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Due to the stable existence of HBV cccDNA, the original template for HBV replication, chronic hepatitis B (CHB) is difficult to cure completely. Despite current antiviral strategies being able to effectively limit the progression of CHB, complete CHB cure requires directly targeting HBV cccDNA. In this review, we discuss strategies that may achieve a complete cure of CHB, including inhibition of cccDNA de novo synthesis, targeting cccDNA degradation through host factors and small molecules, CRISP-Cas9-based cccDNA editing, and silencing cccDNA epigenetically.<\/jats:p>","DOI":"10.3390\/pathogens13121100","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T03:51:08Z","timestamp":1734061868000},"page":"1100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Targeting HBV cccDNA Levels: Key to Achieving Complete Cure of Chronic Hepatitis B"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1821-8547","authenticated-orcid":false,"given":"Wei","family":"He","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China"},{"name":"Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.idc.2019.08.004","article-title":"Viral Hepatitis: Etiology, Epidemiology, Transmission, Diagnostics, Treatment, and Prevention","volume":"33","author":"Lanini","year":"2019","journal-title":"Infect. 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