Background and aims: Immune tolerance is defined as HBeAg positive, high hepatitis B virus load (HBV), persistent normal alanine aminotransferase (ALT), no or slight inflammation or fibrosis in liver histology. However, it is still unclear the threshold of high hepatitis B virus load and how to predict histology without liver biopsy. The aim of this study was to predict immune tolerance in HBeAg positive, alanine aminotransferase-normal populations with non-invasive indicators. Methods: Two multi-center prospective cohort study recruited 907 treatment-naive chronic hepatitis B (CHB) patients who had undergone liver biopsy in mainland China from August 2013 to September 2016 and April 2018 to June2019. Quantitative hepatitis B core antibody, AST and HBV DNA were investigated using commercial diagnostic assays and histological grading and staging was assessed by the Ishak scoring system. Results: One hundred and thirteen untreated CHB patients with HBeAg-positive, normal alanine aminotransferase (ALT) and high level of HBV DNA (>= 5log10 IU/mL) were enrolled in this study. The area under the receiver operating characteristic curves (AUROCs) of qHBcAb, AST, HBV DNA and qHBcAb-AST index were 79.6%, 80.5%, 76.4% and 87.7%. Our novel qHBcAb-AST index, which combined qHBcAb and AST showed better performance with higher sensitivity (88.6% [95% confidence interval (CI) 72.3% - 96.3%]) and negative predictive value (NPV) (93.8% [95% CI 84.2%- 98.0%]). Conclusions: The combination of qHBcAb and AST can more accurately predict the immune tolerance of people with HBeAg-positive, normal alanine aminotransferase (ALT). (c) 2020 Published by Elsevier Masson SAS.