Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone

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 ≤10 6 IU/ml (GZ‐A); HBeAg‐positive, elevated ALT and HBV DNA ≤2 × 10 4 IU/ml (GZ‐B); HBeAg‐negative, normal ALT and HBV DNA ≥2 × 10 3 IU/ml (GZ‐C) and HBeAg‐negative, elevated ALT and HBV DNA ≤2 × 10 3 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.