Large-scale profile study on hepatitis B surface antigen levels in chronic hepatitis B: implications for drug development targeting functional cure

Abstract

Background Quantitative hepatitis B surface antigen (qHBsAg) is an important biomarker in chronic hepatitis B (CHB). Objective Establish qHBsAg profiles to guide novel drug development. Design Baseline qHBsAg profiles, longitudinal qHBsAg trajectories and predictors of HBsAg seroclearance were determined in a large CHB cohort. Results This study included 4287 patients with qHBsAg measurements between 2009 and 2020 (62.5% male; mean age 48.0; 45.2% on nucleos(t)ide analogues (NUC)) with median baseline qHBsAg of 630.8 (117.1–1875.5) IU/mL. 3437 (80.2%), 2516 (58.7%) and 997 (23.3%) patients had baseline qHBsAg <3000 IU/mL, <1000 IU/mL and <100 IU/mL, respectively (69.2%, 46.9% and 22.9% in treatment-naïve; 93.4%, 73.0% and 23.6% in NUC-treated patients correspondingly). Among patients with recent qHBsAg measurements in 2018 (n=1593), 98.9%, 71.1% and 26.9% of patients had baseline qHBsAg <3000 IU/mL, <1000 IU/mL and <100 IU/mL, respectively (99.3%, 67.1% and 34.2% in treatment-naïve; 98.7%, 73.1% and 23.0% in NUC-treated patients correspondingly). Age (OR 1.019–1.049), hepatitis B e antigen positivity (OR 0.264–0.349) and HBV DNA (OR 0.675–0.832) were independent determinants of qHBsAg <100 or 1000 IU/mL, respectively (all p<0.05). Among patients with serial qHBsAg measurements, the median qHBsAg reduction was 0.10 (0.02–0.27) log IU/mL/year. After median follow-up for 6.3 (5.7–14.3) years, 526 patients (12.3%) achieved HBsAg seroclearance. Baseline alanine aminotransferase/qHBsAg ratio ≥0.27 independently predicted HBsAg seroclearance (HR 4.904, p<0.001). Conclusion In an endemic population, >40% of patients with CHB have qHBsAg >1000 IU/mL. These patients are unlikely to achieve spontaneous HBsAg seroclearance, but also have suboptimal responses to novel antivirals. Our data has important implications for novel antiviral development. Data are available upon reasonable request.