Dear Editor,
Thank you for your interest in and comments on our article entitled “Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0 [
1],” published in
Clinical and Molecular Hepatology [
2]. This consensus (review) represents an updated version of the expert consensus originally published in the
Journal of Viral Hepatitis in 2019 [
3], and it incorporated relevant published data available up to the end of 2024.
Based on the milestones of treatment outcomes and the classification of existing and emerging therapies, we proposed a simplified navigation flowchart for achieving functional cure of chronic hepatitis B (CHB) in Figure 2. As appropriately noted in the letter, however, this figure may not fully illustrate the potential combinations of agents with distinct modes of action [
4], particularly since several novel therapeutics are still under development. Specifically, the category labeled “cccDNA inhibitors” refers to a novel therapeutic strategy comprising interventions that directly target cccDNA, including promising gene-based and epigenetic approaches, as highlighted in the letter. Since all these modalities are still in early clinical or preclinical development, and relevant clinical data were unavailable at the time, they were grouped under the collective term “cccDNA inhibitors”.
Figure 2 outlined a proposed “lead-in” timeline for implementing anti-HBV agents within a sequential therapeutic strategy aimed at facilitating functional cure. Each box corresponded to a potential stage for introducing new classes of therapies and may not be interpreted as implying that the intended outcomes are achievable exclusively with the agents listed in that specific stage. Following a typical treatment pathway, HBeAg-positive patients with high-level viremia may initially receive nucleos(t)ide analogues (NUCs) to establish sustained viral suppression. For those who remain HBeAg-positive despite long-term NUC therapy, pegylated interferon (Peg-IFN) could be considered to encourage HBeAg seroclearance or ideally, hepatitis B surface antigen (HBsAg) loss. mRNA-targeting therapies, such as antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs), can be introduced to rapidly and substantially lower, and in some cases, clear HBsAg. It is generally recognized that only patients who achieve low-level HBsAg are likely to be suitable candidates for immunomodulatory agents aimed at HBsAg loss, as many such agents are anticipated to demonstrate optimal efficacy primarily in the context of reduced antigen burden [
5]. However, we acknowledged even this multi-step strategy may not lead to functional cure in all individuals, we propose that cccDNA inhibitors may represent a crucial future therapeutic direction to target the persistent viral reservoir, which remains one of the key barriers to CHB cure.
mRNA-targeting agents, chiefly represented by ASOs and siRNAs, constitute an emerging class of therapeutics designed to induce profound and direct suppression of viral protein synthesis in hepatitis B virus infection. Their mechanism of action operates at the post-transcriptional level, specifically through the sequence-specific degradation of viral messenger RNA (mRNA), thereby preventing its translation into proteins that are essential for viral replication, assembly, and persistence. Available evidence indicates that while ASOs may exhibit not only direct antiviral activity but also induce additional immunological alterations, as suggested by preliminary experimental and clinical observations [
6], although it may also be related to the secondary effect due to the pronounced reduction in HBsAg levels. HBsAg is widely recognized as a key viral antigen that exerts suppressive influence on host immune responses, and its rapid decline may consequently alleviate immune exhaustion and facilitate the restoration of virus-specific immunity. Thus, although the primary pharmacological action of mRNA-targeting agents lies in post-transcriptional silencing, their overall therapeutic profile may involve both direct virological suppression and indirect immune reconstitution, the relative contributions of which warrant further elucidation in ongoing and future clinical studies. The role of ASO in the therapeutic landscape towards functional cure of CHB will evolve as new evidence emerges.
With the continuous advancement of novel anti-HBV therapies, a variety of regimens that incorporate either existing or emerging agents, used alone or in combination, have shown encouraging clinical efficacy [
7-
10]. Notably, several recent studies have reported functional cure rates approaching or exceeding 30% in selected patients with CHB. Moreover, spontaneous or treatment-related functional cure has demonstrated satisfactory durability across various therapeutic regimens, including but not limited to NUCs, Peg-IFN, and ASO-based strategies [
11,
12], making it a more meaningful endpoint than end-of-treatment HBsAg loss. This suggests that functional cure represents a well-defined and clinically optimal outcome, consistently associated with improved long-term prognosis of CHB patients. Therefore, it constitutes an ideal and attainable treatment goal that merits extensive investigation. This expert consensus will be iteratively updated to incorporate emerging evidence, thereby integrating new data that are expected to refine, and potentially reshape, the current understanding of functional cure for CHB.
FOOTNOTES
-
Authors’ contributions
DW, QN drafted the manuscript. All authors gave final approval of the version to be published.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
antisense oligonucleotide
hepatitis B surface antigen
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