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.