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Nucleos(t)ide analogs provide durable suppression of hepatitis B virus (HBV) replication but rarely achieve hepatitis B surface antigen (HBsAg) loss, and interferon\u2010based regimens are limited by modest efficacy and poor tolerability. Consequently, functional cure, defined as sustained HBsAg loss with undetectable HBV DNA after treatment, has become the central therapeutic goal. Recent advances highlight the promise of RNA\u2010targeting agents, including small interfering RNAs, antisense oligonucleotides, and RNA destabilizers, which directly reduce viral transcripts and antigen production. In parallel, immunomodulators such as pegylated interferon, checkpoint inhibitors, and therapeutic vaccines aim to restore HBV\u2010specific immunity. Emerging evidence shows that rationally designed combination regimens, integrating nucleos(t)ide analogs as a backbone with antigen\u2010lowering agents and immunotherapies, can synergistically enhance functional cure rates. As therapeutic strategies evolve, monitoring biomarkers beyond HBV DNA will be critical. Quantitative HBsAg reflects both covalently closed circular DNA and integrated HBV DNA activity, whereas hepatitis B core\u2010related antigens (HBcrAgs) provide complementary information on covalently closed circular DNA transcriptional activity. Together, these markers enable more precise assessment of treatment response, prediction of relapse risk, and evaluation of long\u2010term outcomes. In summary, the pursuit of functional cure in chronic hepatitis B is shifting toward multidrug strategies that combine potent viral suppression, antigen reduction, and immune restoration. Within this framework, the parallel monitoring of HBsAg and HBcrAg alongside HBV DNA will be indispensable for guiding therapeutic decisions, benchmarking clinical trial end points, and advancing personalized treatment strategies.<\/jats:p>","DOI":"10.1111\/hepr.70179","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:09:17Z","timestamp":1777536557000},"page":"903-913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toward a Functional Cure for Chronic Hepatitis B: Current Landscape and Future Directions in Japan"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-3258","authenticated-orcid":false,"given":"Yutaka","family":"Handa","sequence":"first","affiliation":[{"name":"Specialty Care Medical Affairs, GSK  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3151-8323","authenticated-orcid":false,"given":"Ethan Yichen","family":"Lee","sequence":"additional","affiliation":[{"name":"Specialty Care Medical Affairs, GSK  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":false,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"e_1_2_15_2_1","unstructured":"World Health Organization. \u201cGlobal Hepatitis Report 2024: Action for Access in Low\u2010 and Middle\u2010Income Countries.\u201d Accessed July 30 2025 https:\/\/www.who.int\/publications\/i\/item\/9789240091672."},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanwpc.2022.100428"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2468\u20101253(25)00069\u2010x"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.00385\u201025"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104925"},{"key":"e_1_2_15_7_1","first-page":"149","article-title":"Fundamental Performance and Clinical Utilities of Lumipulsepresto\u00ae iTACT\u00ae HBcrAg, A Novel Highly Sensitive Immunoassay for Hepatitis B Core\u2010Related Antigen","volume":"46","author":"Yagi S.","year":"2023","journal-title":"Journal of Analytical Bio\u2010Science"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2022.00289"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/boc.202200060"},{"key":"e_1_2_15_10_1","volume-title":"Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection","year":"2022"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072\u2010024\u201010763\u20106"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14225"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14147"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.06.002"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.03.018"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i42.11954"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14146"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.10.014"},{"key":"e_1_2_15_19_1","unstructured":"M.Drysdale L.Antunes C.Camarinha et\u00a0al. \u201cImpact of Hepatitis B Surface Antigen (HBsAg) Loss on the Long\u2010Term Clinical Outcomes in Hong Kong SAR China Patients With Chronic Hepatitis B Virus (HBV) Infection: A Retrospective Cohort Study \u201d Presented at: The 34th Annual Meeting of the Asian Pacific Association for the Study of the Liver (APASL); 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