Abstract: Objective To re-explore the functional cutoff values for serum hepatitis B core antibody (anti-HBc), alanine transaminase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus (HBV) DNA in identifying hepatitis B e antigen (HBeAg)-positive non-aggressive hepatitis (NAH) in patients with chronic HBV infection, in the context of disaffiliating the criteria for the natural history phases that have always been subject to disagreements and controversies, and to reappraise the performance of anti-HBc versus ALT tandem HBsAg, HBcrAg, and HBV DNA in identifying HBeAg-positive NAH. Methods 176 HBeAg-positive patients were enrolled from Shanghai Public Health Clinical Center between Feburary 2011 and August 2018, they were without antiviral therapy and followed up for 6.0 to 129.0 months, of which 43 patients had experienced spontaneous HBeAg sero-conversion (ESC). According to the sequential Kaplan-Meier survival analyses based on receiver operating characteristic (ROC) curve analyses, the functional cutoffs for anti-HBc, ALT, HBsAg, HBcrAg and HBV DNA for predicting spontaneous ESC and determining HBeAg-positive NAH termination were designated. Results Anti-HBc ≤3 lgIU/mL, ALT ≤60 U/L, HBsAg >4.602 lgIU/mL, HBcrAg >5.477 lgkU/mL and HBV DNA>7.477 lgIU/mL were designated as the functional cutoffs for identifying HBeAg-positive NAH. With criteria of the functional cutoffs, the sensitivities and specificities of low levels of anti-HBc tandem high levels of HBsAg, HBcrAg, and HBV DNA in identifying liver pathological “grade ≤G1 and stage ≤S1” were 17.6% and 94.9%, 15.7% and 96.6%, and 15.7% and 91.5%, respectively, and the positive and negative likelihood ratios of which were 3.451 and 0.868, 4.618 and 0.873, and 1.847 and 0.921, respectively; the sensitivities and specificities of low levels of ALT tandem high levels of HBsAg, HBcrAg, and HBV DNA in identifying liver pathological “grade ≤G1 and stage ≤S1” were 30.6% and 85.7%, 31.8% and 89.0%, and 34.1% and 79.1%, respectively, and the positive and negative likelihood ratios of which were 2.140 and 0.810, 2.891 and 0.766, and 1.632 and 0.833, respectively. Conclusion Low levels of anti-HBc, and ALT tandem high levels of HBsAg, HBcrAg, and HBV DNA are all effective combinations and have close capablity and similar performance in identifying HBeAg-positive NAH.

Key words: Hepatitis B core antibody, Alanine transaminase, Hepatitis B surface antigen, Hepatitis B core-related antigen, Natural history