{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:35:26Z","timestamp":1790213726988,"version":"4.1.0"},"reference-count":189,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01AI144112"],"award-info":[{"award-number":["R01AI144112"]}]},{"name":"National Institutes of Health","award":["R01AI146917"],"award-info":[{"award-number":["R01AI146917"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Hepatitis B Virus (HBV) presents a formidable global health challenge, impacting hundreds of millions worldwide and imposing a considerable burden on healthcare systems. The elusive nature of the virus, with its ability to establish chronic infection and evade immune detection, and the absence of curative agents have prompted efforts to develop novel therapeutic approaches beyond current antiviral treatments. This review addresses the challenging concept of a functional cure for HBV, a state characterized by the suppression of HBV and HBsAg, mitigating disease progression and transmission without a complete cure. We provide an overview of HBV epidemiology and its clinical impact, followed by an exploration of the current treatment landscape and its limitations. The immunological basis of a functional cure is then discussed, exploring the intricate interplay between the virus and the host immune response. Emerging therapeutic approaches, such as RNA interference-based interventions, entry inhibitors, nucleic acid polymers, and therapeutic vaccines, are discussed with regard to their success in achieving a functional cure. Lastly, the review underscores the urgent need for innovative strategies to achieve a functional cure for HBV.<\/jats:p>","DOI":"10.3390\/ijms26083633","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T10:05:51Z","timestamp":1744365951000},"page":"3633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Functional Cure for Hepatitis B Virus: Challenges and Achievements"],"prefix":"10.3390","volume":"26","author":[{"given":"Oren","family":"Shechter","sequence":"first","affiliation":[{"name":"Eastern Virginia Medical School, Norfolk, VA 23501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Sausen","sequence":"additional","affiliation":[{"name":"Naval Medical Center Portsmouth, Portsmouth, VA 23708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-1817","authenticated-orcid":false,"given":"Harel","family":"Dahari","sequence":"additional","affiliation":[{"name":"The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1433-0700","authenticated-orcid":false,"given":"Andrew","family":"Vaillant","sequence":"additional","affiliation":[{"name":"Replicor Inc., 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott J.","family":"Cotler","sequence":"additional","affiliation":[{"name":"The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3035-5764","authenticated-orcid":false,"given":"Ronen","family":"Borenstein","sequence":"additional","affiliation":[{"name":"The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1099\/jgv.0.001415","article-title":"ICTV Virus Taxonomy Profile: Hepadnaviridae","volume":"101","author":"Magnius","year":"2020","journal-title":"J. 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