Distribution and clinical characteristics of patients with chronic hepatitis B virus infection in the grey zone

A substantial proportion of patients with chronic hepatitis B (CHB) who do not fit into any of the usual immune states are considered to be in the 'grey zone (GZ)'. We aimed to investigate the distribution and characteristics of GZ in a large cohort of CHB patients. Four thousand seven hundred and fifty-nine consecutive treatment-naïve CHB patients were enrolled. The immune states were defined based on AASLD 2018 Hepatitis B Guidance. GZ CHB patients were classified into four groups: HBeAg positive, normal ALT levels and serum HBV DNA ≤10⁶ IU/ml (GZ-A); HBeAg positive, elevated ALT levels and serum HBV DNA ≤2 × 10⁴ IU/ml (GZ-B); HBeAg negative, normal ALT levels and serum HBV DNA ≥2 × 10³ IU/ml (GZ-C); HBeAg negative, elevated ALT levels and serum HBV DNA ≤2 × 10³ IU/ml (GZ-D). The distributions of different immune states were: 233 (4.90%) patients in immune-tolerant phase, 941 (19.77%) patients in HBeAg-positive immune active phase, 1,717 (36.08%) patients in inactive phase and 546 (11.47%) patients in HBeAg-negative immune active phase. Of note, 1,322 (27.78%) patients did not fit into any of above phases and were defined as the GZ. A high proportion of patients in GZ-B had advanced fibrosis (33.3%) or cirrhosis (25.8%). Older age, HBeAg-positive status and higher ALT levels were independently risk factors of advanced disease in GZ CHB patients. Therefore, our results revealed that more than a quarter of CHB patients were classified into the GZ and a high proportion of patients in GZ-B had advanced fibrosis or even cirrhosis.