Summary Background Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). Aims To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. Methods This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg‐positive, normal ALT and HBV DNA ≤106 IU/ml (GZ‐A); HBeAg‐positive, elevated ALT and HBV DNA ≤2 × 104 IU/ml (GZ‐B); HBeAg‐negative, normal ALT and HBV DNA ≥2 × 103 IU/ml (GZ‐C) and HBeAg‐negative, elevated ALT and HBV DNA ≤2 × 103 IU/ml (GZ‐D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. Results Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg‐positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg‐negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ‐D (42.6%) was the dominant category, followed by GZ‐C (38.8%), GZ‐A (10.3%) and GZ‐B (8.3%). The highest proportion of significant histological disease was observed patients in GZ‐B (100.0%), followed by GZ‐A (84.0%), GZ‐D (69.9%) and GZ‐C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg‐negative GZ. Conclusions Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg‐positive and HBeAg‐negative GZ CHB patients with high PT.

Liver biopsies are recommended to exclude significant liver inflammation in patients with chronic hepatitis B (CHB) with elevated HBV DNA but without other indications for antiviral treatment. We aimed to investigate the proportions and determinants of significant inflammation in Asian patients with CHB with detectable HBV DNA. We conducted a cross‐sectional study that retrospectively included 581 patients with CHB with detectable HBV DNA who had undergone liver biopsy. Liver inflammation and fibrosis were staged by Scheuer’s classification. Significant inflammation and significant fibrosis were defined as G ≥ 2 and S ≥ 2, respectively. There were 179 (30.8%) patients with alanine aminotransferase (ALT) < 1 × upper limit of normal (ULN), 205 (35.3%) patients with ALT 1‐2 × ULN, and 197 (33.9%) patients with ALT > 2 × ULN. A total of 397 (68.3%) patients had significant inflammation, and 340 (58.5%) patients had significant fibrosis. Significant inflammation was found in 85% of patients with significant fibrosis and in 44.8% of patients without significant fibrosis. Furthermore, 28.7% of patients with CHB with detectable HBV DNA and normal ALT in the absence of significant fibrosis had significant inflammation. Moderate HBV DNA (5‐7 log10 IU/mL) was a risk factor for significant inflammation (odds ratio [OR] 6.929, 95% confidence interval [CI] 2.830‐16.966, P < 0.001) in patients with CHB with detectable HBV DNA, especially for patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis (adjusted OR 13.161, 95% CI 1.026‐168.889, P = 0.048). Conclusion: A high proportion of CHB patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis have significant liver inflammation. Liver biopsies are recommended to evaluate liver inflammation in such patients, especially for those with moderate HBV DNA.

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