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Targeting the innate immune system in treating hepatitis B: prospects for functional cure

Karen Cheuk-Ying Ho1, Rex Wan-Hin Hui1, Wai-Kay Seto1,2, Man-Fung Yuen1,2, Lung-Yi Mak1,2orcid
Clinical and Molecular Hepatology 2026;32(1):184-199.
Published online: November 11, 2025

1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, China

2State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China

Corresponding author : Lung-Yi Mak Department of Medicine, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China Tel: +852-28162863, Fax: +852-28162863, E-mail: loeymak@gmail.com

Editor: Tai-Chung Tseng, National Taiwan University Hospital, Taiwan

• Received: August 21, 2025   • Revised: October 29, 2025   • Accepted: November 5, 2025

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Chronic hepatitis B (CHB) infection remains a significant global public health concern. Functional cure, defined as hepatitis B surface antigen seroclearance with unquantifiable HBV DNA at 24 weeks off treatment, is a desirable endpoint in the treatment of CHB, yet challenging to achieve. Given the limitations of current therapies including nucleos(t)ide analogues and pegylated interferon alpha, novel agents targeting functional cure are emerging. As hepatitis B virus (HBV) is a non-cytolytic virus, liver damage stems from the host immune response towards HBV-infected cells. The innate immune response during the initial phase of HBV infection is crucial in establishing an adequate level of immunity against the virus. However, HBV adopts various mechanisms to evade the host’s innate immunity, partly contributing to the chronicity of infection. This article provides a comprehensive review on how the HBV life cycle interacts with the host’s innate immune system. The latest evidence of novel agents targeting the innate immunity will also be covered. Retinoic acid inducible gene I agonists, toll-like receptor agonists, and interferons are therapies that target the HBV evasion strategies against host’s innate immunity. While small interfering RNAs and antisense oligonucleotides are originally designed for antigen knockdown and reinvigoration of the adaptive immune response, they have also shown additional impacts on the innate immunity. With ongoing research and innovation in combination strategies, advancement in the management of CHB is anticipated in the future.
  • Keywords: Hepatitis B virus; Functional cure; Immunity; Hepatitis B surface antigen; Chronic hepatitis B
Chronic hepatitis B (CHB) infection remains as a global public health threat and is one of the most prevalent infectious diseases worldwide. It has been estimated that there are 292 million CHB carriers globally [1], with the majority of the chronic carriers residing in Asia and the Western Pacific. Evidence revealed that 15–40% of patients with CHB infection will eventually develop liver cirrhosis, liver failure, or hepatocellular carcinoma (HCC) [2], indicating a substantial burden of hepatitis B virus (HBV) due to its high prevalence.
Current treatment of CHB includes nucleos(t)ide analogues (NUCs) and pegylated interferon alpha (Peg-IFNα). While NUCs and Peg-IFNα can effectively suppress HBV replication, they cannot completely eliminate HBV [3,4]. Functional cure is defined as the state of sustained hepatitis B surface antigen (HBsAg) seroclearance with unquantifiable HBV DNA in the blood at 24 weeks off therapy [5]. Functional cure is associated with liver fibrosis regression [6,7], reduced HCC risks [8], and a state of viral quiescence with minimal risk of viral reactivation, allowing finite treatment duration. Functional cure has therefore been established as a favourable and feasible endpoint of CHB treatment. Current evidence revealed that the annual rate of HBsAg seroclearance in patients with CHB is only 1–2%, regardless of whether NUCs were given [9]. This is partly attributable to the immune dysfunction in patients with CHB infection, as evidenced by the reduced T cell responses against HBV, resulting in persistently high level of HBV DNA and viral antigens [10]. Both NUCs and Peg-IFNα had limited effect on restoring virus-specific T cells in vivo even with prolonged treatment [11,12], possibly accounting for their low efficacy in achieving functional cure. Discontinuation of treatment before attaining HBsAg seroclearance can lead to a high likelihood of viral relapse. As a result, most patients necessitate long-term therapy with NUCs [13-15]. Furthermore, risk of liver-related complications still persists despite long-term NUCs therapy due to persistence of covalently-closed circular DNA (cccDNA) and integrated DNA [16,17]. In light of the abovementioned limitations of current HBV treatments, novel agents for enhancing functional cure are emerging [18].
HBV is a hepatotropic and non-cytolytic virus [10]. Liver damage in patients with CHB infection is mediated by host immune response directed against infected hepatocytes. Acting as a double-edged sword, the host immune response defends against HBV by eliminating the viral-infected cells, albeit ineffective, simultaneously inducing hepatic inflammation, which may cause persistent liver injury and fibrogenesis, leading to cirrhosis and/or HCC [10]. Both innate and adaptive immune responses play a pivotal role during HBV infection. Myeloid cells, such as macrophages and dendritic cells (DC), recognise pathogen-associated molecular patterns (PAMPs) including viral proteins and nucleic acids via toll-like receptors (TLRs), which are a type of pattern recognition receptors (PRRs). They are capable of triggering antiviral responses including cytokines production, cell killing and phagocytosis [19]. These cells also act as antigen presenting cells (APCs) as one of the main bridges of both innate and adaptive compartments by presenting the processed viral antigen to CD4+ T cells, which in turn activate the humoral and cellular responses that are virus-specific [20]. CD4+ T cells are necessary populations of adaptive immunity that work synergistically with components of the innate immunity to control HBV infection [21].
This article provides a comprehensive review of the HBV life cycle and the mechanisms of HBV evasion from the innate immunity, as well as the latest evidence on novel agents targeting the innate immunity in pursuit of functional cure.
HBV is an enveloped DNA virus that belongs to the hepadnavirus family [22]. Upon entry into hepatocytes via sodium taurocholate polypeptide receptor [23], the HBV genome is transported to the nucleus, where the relaxed circular DNA (rcDNA) forms cccDNA [24]. This cccDNA acts as a transcription template for viral messenger RNA (mRNA) and pregenomic RNA (pgRNA) [25]. HBV mRNAs are translated into various viral proteins, including HBV polymerase, HBsAg, hepatitis B e antigen (HBeAg), hepatitis B X protein (HBx) and hepatitis B core antigen [26]. Reverse transcription of the pgRNA occurs in the nucleocapsid, forming rcDNA and to a lesser extent, the double-stranded linear DNA. The nucleic acid-containing nucleocapsids are either enveloped and secreted as infectious virions, or redirected to the nucleus to restore the intranuclear cccDNA pool [27]. The persistence of cccDNA pool in the hepatocytes poses a great hurdle for virus eradication, leading to the chronicity of infection. The life cycle of HBV is depicted in Figure 1. The viral proteins, especially HBsAg and HBeAg, are known for their negative regulatory effect on the antiviral immunity. Notably, cytosolic pgRNA and viral RNA species play a critical role in immune sensing [28]. Not only do they trigger host’s innate immune responses, but they also set the stage for adaptive immunity. Understanding their intricate relationships with the immune system offers insights into various immune recognition pathways and the corresponding evasion strategies adopted by HBV. Details of the interaction between HBV and the innate immunity will be discussed in the following sections.
Both the adaptive and innate immunity contributed to the pathogenesis of CHB infection [19]. Recent advancements in understanding the immune mechanisms have shed light on CHB pathogenesis, paving the way for the development of potential therapeutic agents in achieving functional cure. For instance, RNA interference (RNAi) therapies are capable of modulating both the innate and adaptive immune systems [29], and have recently demonstrated promising results in achieving HBsAg seroclearance. Details on this will be discussed in the subsequent section. In addition, targeting dysfunctional T cells in the adaptive immune system has recently emerged as another promising avenue for HBV treatment [30-32]. In this article, we focus specifically on the interactions between HBV and the innate immunity, the evasion strategies adopted by HBV against immune defenses, and the novel therapies developed to intervene in HBV’s evasion of the innate response in pursuit of functional cure.
The innate immunity plays an active role in the pathogenesis of CHB infection. HBV is considered a “stealth virus” as it establishes chronic infection by evading the host immune system. That said, the innate immune response during the initial phase of HBV infection is crucial to augment a sufficient level of immunity against the virus. To comprehend how HBV evades the host’s innate immunity, it is essential to understand the distinct pathways involved in the innate immune response.
One of the pathways involves TLRs including TLR3, 7, 8, and 9 [33], which are endosomal PRRs. They are responsible for sensing HBV nucleic acids following viral particle endocytosis. These TLRs are located within endosomes and lysosomes in the APCs, including hepatocytes. Upon sensing PAMPs (i.e., viral proteins and nucleic acids in the case of HBV), they recruit adaptor proteins such as myeloid differentiation primary response gene 88 (MyD88) [34] and toll-like receptor adaptor molecule 1 (TRIF) [35], leading to a cascade of activation of protein kinases [36,37], enhancing the secretion of interferons (IFNs) that bind to the receptors on HBV-infected cells. IFN receptors also activate the janus kinase-signal transducer and transcription signalling pathway, leading to the enhanced expression of interferon-stimulated genes (ISGs), which are IFN-induced protein-coding mRNAs that suppress HBV replication and assembly [38].
The interaction between DC and natural killer (NK) cells is also highly relevant in fighting against HBV. NK cell cytotoxicity varies depending on the phase of HBV infection [39-41]. Some in vitro studies suggest that HBV-plasmid DNA promotes NK cell activation through TLR/IFN-α-mediated signaling pathways as NK cells also express mRNAs coding for TLR1 to TLR9 [42]. The stimulation and activation of NK cells are mainly altered by DC. The secretion of various cytokines including interleukin (IL)-12, IL-15 and IL-18, as well as chemokine CXCL10 is essential for NK cell activation [43-45].
Retinoic acid inducible gene I (RIG-I)-like receptors are another group of PRRs that take part in the innate immunity [29,33]. By binding to HBV double-stranded RNA (dsRNA), it activates the adaptor protein called mitochondrial antiviral signalling protein (MAVS) [46]. MAVS molecules recruit other proteins including TANK-binding kinase 1 (TBK1) and IKB kinase epsilon (IKKe) [46], which activate other transcription factors, eventually leading to the production of type 1 IFN and other pro-inflammatory cytokines.
The cyclic GMP-AMP (cGAMP) synthase-stimulator of interferon genes (cGAS-STING) pathway is also crucial in the immune defense system. Upon activation by double-stranded DNA, cGAS synthesizes cGAMP and activates the immune regulator STING [47]. Subsequent recruitment of TBK1 and IFN regulatory factor 3 triggers the transcription of inflammatory cytokines including type 1 IFN [47]. NLRP3 inflammasome is another molecule that takes part in the antiviral defense. It activates caspase-1, IL-1β and IL-18 [48], which induce proinflammatory cell death of DC and macrophages.
A thorough understanding of how our innate immunity fights against HBV is of paramount importance, as the various strategies employed by HBV to evade host immunity stem from this concept.
The complete pathways through which HBV evades the host’s innate immunity are not fully understood. Numerous in vitro studies have provided insights into the mechanisms behind HBV immune evasion, awaiting validation in clinical studies. The various pathways through which HBV evades the host’s innate immunity [49] are depicted in Figure 2. At the extracellular level, HBeAg inhibits TLR2 signalling on Kupffer cells by direct interaction with the key adaptive proteins involved in the TLR2 pathway [50]. This was also supported by evidence showing a significant lower level of IFN-α and IFN-β mRNA in HBeAg-positive HepG2 cells compared to an HBeAg-negative HepG2 cell [51]. Hepatitis B virus subviral particles (HBVsvp), apart from their well-known effects to induce T cell exhaustion and immunological decoy, are also involved in the evasion of the innate immunity. Studies revealed that HBVsvp can cause phenotypic alteration of the peripheral NK cells, leading to a reduction in the pro-inflammatory cytokines [41]. In addition, the regulation of T cell responses by NK cells is mediated through tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). In the context of HBV infection, TRAIL expression is upregulated on NK cells, resulting in the apoptosis of HBV-specific T cells [52]. Furthermore, HBV promotes myeloid-derived suppressor cells, leading to the production of IL-10 (an immunosuppressive cytokine) through arginase-dependent pathways [53], which in turn suppresses T cell responses to HBV.
At the intra-cellular level, various mechanisms are adopted by HBV to evade the innate immunity. Firstly, HBV polymerase inhibits the production of myeloid differentiation primary response protein MyD88 by blocking the nuclear translocation of STAT1 [54], hence interfering TLR signalling. On the other hand, HBx targets multiple points of the signalling pathways to downregulate type I IFN production [55]. HBx triggers degradation of structural maintenance of chromosome 5/6, which is a restriction factor that normally hinders cccDNA transcription [56]. It also attenuates autophagic degradation by impairing the lysosomal maturation [57]. Furthermore, HBV proteins including HBsAg and HBeAg are capable of reducing the expression and impairing the function of TLR [58]. This inhibitory mechanisms is attributable to the downregulation of IFN-β, ISG and other pro-inflammatory transcription factors such as IFN regulatory factor 3 and NF-κB [59]. Particularly, HBeAg activates the mitogen-activated protein kinase (MAPK) pathway [60], which is a key signalling pathway for cellular regulation. Dysregulation of MAPK pathway leads to excess inflammation and abnormal cell proliferation [61].
The demarcation between innate and adaptive immune systems is not distinctly defined in many viral infections, which has been reported in hepatitis A, B, C, and E infections [62-65]. Emerging evidence suggests that there is a great overlap between the innate and adaptive immune systems, and their interactions determine disease progression and outcomes [63,66]. In the context of CHB infection, recent studies demonstrated persistent immune dysfunction in innate-like CD8+ T cells among patients undergoing treatment with NUCs compared to patients with bona fide viral control [67], underscoring the intricate interactions between innate and adaptive immunity.
To effectively achieve functional cure of CHB infection, it is essential to target each step in the evasion strategies employed by HBV against the host immunity. While these studies may not completely reflect in vivo conditions, they do offer valuable insights, and ongoing research will further prove their clinical relevance.
In the following sections, we outline four key areas where novel therapies can intervene to prevent HBV from evading the innate response, thereby effectively combating HBV. To enhance coverage, we utilized PubMed and supplemented it with a backward search of relevant references from the existing literature. In addition, the conference abstracts from the last 5 years presented at The Liver Meeting (organized by the American Association for the Study of Liver Diseases [AASLD])) and the International Liver Congress (organized by the European Association for the Study of the Liver [EASL]) were reviewed with relevant abstracts considered. An overview of therapies with immunomodulatory effects on the innate immunity for hepatitis B treatment is depicted in Table 1.
SB9200 (inarigivir) is an oral selective dinucleotide agonist of RIG-I and nucleotide-binding oligomerization domain 2 [68]. It works by binding to RIG-I to prevent viral polymerase from engaging the viral RNA. It also enhances RIG-I induced endogenous type III IFN production [68]. A phase 2, open-label, randomized trial demonstrated that twelve-week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels [69]. Remarkably, there was an HBsAg decline of ≥0.5 logs from baseline in 17% patients at 24 weeks [69]. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir. However, the phase 2b trial for Inarigivir was terminated after the occurrence of one serious adverse event, including one patient death from necrotizing pancreatitis [70]. No other RIG-I agonists have been developed since the termination of Inarigivir.
As mentioned in the previous section, TLRs are important PRRs that stimulate various leukocytes involved in the innate immunity. TLR7 and TLR8 function as endosomal sensors of single-stranded RNA molecules [71]. Currently, several TLR7 and TLR8 agonists are under evaluation for the treatment of CHB.
GS-9620 (vesatolimod) is an oral TLR7 agonist that was shown to activate intrahepatic DC and NK cells in mice model [70]. In a phase 2 double-blind, placebo-controlled trial, Vesatolimod was shown to induce at least 2-fold expression of ISG15 in a dose-dependent manner. However, no significant HBsAg decline could be demonstrated at week 24 of treatment [72]. RO7020531 (ruzotolimod) is another TLR7 agonist, which was shown to only reduce mean HBsAg level from 0.07–0.15 log IU/mL at week 6 [73]. On the other hand, GS-9688 (selgantolimod) is a TLR8 agonist that was shown to reduce mean HBsAg from 0.12–0.16 log10 IU/mL when given in combination with NUCs [74]. In another study, Selgantolimod up to 3 mg was proven to be safe and well tolerated with an increased production of serum cytokines and chemokines [75]. However, no patients on Selgantolimod monotherapy could achieve an HBsAg decline of more than 1 log at week 24, although HBsAg decline of ≥0.5 log10 IU/mL were observed in 2 of 24 (8%) recipients of selgantolimod 3 mg. In the same study, a rebound of HBV DNA to baseline level was also observed during treatment-free follow up when NUCs were also discontinued [75]. These results indicate that TLR-agonist monotherapy has very modest suppressive effect on HBsAg levels. Instead, recent emerging studies have indicated the potential effectiveness of TLR-agonist when used in conjunction with other therapies, particularly small interfering RNAs (siRNAs). The combination of TLR-agonist and siRNAs will be discussed in the next section.
Interferon-α (IFN-α) therapy has been an established treatment for CHB since 1991 [76]. Compared to NUCs, IFN-α has the advantage of a finite treatment duration and a higher rate of functional care [77]. Apart from directly activating other immune cells, interferon-α also induces the expression of ISGs in the host cells which in turn inhibits HBV replication via different mechanisms, including inhibition of cccDNA transcription, degradation of cccDNA, and the modulation of nuclear viral minichromosomes [78]. However, the application of IFN-α is not widely accepted due to the need to perform subcutaneous injection and its pronounced side effects. IFN-α is also contraindicated in decompensated cirrhosis, autoimmune diseases and in patients with psychiatric comorbidities [79]. Furthermore, the best response to Peg-IFNα is observed in patients infected with genotype A HBV, with lower efficacy for other genotypes [79].
In recent years, Peg-IFNα has reignited interest as an immunomodulating adjunct in CHB treatment. Different combinations of therapies have been studied with regard to their efficacy in achieving functional cure. Numerous studies have demonstrated the effectiveness of combining Peg-IFNα and NUCs. A non-randomized clinical trial in 2021 demonstrated that 50.9% of patients receiving prolonged Peg-IFNα-2b as an add-on therapy to NUCs were able to enhance HBsAg clearance among patients with low baseline HBsAg, with the majority of the patients (48.1%) achieving HBsAg seroconversion by week 48 [80]. Recent data also suggested that 76.3% of the individuals with persistently low level of HBV DNA could achieve HBV DNA undetectability after adding on Peg-IFNα-2b to NUCs therapy [81]. Another retrospective study investigated the combination of Peg-IFNα with tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF). Among 33 patients receiving Peg-IFNα with TAF, 15.2% and 21.2% achieved HBsAg loss by week 24 and week 48 respectively [82]. A multi-centre study conducted in China illustrated that the combination of Peg-IFNα and NUCs could achieve an HBsAg loss rate of 65.8% at week 48 [83] in inactive HBsAg carriers. Of note, 38.2% of the participants in this study had a baseline HBsAg <100 IU/mL. Another study from China demonstrated the combination of entecavir and Peg-IFNα could lead to HBsAg loss in 30.1% of the patients with baseline quantitative HBsAg <3,000 IU/mL by week 96 [84]. The efficacy of Peg-IFNα as an add-on therapy was further validated in a recent phase 3 trial. This trial showed that 30% of patients with negative HBeAg and baseline HBsAg levels below 1,500 IU/mL were able to achieve functional cure following treatment with TDF and intermittent doses of Peg-IFNα over a period of 144 weeks [85].
Overall, the efficacy of Peg-IFNα alone or in combination with NUC is more observable in patients with lower viral burdens. The combination of Peg-IFNα with siRNAs including imdusiran, elebsiran, and daplusiran/tomligisiran has also been extensively researched [86-88], details of such will be discussed in the subsequent sections. Notably, the combination of imdusiran and Peg-IFNα demonstrated promising results, with 28% of patients achieving HBsAg seroclearance at the end of 24 weeks of treatment [88].
Despite the growing evidence of the benefits of Peg-IFNα, the primary challenge with Peg-IFNα lies in its side effects, which include flu-like syndrome, myalgia, headache, fatigue and localized reactions at the injection site, potentially leading to dose reduction and treatment discontinuation [89]. Importantly, synthetic interferon may provide new insights to address this issue. Recent study confirmed that synthetic interferon-α demonstrated robust antiviral activity against HBV both in vitro and in vivo with a better safety profile [90]. This advancement may promote the use of Peg-IFNα in the future.
RNAi therapies include antisense oligonucleotides (ASO) and siRNAs. Both classes of agents regulate gene expression through post-transcriptional sequence-specific gene silencing, demonstrating potent dose-dependent HBsAg suppression. Overall, >50% of patients achieved HBsAg <100 IU/mL while on RNAi therapy, and incidences of functional cure have been reported [91]. While RNAi therapies were initially designed to knockdown HBsAg expression and to mitigate HBsAg-induced exhaustion of HBV-specific T cells [92], emerging evidence suggests that RNAi therapies may also play a role in modulating the innate immunity, again highlighting the close relationship between the innate and adaptive immunity in CHB infection.
Bepirovirsen is an unconjugated ASO that has demonstrated efficacy in inducing functional cure [93,94]. Aside from its primary action in targeting post-transcriptional RNA, bepirovirsen is established to have TLR-8 activity [95], and may potentiate apoptosis of infected hepatocytes as evidenced by the B-Together analysis [96]. Of note, the TLR-mediated pathways of bepirovirsen appear to manifest in non-parenchymal cells. GSK3389404 is a GaINAc-conjugated variant of bepirovirsen which is predominantly taken up by hepatocytes. In contrast to bepirovirsen, GSK3389404 had minimal effects on HBsAg suppression [97], which is likely attributable to reduced activation of PRR (TLR-8 and TLR-9) in non-parenchymal cells from the GaINAc-conjugation when compared with bepirovirsen.The addition of TLR7/8 to ASO and NUCs may also lead to additive HBsAg decline [98].
A number of siRNAs including AB-729 (imdusiran), GSK5637608 (daplusiran/tomligisiran), VIR-2218 (elebsiran), RBD-1016 and RG-6346 (xalnesiran) are currently being studied in ongoing clinical trials, yet their off-treatment functional cure rate is far from the 30% benchmark. For instance, in the phase IIa trial involving daplusiran/tomligisiran (GSK5637608, formerly JNJ-3989), 97.5% of patients achieved ≥1 log IU/mL HBsAg reduction during treatment and 75.0% of patients achieved HBsAg <100 IU/mL at the end of treatment [99]; however, only 32.1% maintained HBsAg below 100 IU/mL and barely 1.9% attained HBsAg seroclearance in an average follow-up of 52.5 months [100]. Bepirovirsen is somewhat more potent, as shown in the phase 2b randomized controlled trial that a weekly dosage of 300 mg bepirovirsen for 24 weeks could result in sustained loss of HBsAg and HBV DNA in 9% to 10% of patients with CHB [94]. While other ASOs such as GSK3389404 and RO7062931 have been explored [93,101], bepirovirsen remains the only ASO that has advanced to phase III of development with a good safety profile when co-administered with NUCs [93,102]. However, the results regarding HBsAg seroclearance remain unsatisfactory based on these monotherapy studies. Therefore, the investigation of combination therapies has emerged as the most promising strategy for attaining functional cure in CHB.
The combination of various RNAi therapies with Peg-IFNα has been extensively researched [86]. The IM-PROVE I trial recently reported data on how siRNAs can modulate the innate immunity. This trial involved imdusiran for 24–40 weeks of followed by 12–24 weeks Peg-IFNα [103]. The highest HBsAg loss rate was observed in participants who received lead-in imdusiran, followed by 24-week Peg-IFNα. Up to 36% of the participants in this group achieved HBsAg seroclearance at 24 weeks post–end-of-treatment. In this trial, siRNA monotherapy stimulated soluble immune biomarker production within the innate immune system, including IL-6, IL-12 p40, IL-12 p70, IL-7 and IL-10 [103,104]. These transient increases in soluble immune markers were observed during Imdusiran lead-in, which peaked with the occurrence of HBsAg nadir even before Peg-IFNα [105], highlighting the potential of siRNAs in modulating both the innate and adaptive immunity against HBV. Another phase 2 randomized trial investigated the effectiveness of xalnesiran, administered alone or in combination with ruzotolimod, pegylated interferon alfa-2a (Peg-IFNα 2a), or NUCs [106]. At 24 weeks post-treatment, HBsAg seroclearance rates were observed in 12% of participants receiving xalnesiran with ruzotolimod and 23% in those receiving xalnesiran with Peg-IFNα 2a [106]. In addition, another study evaluated the combination of elebsiran and Peg-IFNα, and showed that this combination resulted in higher HBsAg loss rate at 24 weeks post end of treatment compared to Peg-IFNα alone [87]. Notably, the combination of imdusiran and Peg-IFNα demonstrated promising results, with 28% of patients achieving HBsAg seroclearance at the end of 24 weeks of treatment [88]. All of these studies demonstrated the efficacy of combining siRNA with an immunomodulator in achieving functional cure. Interestingly, the B-Together study indicated that sequential therapy with 12 or 24 weeks of bepirovirsen followed by 24 weeks of Peg-IFNα could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with CHB [107]. Not only did this study demonstrate the proof-of-concept for sequential therapy, but it also emphasized the significance of combining HBV antigens suppression and innate immunity modulation.
All of the above-mentioned studies highlighted the potential of RNAi therapies, especially when used in combination with other therapies, in achieving functional cure. The efficacy of RNAi therapies may stem from their capacity to mitigate the underlying immune dysfunction [108]. A recent study proved that a significant reduction in the degree of immune dysfunction was observed in the peripheral blood lymphocytes in patients who received siRNAs with sustained low HBsAg levels below 100 IU/mL for over five years after treatment [108]. Preliminary data (unpublished) shows significantly different transcriptomic features between high HBsAg and low HBsAg groups, with top pathways involving neutrophil degranulation and innate immune system years after siRNA treatment. Clearly, correcting the dysfunction of multiple components in the immune system is necessary to revert the viral mechanisms for chronicity.
This article highlights the critical involvement of innate immunity in controlling HBV infection. Among all the treatments discussed above, combination of RNAi therapies and immunomodulators stands out as a promising strategy in achieving functional cure [91]. Integration of immune checkpoint inhibitors or therapeutic vaccines with immunomodulators is also gaining popularity [109], although this is not discussed in the above sections as we mainly focus on innate immunity.
Targeting both the adaptive and innate immunity is essential in successfully combating HBV. Similar to other areas of the medical field, personalized medicine is expected to play a pivotal role in CHB management. For instance, monotherapy with RNAi may be an effective treatment in patients with low baseline HBsAg levels; on the other hand, patients with high baseline HBsAg levels will likely require combination therapy such as integration of RNAi and immunomodulators, in order to achieve functional cure. Given that a significant proportion of CHB patients have high baseline HBsAg levels [110], we anticipate that many of them will necessitate combination therapy in the pursuit of functional cure. In view of this, there is a calling need for predictive biomarkers to triage patients for treatment and/or monitor treatment responses. Ongoing research reveals the potential role of surrogate biomarkers for cccDNA [111,112] and pgRNA in evaluating long-term treatment responses [113]. Apart from viral biomarkers, immunological biomarkers, such as rapid whole-blood immune profiling, will be helpful to identify patients who are unlikely to respond to NUC and should be prioritized for novel therapy [114].
Future clinical trials should include standardized NUC stopping rules and durable off-therapy endpoints to enhance trial effectiveness [115]. Importantly, functional cure is not routinely assessed in every trial, which necessitates NUC cessation and off-treatment follow-up. Safety and tolerability of these agents, particularly in patients with cirrhosis should also be addressed as most studies only involved non-cirrhotic pateints. Last but not least, accessibility and affordability of these agents are of paramount importance from a public health perspective.
Recent advancements in research are paving the way for greater possibilities for functional cure in CHB despite the formidable challenges. Targeting the various evasion strategies adopted by HBV through novel therapeutics, such as TLR agonists, interferon and RNAi, may offer a promising approach for CHB treatment through stimulation or reinvigoration of the innate immune response. Combination therapies emerge as the most promising approach for attaining functional cure in CHB.

Authors’ contributions

KCY Ho was involved in literature review and drafting of manuscript. RWH Hui, WK Seto and MF Yuen were involved in critical revision of the manuscript. LY Mak was involved in conceptualization and critical revision of manuscript and overall supervision. The authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version.

Conflicts of Interest

WK Seto received speaker’s fees from Echosesns and MSD, is an advisory board member and received speaker’s fees of Abbott, received research funding from Astrazeneca, Alexion Pharmaceuticals, Boehringer Ingelheim, Pfizer and Ribo Life Science, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. MF Yuen is an advisory board member and/ or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals; and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation and Sysmex Corporation. LY Mak received research grant support from Roche Diagnostics and Gilead Sciences.

Figure 1.
HBV life cycle. cccDNA, closed circular DNA; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HBx, hepatitis B X protein; mRNA, messenger RNA; NTCP, sodium taurocholate co-transporting polypeptide; pgRNA, pregenomic RNA; rcDNA, relaxed circular DNA.
cmh-2025-0935f1.jpg
Figure 2.
Mechanisms of HBV to counteract the host immune response at the extra-cellular level. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IL, interleukin; MDSC, myeloid-derived suppressor cell; NK, natural killer; RIG-I, retinoic acid inducible gene I; TLR, tolllike receptor; TNF, tumour necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.
cmh-2025-0935f2.jpg
Table 1.
Overview of novel treatment of hepatitis B with immunomodulatory effects on the innate immunity
Table 1.
Drug class Agent(s) Future development Ongoing clinical trial (if any) One representative trial
Name of compound (and trial name if applicable) Patient selection Study efficacy
RIG-I agonist SB9200 (Inarigivir) Trial terminated due to serious adverse event Not applicable Inarigivir (SB9200) ACHIEVE trial [68] -Both HBeAg+ve and HBeAg-ve patients were included -Up to 13% of patients achieved >0.5 log10 IU/mL reduction in HBsAg
-Some patients were sequentially-dosesd with NUC -Trial terminated due to serious adverse event (one patient death due to necrotizing pancreatitis)
-All patients were treatment naive
TLR agonist TLR7 agonist Combination therapy with siRNAs Ruzotolimod (TLR7 agonist)+Xalnesiran (siRNA) (phase II) Selgantolimod (GS-9688) [75] -Both HBeAg+ve and HBeAg-ve patients were included -At week 24, HBsAg decline of ≥0.5 log10 IU/mL were observed in 2 of 24 (8%), 1 of 28 (4%), and 0 patients receiving selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo, respectively
GS-9620 (Vesatolimod) -Baseline median HBsAg: 4log10 IU/mL
RO7020531 (Ruzotolimod) -Not virally suppressed with baseline HBV DNA >2,000 IU/mL -None achieved HBsAg seroclearance at 24/48 weeks post-EOT
TLR8 agonist
GS-9688 (Selgantolimod)
Interferons Peg-IFNα-2a (Pegasus) -Approved therapy for CHB -Elebsiran+tobevibart±Peg-IFNα (phase II) [MARCH] Peg-IFNα+Imdusiran (AB-729) -HBeAg-ve patients were included -Up to 33% of patients achieved HBsAg seroclearance at 24 weeks post-EOT if given lead-in AB-729 followed by 24 weeks of PEG-IFN, compared to 0% if PEG-IFN was only given for 12 weeks
-Novel drug development: as add-on therapy with background NUCs -Xalnesiran (siRNA)+Peg-IFNα or ruzotolimod (TLR7 agonist) (phase II) [PIRANGA] IM-PROVE I [103] -Baseline mean HBsAg: 1,555 IU/mL
-Combination with compounds involved in adaptive immunity e.g., siRNAs, monoclonal antibodies -Elebsiran (siRNA)+Peg-IFNα (phase II) [ENSURE] -Virally suppressed by NUC
-Imdusiran (siRNA)+Peg-IFNα (phase II) [IM-PROVE-I]
-Synthetic interferons -Daplusiran/tomligisiran+Peg-IFNα (phase II)
ASO Bepirovirsen Unconjugated ASO but not conjugated ASO will move forward in clinical development -Sequential therapy of Bepirovirsen after daplusiran/tomligisiran Bepirovirsen (GSK3228836) -Both HBeAg+ve and HBeAg-ve patients were included -9–15% of patients chieved HBsAg seroclearance at 24 weeks post-EOT after sequential bepirovirsen for 12–24 weeks, followed by PEG-IFNα for 24 weeks
GSK3389404 -AHB-137 and sequential PEG-IFNα B-Together trial [107] -Baseline mean HBsAg: 5,225 IU/mL
RO7062931 -Virally suppressed by NUC
AHB-137
siRNAs AB-729 (Imdusiran) Combination therapy with interferon, TLR agonist -Elebsiran+tobevibart±Peg-IFNα (phase II) [MARCH] Xalnesiran -Both HBeAg+ve and HBeAg-ve patients were included -23% of patients who received xalnesiran+Peg-IFNα achieved HBsAg seroclearance at 24 weeks post-EOT, compared to 12% among recipients of xalnesiran+ uzotolimod, and 7% in xalnesiran monotherapy
GSK5637608 (Daplusiran/Tomligisiran) -Xalnesiran (siRNA)+Peg-IFNα or ruzotolimod (TLR7 agonist) (phase II) [PIRANGA] PIRANGA [106]
VIR-2218 (Elebsiran) -Elebsiran (siRNA)+Peg-IFNα (phase II) [ENSURE] -Baseline mean HBsAg: 2.8log10 IU/mL
RBD-1016 -Imdusiran (siRNA)+Peg-IFNα (phase II) [IM-PROVE-I]
RG-6346 (xalnesiran) -Daplusiran/tomligisiran+Peg-IFNα (phase II) -Virally suppressed by NUC

ASO, antisense oligonucleotides; CHB, chronic hepatitis B; EOT, end-of treatment; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NUCs, nucleos(t)ide analogues; Peg-IFNα, pegylated interferon alpha; Peg-IFNα-2a, pegylated interferon alfa-2a; qHBsAg, quantitative hepatitis B surface antigen; RIG-I, retinoic acid inducible gene I; RNAi, RNA interference; siRNAs, small interfering RNAs; TLR, toll-like receptor.

AGO

argonaute

APCs

antigen presenting cells

ASO

antisense oligonucleotides

CHB

chronic hepatitis B

cccDNA

closed circular DNA

DC

dendritic cell

dslDNA

double-stranded linear DNA

dsRNA

double-stranded RNA

HBcAg

hepatitis B core antigen

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HBVsvp

hepatitis B virus subviral particles

HBx

hepatitis B X protein

HepG2

hepatocellular gastric 2

HCC

hepatocellular carcinoma

IRF

interferon regulatory factor

IKKe

IKB kinase epsilon

IFN

interferon

IFN-β

interferon β

ISGs

interferon-stimulated genes

IFN-α

interferon-α

mRNA

messenger RNA

MAVS

mitochondrial antiviral signalling protein

MAPK

mitogen-activated protein kinase

MyD88

myeloid differentiation primary response gene 88

NK

natural killer

NUCs

nucleos(t)ide analogues

PAMPs

pathogen-associated molecular patterns

PRRs

pattern recognition receptors

Peg-IFNα-2a

pegylated interferon alfa-2a

Peg-IFNα

pegylated interferon alpha

pgRNA

pregenomic RNA

rcDNA

relaxed circular DNA

RIG-I

retinoic acid inducible gene I

RNAi

RNA interference

siRNAs

small interfering RNAs

SMC5/6

structural maintenance of chromosome 5/6

TAF

tenofovir alafenamide

TBK1

TANK-binding kinase 1

TDF

tenofovir disoproxil fumarate

TRAIL

tumor necrosis factor-related apoptosis-inducing ligand

TLR

toll-like receptor

TRIF

toll-like receptor adaptor molecule 1

TNF-α

tumour necrosis factor alpha
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Targeting the innate immune system in treating hepatitis B: prospects for functional cure
Clin Mol Hepatol. 2026;32(1):184-199.   Published online November 11, 2025
DOI: https://doi.org/10.3350/cmh.2025.0935
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Targeting the innate immune system in treating hepatitis B: prospects for functional cure
Clin Mol Hepatol. 2026;32(1):184-199.   Published online November 11, 2025
DOI: https://doi.org/10.3350/cmh.2025.0935
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Targeting the innate immune system in treating hepatitis B: prospects for functional cure
Image Image
Figure 1. HBV life cycle. cccDNA, closed circular DNA; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HBx, hepatitis B X protein; mRNA, messenger RNA; NTCP, sodium taurocholate co-transporting polypeptide; pgRNA, pregenomic RNA; rcDNA, relaxed circular DNA.
Figure 2. Mechanisms of HBV to counteract the host immune response at the extra-cellular level. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IL, interleukin; MDSC, myeloid-derived suppressor cell; NK, natural killer; RIG-I, retinoic acid inducible gene I; TLR, tolllike receptor; TNF, tumour necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.

Figure 1.

Figure 2.

Targeting the innate immune system in treating hepatitis B: prospects for functional cure
Drug class Agent(s) Future development Ongoing clinical trial (if any) One representative trial
Name of compound (and trial name if applicable) Patient selection Study efficacy
RIG-I agonist SB9200 (Inarigivir) Trial terminated due to serious adverse event Not applicable Inarigivir (SB9200) ACHIEVE trial [68] -Both HBeAg+ve and HBeAg-ve patients were included -Up to 13% of patients achieved >0.5 log10 IU/mL reduction in HBsAg
-Some patients were sequentially-dosesd with NUC -Trial terminated due to serious adverse event (one patient death due to necrotizing pancreatitis)
-All patients were treatment naive
TLR agonist TLR7 agonist Combination therapy with siRNAs Ruzotolimod (TLR7 agonist)+Xalnesiran (siRNA) (phase II) Selgantolimod (GS-9688) [75] -Both HBeAg+ve and HBeAg-ve patients were included -At week 24, HBsAg decline of ≥0.5 log10 IU/mL were observed in 2 of 24 (8%), 1 of 28 (4%), and 0 patients receiving selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo, respectively
GS-9620 (Vesatolimod) -Baseline median HBsAg: 4log10 IU/mL
RO7020531 (Ruzotolimod) -Not virally suppressed with baseline HBV DNA >2,000 IU/mL -None achieved HBsAg seroclearance at 24/48 weeks post-EOT
TLR8 agonist
GS-9688 (Selgantolimod)
Interferons Peg-IFNα-2a (Pegasus) -Approved therapy for CHB -Elebsiran+tobevibart±Peg-IFNα (phase II) [MARCH] Peg-IFNα+Imdusiran (AB-729) -HBeAg-ve patients were included -Up to 33% of patients achieved HBsAg seroclearance at 24 weeks post-EOT if given lead-in AB-729 followed by 24 weeks of PEG-IFN, compared to 0% if PEG-IFN was only given for 12 weeks
-Novel drug development: as add-on therapy with background NUCs -Xalnesiran (siRNA)+Peg-IFNα or ruzotolimod (TLR7 agonist) (phase II) [PIRANGA] IM-PROVE I [103] -Baseline mean HBsAg: 1,555 IU/mL
-Combination with compounds involved in adaptive immunity e.g., siRNAs, monoclonal antibodies -Elebsiran (siRNA)+Peg-IFNα (phase II) [ENSURE] -Virally suppressed by NUC
-Imdusiran (siRNA)+Peg-IFNα (phase II) [IM-PROVE-I]
-Synthetic interferons -Daplusiran/tomligisiran+Peg-IFNα (phase II)
ASO Bepirovirsen Unconjugated ASO but not conjugated ASO will move forward in clinical development -Sequential therapy of Bepirovirsen after daplusiran/tomligisiran Bepirovirsen (GSK3228836) -Both HBeAg+ve and HBeAg-ve patients were included -9–15% of patients chieved HBsAg seroclearance at 24 weeks post-EOT after sequential bepirovirsen for 12–24 weeks, followed by PEG-IFNα for 24 weeks
GSK3389404 -AHB-137 and sequential PEG-IFNα B-Together trial [107] -Baseline mean HBsAg: 5,225 IU/mL
RO7062931 -Virally suppressed by NUC
AHB-137
siRNAs AB-729 (Imdusiran) Combination therapy with interferon, TLR agonist -Elebsiran+tobevibart±Peg-IFNα (phase II) [MARCH] Xalnesiran -Both HBeAg+ve and HBeAg-ve patients were included -23% of patients who received xalnesiran+Peg-IFNα achieved HBsAg seroclearance at 24 weeks post-EOT, compared to 12% among recipients of xalnesiran+ uzotolimod, and 7% in xalnesiran monotherapy
GSK5637608 (Daplusiran/Tomligisiran) -Xalnesiran (siRNA)+Peg-IFNα or ruzotolimod (TLR7 agonist) (phase II) [PIRANGA] PIRANGA [106]
VIR-2218 (Elebsiran) -Elebsiran (siRNA)+Peg-IFNα (phase II) [ENSURE] -Baseline mean HBsAg: 2.8log10 IU/mL
RBD-1016 -Imdusiran (siRNA)+Peg-IFNα (phase II) [IM-PROVE-I]
RG-6346 (xalnesiran) -Daplusiran/tomligisiran+Peg-IFNα (phase II) -Virally suppressed by NUC
Table 1. Overview of novel treatment of hepatitis B with immunomodulatory effects on the innate immunity

ASO, antisense oligonucleotides; CHB, chronic hepatitis B; EOT, end-of treatment; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NUCs, nucleos(t)ide analogues; Peg-IFNα, pegylated interferon alpha; Peg-IFNα-2a, pegylated interferon alfa-2a; qHBsAg, quantitative hepatitis B surface antigen; RIG-I, retinoic acid inducible gene I; RNAi, RNA interference; siRNAs, small interfering RNAs; TLR, toll-like receptor.

Table 1.

CMH : Clinical and Molecular Hepatology
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