Oligonucleotide and RNA-targeted therapeutics for chronic hepatitis B: Antigen reduction, delivery, and functional cure strategies

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.

Abstract from PubMed Central (PMID 42959269, PMC13717019). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.