores are significantly associated with hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. Nonetheless, the relationship between HBV DNA levels and liver fibrosis scores is unclear. Methods: A historical cohort comprising 6,949 non-cirrhotic Korean CHB patients without significant alanine aminotransferase elevation was investigated. The association of HBV DNA levels with the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis (FIB)-4 score at baseline was analyzed using general linear models. Results: In HBeAg-negative patients (n=4,868), HBV DNA levels correlated linearly with both APRI and FIB-4 scores. In contrast, in HBeAg-positive patients (n=2,081), HBV DNA levels correlated inversely with both APRI and FIB-4 scores. Across the entire cohort, a significant non-linear parabolic relationship was identified between HBV DNA levels and fibrosis scores, independent of age and other covariates. Notably, moderate viral loads (6-7 log10 IU/ mL) corresponded to the highest APRI and FIB-4 scores (P<0.001). Over a median 10-year follow-up, 435 patients (6.3%) developed HCC. Higher APRI scores >= 0.5 and FIB-4 scores >= 1.45 were significantly associated with elevated HCC risk (P<0.001 for both). HBV DNA level remained a significant predictive factor for HCC development, even after adjusting for APRI or FIB-4 scores. Conclusions: HBV viral load is significantly correlated with APRI and FIB-4 scores, and is also associated with HCC risk independent of those scores in CHB patients. These findings suggest that HBV DNA level is associated with hepatocarcinogenesis through both direct and indirect pathways.