Oligonucleotide and RNA-targeted therapeutics for chronic hepatitis B: Antigen reduction, delivery, and functional cure strategies
Year: 2026
Type: review
Abstract: Chronic hepatitis B (CHB) remains difficult to cure because nucleos(t)ide analogs suppress hepatitis B virus (HBV) replication but do not eliminate covalently closed circular DNA (cccDNA) or integrated HBV DNA, which sustain viral RNA and hepatitis B surface antigen (HBsAg) production. RNA-targeted therapeutics, including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and CRISPR-Cas13 platforms, offer sequence-directed approaches to suppress HBV transcripts and reduce antigen burden. Clinical evaluation of emerging HBV-directed therapies, including JNJ-3989, bepirovirsen, imdusiran, and related candidates, has demonstrated meaningful declines in circulating HBsAg levels. The recent phase III B-Well data further support the role of ASO-mediated antigen reduction as a potential therapeutic approach to increase the likelihood of functional cure within finite treatment regimens for selected patients. However, therapeutically induced HBsAg reduction alone rarely guarantees durable off-treatment control. This review summarizes HBV-directed RNA and oligonucleotide therapeutics from a translational pharmacology perspective, emphasizing transcript-silencing mechanisms, delivery constraints, pharmacodynamic endpoints, safety considerations, biomarker-guided patient selection, and integration with nucleos(t)ide analogs and immunomodulatory interventions. We propose that RNA-mediated antigen reduction may support finite therapy in biomarker-selected patients and may also serve as an antigen-conditioning component within staged functional cure strategies.
Institution: Yunnan University
Language: English
Topic: Hepatitis B Virus Studies
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,900
Award: G5511884108
OpenAlex ID: W7215085937