Editorial: A Step Back to Leap Forward—Strategic Nucleos(t)ide Analogue Discontinuation Towards HBV Functional Cure

Treatment discontinuation in patients with chronic hepatitis B (CHB) may be a viable strategy to achieve functional cure in selected individuals. However, concerns about relapse and safety remain. This study by Hume et al. provides valuable data on nucleos(t)ide analogue (NA) discontinuation in hepatitis B e antigen (HBeAg)-negative CHB patients [1]. A low end-of-treatment hepatitis B surface antigen (HBsAg) level (≤ 10 IU/mL) predicted earlier seroclearance with minimal hepatitis flares, whereas higher levels were linked to delayed seroclearance and flares. These findings highlight the clinical utility of HBsAg quantification at treatment cessation. Understanding why some patients achieve HBsAg seroclearance while others do not require consideration of both viral and host immune factors [2]. Hepatitis B virus (HBV) persistence results from HBV-mediated immune tolerance and the HBV's replication dynamics, making immune restoration another key factor for achieving functional cure [3]. Once immune tolerance is abrogated, HBV-specific immune responses can eliminate infected hepatocytes through cytolytic and non-cytolytic mechanisms, reducing intrahepatic covalently closed circular DNA (cccDNA) [4]. A notable example is that HIV/HBV co-infected patients may achieve higher HBsAg loss rates after antiretroviral-induced immune reconstitution, likely reflecting a rejuvenated, HBV-unexhausted immune response [5]. In CHB, sustained antigenic stimulation drives functional exhaustion of virus-specific T cells, leading to impaired proliferation, weakened cytolytic function and reduced cytokine production [6]. Long-term NA therapy suppresses replication, reduces antigenic stimulation and permits gradual immune recovery [7]. Upon NA discontinuation, HBV rebound in the context of immune recovery may progress through three phases, ultimately resulting in (1) immune–viral re-equilibration with persistent infection, (2) severe hepatitis with potential progression to liver failure or (3) effective immune-mediated HBsAg seroclearance, depending on immune status and viral burden (Figure 1). Defining an optimal HBsAg threshold and combining it with reliable immune markers will be critical for identifying patients who can safely discontinue therapy. An HBsAg level < 10 IU/mL often reflects low viral burden, reduced viral transcriptional activity, a smaller cccDNA reservoir and closer proximity to functional cure [8]. However, if immunity remains severely compromised, functional cure may be unattainable even at this threshold. Conversely, patients with higher viral burdens may still achieve HBsAg loss if immune function is restored, albeit over a longer period and with an increased risk of severe flares and liver failure. To date, no direct immune marker has been identified to assess immune restoration [9]. Although several have been proposed, most lack large-scale validation. Identifying accessible markers that reflect HBV-specific immune restoration would enable the integration of viral and immune biomarkers, facilitating personalised, risk-stratified NA discontinuation [10]. In addition, if validated, such markers could serve as both prognostic tools and therapeutic targets. Immunomodulatory strategies that enhance immune restoration may not only increase HBsAg seroclearance rates but also benefit patients who remain HBeAg-positive despite long-term HBV suppression. In conclusion, this study supports HBsAg as a biomarker for guiding NA discontinuation. Comparing the immune profiles of patients with HBsAg < 10 IU/mL at treatment cessation who ultimately achieve HBsAg loss versus those who do not may reveal immune regulatory mechanisms and accessible biomarkers. Such insights, integrated with viral markers, may enable safer, individualised approaches to functional cure in CHB. Xuwen Xu: visualization, writing – original draft, writing – review and editing, software. Aili Lu: writing – original draft, writing – review and editing, visualization, software. Shaohang Cai: conceptualization, supervision, writing – review and editing, writing – original draft, project administration, visualization, software. The authors declare no conflicts of interest. This article is linked to Hume et al paper. To view this article, visit https://doi.org/10.1111/apt.70332. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.