Distribution, Characteristics, and Natural History of Diverse Types of Indeterminate Chronic Hepatitis B: A REAL-B Study

Abstract

Background and aims: Chronic hepatitis B (CHB) with indeterminate phase comprises a heterogeneous group of patients. We determined the prevalence of indeterminate CHB overall and characterised novel types and phase transition probabilities of novel types of indeterminate CHB.

Methods: CHB patients were enrolled retrospectively from 24 centres (9 countries/regions). Indeterminate phase was defined based on the AASLD 2018 guidance.

Results: The cohort included 8375 patients with a mean age of 45.0 ± 13.7 years, 22.5% HBeAg-positive, and median ALT and HBV DNA of 30 U/L and 4.3 ± 2.2 log₁₀IU/mL, respectively. Of the total cohort, half (47.2%) were in the indeterminate phase; and of these, the most prevalent group among HBeAg-positive patients was Type 2 (ALT 1-2 × ULN, HBV DNA≥ 20,000 IU/mL; 12.6%), while in HBeAg-negative patients it was Type 6 (ALT<ULN, HBV DNA≥ 2000 IU/mL; 30.1%). Among the 1530 indeterminate patients with long-term follow-up, the 10-year cumulative incidence of phase transition to immune tolerant, immune active and immune inactive phases were 6.5%, 32.1% and 64.3%, respectively. The majority (73.2%) of Type 2 indeterminate patients transitioned to the immune active phase, while only 16.5% of Type 8 (HBeAg-negative, ALT 1-2 × ULN, HBV DNA < 2000 IU/mL) did.

Conclusions: Indeterminate CHB can be classified into 10 types, with the most prevalent type being those with HBeAg-negative, HBV DNA ≥ 2000 IU/mL and ALT<ULN (30.1%). The most prevalent HBeAg-positive patients with ALT 1-2 × ULN and HBV DNA ≥ 20,000 IU/mL type was also the most likely to transition to the immune-active phase (73.2% by year-10). The monitoring and management of CHB patients with the indeterminate phase should be individualised according to their types.

Keywords: HBV; grey zone; longitudinal; long‐term follow‐up; phase transition; prevalence.