Letter: Advancing Serologic Classification in Indeterminate Chronic Hepatitis B Through Dynamic and Integrated Frameworks—Authors' Reply

We appreciate the insightful letter by Drs. Chun-Chieh Chen and Shiuan-Chih Chen on our recent study regarding the distribution and natural history of diverse types of chronic hepatitis B (CHB) patients with indeterminate phase which classified indeterminate CHB patients into 10 types and evaluated the rates of phase transition [1, 2].

We agree with Drs. Chen that a significant proportion of indeterminate patients had high FIB-4 or liver inflammation despite having normal ALT, relatively low HBV DNA or only minimally elevated alanine aminotransferase (ALT) 1–2 × upper limit of normal (ULN) [2-5]. As shown in the current study and another recent study of indeterminate patients [2, 6], these patients are at high risk of transitioning to the immune active phase and developing hepatocellular carcinoma (HCC). As such, we would advocate expanding treatment eligibility to include patients with lower thresholds of HBV DNA (> 2000 IU/mL) and ALT (>ULN) as recently proposed by the World Health Organisation (WHO) 2024 guideline and European Association for the Study of the Liver 2025 guideline [7, 8]. Metabolic comorbidities and the presence of hepatic steatosis may affect laboratory parameters and the natural history of CHB and have also been incorporated in the algorithm for patient selection for antiviral treatment by the 2024 WHO guideline [7, 9].

We also agree with Drs. Chen that models capable of capturing more detailed longitudinal changes of viral and biochemical activities may assist in more precise risk stratifications of indeterminate CHB patients and should be addressed in future studies. Nevertheless, as approximately three in four of our indeterminate CHB patients who initially transitioned to the immune inactive phase eventually reverted back to the indeterminate phase, the need for regular long-term monitoring of indeterminate CHB patients cannot be over-emphasised.

On the other hand, while we appreciate Drs. Chen's suggestion of using unsupervised clustering or latent class modelling for classifying the heterogeneous indeterminate CHB population, we would raise caution against over-complicating the classification of indeterminate patients as that may pose a barrier for understanding and implementing management strategies of indeterminate CHB patients, especially for non-hepatology or infectious disease specialists. Currently, we classified indeterminate patients into 10 subtypes but have also attempted to group them into just two main groups as having either intermediate-high (~35%–75%) or low (< 20%) 8–10 year rates of transition to the immune active phase for practical implementation [2].

Rui Huang: writing – original draft. Mindie H. Nguyen: supervision, writing – review and editing.

Mindie H. Nguyen: Research support: Pfizer, Enanta, Astra Zeneca, Glycotest, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Helio Health, National Institute of Health, Roche. Consulting and/or Advisory Board: GSK, Exelixis. Rui Huang: none to disclose.

This article is linked to Huang et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70194 and https://doi.org/10.1111/apt.70227.