Dear Editor,
We read with great interest the article by Wu et al. [
1] published in
Clinical and Molecular Hepatology, which described an updated consensus on treatment approaches to achieve functional cure (FC) in chronic hepatitis B virus (HBV) infection. The authors are mainly acknowledged Asian experts in HBV, and we commend them on this comprehensive work. However, we would like to raise the following comments regarding their proposed treatment approaches toward FC, as depicted in Figure 2 in the published article [
1].
Firstly, although there is ongoing clinical research, no covalently closed circular DNA (cccDNA) inhibitors have yet been developed for the treatment of HBV infection, while gene/epigenetic therapy, a highly promising approach to FC, was not mentioned. Additionally, the figure proposes a very prescriptive simplified and linear strategy toward FC that does not reflect the range of different emerging therapeutic strategies: antisense oligonucleotides (ASOs), small interfering RNA (siRNA) or immunotherapeutic agents (pegylated interferon, anti-programmed death 1/programmed death-ligand 1, toll-like receptor agonists, therapeutic vaccines). 2 As novel agents, combinations and strategies continue to be evaluated, the pathway to FC in chronic HBV infection is becoming increasingly complex and dynamic [
2]. Hence, the figure is not representative of the complexity of approaches toward achieving FC in this rapidly evolving field.
We were somewhat surprised to see that the authors only show ASOs as being able to achieve partial cure. Data have shown that some clinical study participants who received treatment with bepirovirsen, an unconjugated ASO, were able to achieve and maintain FC after cessation of all HBV treatment. While the authors do mention the results from the phase 2a (NCT02981602) and phase 2b (B-Clear, NCT04449029) bepirovirsen studies, they do not report any results from the B-Sure long-term follow-up study (NCT04954859), which aims to assess the achievement and durability of FC [
3]. The latest interim data from participants in the B-Clear study who were eligible to enter B-Sure were presented at the European Association for the Study of the Liver congress in 2025 [
4,
5]. Among the 10 participants who were on stable nucleos(t)ide analogue (NA) therapy in B-Clear, achieved a complete response at the end of the B-Clear study and stopped NA in B-Sure, eight (80%) achieved FC 6 months post NA cessation in B-Sure and all eight (100%) maintained FC for 24 months [
5]. Similarly, among the 11 participants who were not on NA therapy in B-Clear and achieved a complete response at the end of the B-Clear study, eight (73%) achieved FC in B-Sure and all eight (100%) maintained FC for 18 months [
4]. Results from the interim analysis of B-Sure data in participants from the bepirovirsen phase 2b B-Together study (NCT04676724) were consistent with these findings [
6]. Collectively, these data show that FC can be both achieved and maintained following bepirovirsen treatment [
4-
6]. The B-Well 1 and B-Well 2 studies (NCT05630807 and NCT05630820), the first phase 3 studies to assess FC as a primary endpoint [
7,
8], are expected to provide further support for bepirovirsen as a finite therapy capable of achieving FC.
Next, we agree with Wu et al. [
1] about the importance of layering multiple strategies with different agents to achieve the next step toward FC. Indeed, achieving FC likely requires targeting HBV DNA, reducing hepatitis B surface antigen (HBsAg) and stimulating the immune system [
9]. In this respect, we wanted to note that bepirovirsen has been shown to impact HBV infection in three ways, layering virologic response, serologic response and immunologic response to help achieve FC [
10]. Unlike its precursor, GSK3389404, or siRNAs in clinical development, bepirovirsen is not conjugated to N-acetylgalactosamine for targeted hepatocyte delivery [
10,
11], which may in turn facilitate its distribution in non-parenchymal liver cells, where bepirovirsen is thought to stimulate the immune system [
12]. In a longitudinal biomarker analysis of the B-Together study, bepirovirsen treatment induced an increase in cytokine levels, as well as activation/proliferation of immune cells [
12]. Furthermore, recent data from the mechanistic B-Fine study (NCT04544956) showed that bepirovirsen triggers an early humoral response and induces activation of the immune compartment in the liver, irrespective of virological response [
13,
14]. These data provided evidentiary support that, in addition to reducing HBV DNA and viral proteins, such as HBsAg, bepirovirsen also induces an immune response, which could help restore HBV-associated immune exhaustion.9 This immune mechanism is what is thought to contribute to the added efficacy benefits of bepirovirsen versus GSK3389404 [
10].
Based on the above, we feel that the published figure should be amended, not only to remove cccDNA inhibitors and include gene/epigenetic therapy, but also to recognise the role of ASOs for achieving FC, and to provide a more flexible strategy toward FC, which is likely to change as novel therapies and strategies become more mature. We greatly value the authors’ feedback on our comments and hope that addressing the concerns outlined above will enhance the validity and applicability of their findings. Thank you for considering our feedback.
FOOTNOTES
-
Authors’ contributions
All authors contributed to the conception, data acquisition and data analysis, and discussion of the content. All authors reviewed and/or edited the manuscript and approved the final version for submission.
-
Acknowledgements
The B-Clear (study 209668), B-Together (study 209348), B-Sure (study 206882) and B-Well 1 and 2 studies (studies 202009, 219288) were funded by GSK. Editorial support (in the form of writing assistance, collating authors’ comments, grammatical editing, and referencing) was provided by Chrystelle Rasamison, of Fishawack Indicia Ltd., UK, part of Avalere Health, and was funded by GSK.
-
Conflicts of Interest
Seng-Gee Lim has received grant/research support, consulting fees or lecture fees from Abbott, AusperBio, Assembly, Gilead Sciences, Sysmex, Grifols and Roche. Melanie Paff is an employee of GSK, holds financial equities in GSK and is a named inventor on pending bepirovirsen patent applications.
Abbreviations
antisense oligonucleotide
covalently closed circular DNA
hepatitis B surface antigen
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Citations
Citations to this article as recorded by
- Correspondence to letter to the editor on “Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0”
Di Wu, Xiaojing Wang, Weiming Yan, Man-Fung Yuen, Qin Ning
Clinical and Molecular Hepatology.2026; 32(3): e408. CrossRef
