Editorial: HBeAg-Positive Chronic Hepatitis B With Low HBsAg Levels—Exploring Clinical Significance of preS2 Deletion Mutations. Authors' Reply

Abstract

We thank Drs Tsai and Hsu for their insightful editorial on our recent study [1, 2]. Despite hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with low hepatitis B surface antigen (HBsAg) levels constituting only a small proportion of CHB patients, it still deserves our attention because of its unique clinical characteristics and its potential close association with advanced disease progression [3]. For the first time, we showed that these patients had a greater proportion of quasispecies mutations introduced by preS2 deletion, which were associated with increased liver fibrosis scores. However, because of the limitations of the study, several points merit further discussion.

First, as Drs Tsai and Hsu noted, our study is limited by the retrospective design. Prospective studies with a long-term follow-up could provide valuable insight into the clinical outcome of these patients and clarify the impact of preS2 deletion mutations on CHB progression. Given the elevated risk of liver fibrosis and cirrhosis for these patients, our next data highlighted the prompt initiation of antiviral therapy for these patients with CHB. In our study, 23 HBeAg-positive CHB patients with low HBsAg levels received antiviral treatment by nucleos(t)ide analogues (NAs). After 24 weeks of antiviral treatment, serum HBV DNA levels were undetectable in 95.7% (22/23) of patients, and serum alanine transaminase (ALT) levels normalised in all patients. After 48 weeks, although no patient achieved HBeAg seroconversion, all maintained undetectable serum HBV DNA levels and ALT levels remained within the normal range. Despite the limited sample size, these findings suggest that NAs are effective in suppressing viral replication in these patients. However, the long-term trajectory of liver disease in these patients following therapy remains uncertain and requires further investigation.

Second, the role of preS2 deletion mutations as a cause or a consequence of liver disease progression remains unclear. We speculate that the preS2 deletion mutations resulted from the interaction between the host immunity and the virus, reflecting the host immune pressure. This is further supported by the findings that the mutated strains induced weaker host immune responses, and that the deletion regions were localised in complex alpha helix regions and immune response epitopes. However, further prospective cohort studies, cytological studies and animal experiments are needed to validate this hypothesis. Humanised mouse models are particularly important for understanding the pathogenesis of HBV, including virus–host dynamics and immune responses [4]. However, current HBV mouse models face limitations, such as lacking a fully functional human immune system and failing to replicate human-specific virus–host interactions [5]. These limitations underscore the need for cautious interpretation of results and further refinement of these models.

In summary, we agree with Drs Tsai and Hsu. Additional research is required to explore the clinical significance of preS2 deletion mutations in this process. This includes understanding the mechanisms behind preS2 deletion mutations and their impact on liver pathogenesis.

Yuxin Chen: conceptualization, writing – review and editing, investigation, writing – original draft. Rui Huang: conceptualization, investigation, writing – review and editing. Chao Wu: conceptualization, writing – review and editing, supervision. Yong Liu: conceptualization, investigation, supervision, writing – review and editing, writing – original draft, formal analysis, data curation.

The authors declare no conflicts of interest.

This article is linked to Chen et al papers. To view these articles, visit https://doi.org/10.1111/apt.18448 and https://doi.org/10.1111/apt.18480.