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A range of novel agents, broadly classified into virus-targeting agents and immunomodulators, are hence developed with functional cure as the treatment target. As the data on individual novel agents are maturing, the field has gradually shifted to novel combination strategies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This article comprehensively reviewed the data on novel combination strategies against CHB. Potential mechanisms and future developmental directions are also discussed<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>RNA silencers (including antisense oligonucleotides and small-interfering RNAs) form the backbone of most combination strategies. Synergistic effects are observable with the combination of RNA silencers + single or dual immunomodulators, primarily through enhancing the magnitude and rate of hepatitis B surface antigen (HBsAg) decline, prolonging RNA silencer effects, and reducing HBsAg rebound after end-of-treatment. Accumulating data also demonstrate immune dysfunction recovery among patients with significant HBsAg reduction on RNA silencer-based or immune checkpoint inhibitor-based combination therapies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Functional cure is now an attainable endpoint with novel combination treatment. Research is warranted to optimize combination regimens, and personalization of treatment strategies will be necessary. With further development, novel combination strategies have the potential to transform future CHB management.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s12072-025-10828-0","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T21:30:49Z","timestamp":1749591049000},"page":"704-719","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Emerging therapies for HBsAg seroclearance: spotlight on novel combination strategies"],"prefix":"10.1007","volume":"19","author":[{"given":"Rex Wan-Hin","family":"Hui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Kay","family":"Seto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7985-7725","authenticated-orcid":false,"given":"Man-Fung","family":"Yuen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung-Yi","family":"Mak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"10828_CR1","unstructured":"The CDA Foundation. 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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. WK Seto received speaker\u2019s fees from AstraZeneca and Echosens, is an advisory board member and received speaker\u2019s fees of Abbott, received research funding from Alexion Pharmaceuticals, Boehringer Ingelheim, Pfizer and Ribo Life Science, and is an advisory board member, received speaker\u2019s fees and researching funding from Gilead Sciences. The remaining authors have no conflict of interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"This article does not contain any studies with human or animal subjects.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human\/animal rights"}}]}}