Hepatitis B virus (HBV) infection remains a global health problem, which is currently manageable but not yet curable with standard antiviral therapies. Current treatment such as pegylated interferon alfa (PEG-IFNα) or nucleos(t)ide analogs (NAs), including entecavir, tenofovir disoproximal fumarate (TDF) and tenofovir alafenamide (TAF), can suppress HBV DNA replication and decrease liver inflammation. However, hepatitis B surface antigen (HBsAg) loss rarely occurs under these treatment, and viral relapse is common when the treatment is stopped. HBsAg seroclearance occurring in only 3%-5% of patients after 10 years of NAs therapy and 8%-14% within 3-5 years of PEG-IFNα treatment.

Achieving a clinical (functional ) cure has become the ultimate goal of global hepatitis B research and treatment. Clinical (functional) HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. New therapeutic approaches, particularly RNA interference (RNAi)-based therapies, are now being developed to reduce viral antigen production and restore immune control.

Three Major Barriers Preventing HBV Cure

The persistent nature of chronic hepatitis B (CHB) infection is driven by the combined effects of viral survival mechanisms and impaired host immune responses.

Long-term persistence of viral covalently closed circular DNA (cccDNA): After HBV infects hepatocytes, it forms a highly stable viral cccDNA within the nucleus. Acting as a persistent template for viral transcription, cccDNA is difficult for the host immune system to recognize and cannot be directly eliminated by currently available therapies. Once treatment is discontinued, residual cccDNA can resume viral transcription and replication, leading to viral rebound.

Continued expression of integrated HBV DNA within the host genome: HBsAg antigens are not only produced from cccDNA in infected cells, but also produced by integrated HBV DNA (iDNA). HBsAg from iDNA can consequently contribute to the elevated burden of viral antigens and the subsequent exhaustion of anti-HBV immune response, potentially jeopardizing the achievement of HBV functional cure.

Profound exhaustion of HBV-specific immune responses: Persistent high levels of HBsAg expression can drive long-term immune tolerance and lead to functional exhaustion of HBV-specific T cells. In other words, the challenge of curing hepatitis B is not only the continued presence of viral templates and persistent antigen production, but also the failure of the host immune system to effectively control and eliminate the infection.

Why Current Hepatitis B Treatments Cannot Achieve Cure?

Current first-line treatments such as NAs and PEG-IFNα have clear limitations in overcoming the key barriers that prevent HBV cure.

The NAs work mainly by inhibiting HBV DNA polymerase activity and thus suppress HBV replication. Long-term therapy is usually required to achieve sustained hepatitis B e antigen  (HBeAg) seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. NAs offer several advantages, including convenient administration, good safety profiles, high patient adherence, and broad accessibility. However, their activity is largely limited to the viral replication stage. They cannot directly eliminate cccDNA or prevent antigen production from integrated HBV DNA. As a result, most patients require long-term, and often lifelong, maintenance therapy.

PEG-IFNα takes a different approach by targeting the host immune response. They enhances antigen presentation, activates innate immunity, and partially restores HBV-specific T cell function, thereby contributing to the disruption of immune tolerance to some extent. In theory, PEG-IFNα has greater potential to achieve HBsAg clearance within a finite treatment duration. However, its clinical use is limited by lower tolerability, more frequent adverse events, and the need for careful patient selection.

New Therapeutic Strategies for Functional Cure of Hepatitis B

Achieving a functional cure for hepatitis B requires a dual approach: suppressing viral replication while restoring effective host immune control. Global drug development for hepatitis B currently focuses on two main categories: direct-acting antivirals (DAAs) and immunomodulators.

● Direct-Acting Antivirals (DAAs): These agents aim to block viral transcription, replication, and protein production, including RNA interference (e.g. small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs)), capsid assembly modulators (CpAMs/CAMs), and HBsAg inhibitors.
● Immunomodulators: These agents aim to overcome immune tolerance and reactivate the host immune response, including monoclonal antibodies, novel therapeutic vaccines, immune checkpoint inhibitors, and Toll-like receptor (TLR) agonists.

Among these approaches, RNAi therapies represent one of the most active and advanced areas of HBV drug development. Multiple RNAi therapeutics have entered phase II/III clinical trials, demonstrating potent, dose-dependent, and sustainable effects in suppressing HBsAg and improving the likelihood of functional cure.

RNAi-Based Therapies: The Leading Approach Toward HBV Functional Cure

RNA interference (RNAi) is a novel treatment strategy using siRNA or ASO to target HBV post-transcriptional RNA, in turn suppressing viral protein production and replication. 

Bepirovirsen (ASO, Phase III)

Bepirovirsen is an unconjugated antisense oligonucleotide targeting all HBV RNAs, including pregenomic RNA, via RNase H-mediated degradation.In the global Phase 3 B-Well 1 and B-Well 2 trials, 6 months of Bepirovirsen treatment achieved a functional cure rate of 19% in the overall patient population. Among patients with baseline HBsAg levels ≤1,000 IU/mL, representing a population with lower viral activity, the functional cure rate increased to 26%, compared with 0% in the control group. Exploratory analyses showed that nearly half of treated patients maintained very low HBsAg levels (≤100 IU/mL) one year after treatment completion. These findings, published in The New England Journal of Medicine (NEJM), support the potential of RNA-targeted therapies to achieve functional cure with a finite treatment duration. [3]

On Aug 24, 2026, Ionis partner GSK announced Hibsago (bepirovirsen) approved in Japan as first and only functional cure for chronic hepatitis B. 

Imdusiran (GalNAc-conjugated siRNA, Phase II)

Imdusiran (AB-729), a GalNAc-conjugated siRNA, silences all HBV transcripts and may also stimulate immune responses. In Arbutus’ Phase 2a clinical trials, eight patients with cHBV achieved functional cure following treatment with imdusiran and NA therapy in combination with either pegylated interferon alfa-2a or low dose nivolumab plus an immunotherapeutic, with six out of the eight patients continuing to sustain functional cure for over two years. [4]

AHB-137 (ASO, Phase III in China)

AHB-137 is a novel unconjugated ASO capable of simultaneously targeting viral replication and driving profound reductions in HBsAg. It has completed its global Phase I trial and is currently advancing through multiple Phase II trials and a phase III trial in China. AHB-137 demonstrates rapid, potent HBV DNA suppression and sustained antigen clearance in reported Phase II trial results presented at EASL 2026. Result showed 70% functional cure in patients with baseline HBsAg 100–1,000 IU/mL after 24 weeks off-treatment follow-up and 68% complete response rate at end of treatment (HBsAg <100 IU/mL AND HBV DNA <20 IU/mL).

Elebsiran (GalNAc-conjugated siRNA, Phase II) 

Elebsiran (BRII-835/VIR-2218) is a triantennary GalNAc-conjugated siRNA that is being developed for the treatment of chronic HBV infection and chronic hepatitis D virus infection. A study published in 2024 evaluating elebsiran in combination with PEG-IFNα reported an HBsAg loss rate of approximately 30% at the end of treatment (EOT) in participants with chronic HBV infection. [5]

Conclusion

Achieving a functional cure for chronic hepatitis B remains challenging due to the persistence of cccDNA, continuous HBsAg production, and impaired antiviral immunity. Emerging therapies, particularly RNAi-based approaches, have shown the potential to significantly reduce HBsAg levels and improve functional cure rates by targeting viral transcripts.

Supporting RNA Therapeutics with PEG and Nucleic Acid Building Blocks

The development of RNA-based therapeutics relies on a range of specialized building blocks and delivery materials. Lipids and functional PEG derivatives are widely used in nanoparticle formulations, conjugation strategies, and targeted delivery systems, while phosphoramidites and other nucleic acid building blocks support the synthesis and modification of therapeutic oligonucleotides. Biopharma PEG provides Lipids, PEG derivatives, and PEG-lipid related materials for research and development in RNA therapeutics, including siRNA delivery, conjugation, and lipid nanoparticle (LNP) applications.

We also peovide a range of Nucleic Acid Chemistry products, including RNA Phosphoramidites, LNA & BNA Phosphoramidites, Special & Modified Phosphoramidites, GalNAc Conjugation Building Blocks, Lipid Phosphoramidites, PMO & Morpholino Monomers, Fluorescent & Biotin Labeled Nucleotides, and Nucleic Acid Building Blocks. By supplying reliable, high-purity reagents and advanced delivery materials, Biopharma PEG helps biopharmaceutical researchers streamline the transition from oligonucleotide discovery to advanced clinical platforms.

References:
[1] Marrapu S, Soni JR, Kamal K, Kumar R. Hepatitis B functional cure: Current and future perspective. World J Hepatol. 2025 Oct 27;17(10):110107. doi: 10.4254/wjh.v17.i10.110107. PMID: 41179730; PMCID: PMC12576716.
[2] Hui RW, Mak LY, Seto WK, Yuen MF. Investigational RNA Interference Agents for Hepatitis B. BioDrugs. 2025 Jan;39(1):21-32. doi: 10.1007/s40259-024-00694-x. Epub 2024 Dec 7. PMID: 39644435; PMCID: PMC11750937. 
[3] Bepirovirsen achieves unprecedented functional cure rates with potential to redefine treatment for chronic hepatitis B. Retrieved May 28, 2026, from https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-achieves-unprecedented-functional-cure-rates-with-potential-to-redefine-treatment-for-chronic-hepatitis-b/
[4] https://investor.arbutusbio.com/node/19511/pdf Arbutus Receives U.S. FDA Fast Track Designation for Imdusiran for the Treatment of Chronic Hepatitis B 
[5] https://www.ajmc.com/view/ahb-137-demonstrates-high-cure-rates-sustained-viral-suppression-in-chronic-hepatitis-b  AHB-137 Demonstrates High Cure Rates, Sustained Viral Suppression in Chronic Hepatitis B
[6] Yuen, M. F. et al. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol. Hepatol. 9, 1121–1132 (2024).