{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:24:00Z","timestamp":1790061840992,"version":"4.0.1"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the turnover time of preexisting cccDNA pools would be helpful in designing strategies to clear HBV by fully blocking the <jats:italic toggle=\"yes\">de novo<\/jats:italic> generation of cccDNA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In this study, we retrospectively monitored the emergence and reversion of the rtM204I\/V mutant, a signature lamivudine resistance (LAM<jats:sup>R<\/jats:sup>) mutation serving as a biomarker of cccDNA turnover in liver biopsies and longitudinal serum samples from two clinical trials. Methodologies were optimized to differentially isolate and sequence HBV virion DNA, cccDNA, and HBV RNA from clinical samples. A strong correlation was observed between LAM<jats:sup>R<\/jats:sup> composition of cccDNA with that of serum and intrahepatic HBV RNA in paired liver and serum samples (r\u00a0=\u00a00.96 and 0.90, respectively), suggesting that serum HBV RNA can serve as a surrogate marker of cccDNA genetic composition when liver biopsies are unavailable. LAM<jats:sup>R<\/jats:sup> mutations emerged and increased from undetectable to 40%\u201090% within 16\u201028\u00a0weeks in serum HBV RNA from telbivudine\u2010treated patients experiencing virological breakthrough. Similarly, in lamivudine\u2010resistant patients who switched to interferon therapy, serum HBV\u2010RNA population bearing 100% LAM<jats:sup>R<\/jats:sup> mutations fully reversed back to wild type within 24\u201048\u00a0weeks.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The genetic composition dynamics of serum HBV RNA and biopsy cccDNA in treated HBV patients indicates that cccDNA turnover occurs relatively rapidly (several months), offering a possibility of HBV cure with finite therapy through completely blocking cccDNA replenishment.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31240","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T03:55:44Z","timestamp":1584590144000},"page":"41-52","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":80,"title":["Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature\u2010Mutation in Treated Chronic Hepatitis B Patients"],"prefix":"10.1097","volume":"73","author":[{"given":"Qi","family":"Huang","sequence":"first","affiliation":[{"name":"Assembly Biosciences, Inc.,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China"},{"name":"Department of Microbiology and Immunology,Indiana University,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Cai","sequence":"additional","affiliation":[{"name":"Assembly Biosciences, Inc.,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Zong","sequence":"additional","affiliation":[{"name":"Assembly Biosciences, Inc.,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaobo","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Mercier","sequence":"additional","affiliation":[{"name":"Assembly Biosciences, Inc.,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University,Indianapolis,IN"},{"name":"Cancer Virology Program,UPMC Hillman Cancer Center,Department of Microbiology and Molecular Genetics,University of Pittsburgh,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Colonno","sequence":"additional","affiliation":[{"name":"Assembly Biosciences, Inc.,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5320-227X","authenticated-orcid":false,"given":"Jian","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"issue":"Suppl. 1","key":"hep31240-bib-0002-20250905","first-page":"10","article-title":"Management of chronic hepatitis B: experience from China","volume":"17","year":"2010","journal-title":"J Viral Hepat"},{"key":"hep31240-bib-0003-20250905","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1080\/17474124.2018.1530986","article-title":"Improvements in the management of chronic hepatitis B virus infection","volume":"12","year":"2018","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"hep31240-bib-0004-20250905","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.jhep.2004.12.015","article-title":"New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA","volume":"42","year":"2005","journal-title":"J Hepatol"},{"key":"hep31240-bib-0005-20250905","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.antiviral.2015.08.005","article-title":"Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA\u2010targeting antiviral therapeutics","volume":"122","year":"2015","journal-title":"Antiviral Res"},{"key":"hep31240-bib-0006-20250905","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jhep.2005.11.036","article-title":"Cellular and virological mechanisms of HBV drug resistance","volume":"44","year":"2006","journal-title":"J Hepatol"},{"issue":"1 Suppl.","key":"hep31240-bib-0007-20250905","first-page":"S41","article-title":"Attacking hepatitis B virus cccDNA\u2014the holy grail to hepatitis B cure","volume":"64","year":"2016","journal-title":"J Hepatol"},{"key":"hep31240-bib-0008-20250905","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1423-0127-18-96","article-title":"Dynamics of HBV cccDNA expression and transcription in different cell growth phase","volume":"18","year":"2011","journal-title":"J Biomed Sci"},{"key":"hep31240-bib-0009-20250905","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1128\/AAC.00473-12","article-title":"Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation","volume":"56","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"hep31240-bib-0010-20250905","doi-asserted-by":"crossref","first-page":"6356","DOI":"10.1128\/JVI.76.12.6356-6363.2002","article-title":"Half\u2010life of the duck hepatitis B virus covalently closed circular DNA pool in vivo following inhibition of viral replication","volume":"76","year":"2002","journal-title":"J Virol"},{"key":"hep31240-bib-0011-20250905","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1128\/JVI.75.1.311-322.2001","article-title":"Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis","volume":"75","year":"2001","journal-title":"J Virol"},{"key":"hep31240-bib-0012-20250905","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1053\/j.gastro.2004.03.018","article-title":"Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy","volume":"126","year":"2004","journal-title":"Gastroenterology"},{"key":"hep31240-bib-0013-20250905","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.jhep.2016.05.014","article-title":"Decay of ccc\u2010DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV\u2010HBV co\u2010infected patients","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep31240-bib-0014-20250905","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jhep.2016.08.022","article-title":"Reduction of covalently closed circular DNA with long\u2010term nucleos(t)ide analogue treatment in chronic hepatitis B","volume":"66","year":"2017","journal-title":"J Hepatol"},{"key":"hep31240-bib-0015-20250905","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/hep.26277","article-title":"Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load","volume":"58","year":"2013","journal-title":"Hepatology"},{"issue":"Suppl.","key":"hep31240-bib-0016-20250905","article-title":"vidence for the presence of infectious virus in the serum from chronic hepatitis B patients suppressed on nucleos(t)ide therapy with detectable but not quantifiable HBV DNA","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep31240-bib-0017-20250905","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1053\/j.gastro.2009.08.063","article-title":"Hepatitis B virus resistance to nucleos(t)ide analogues","volume":"137","year":"2009","journal-title":"Gastroenterology"},{"key":"hep31240-bib-0018-20250905","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1053\/jhep.2000.17912","article-title":"Long\u2010term therapy of chronic hepatitis B with lamivudine","volume":"32","year":"2000","journal-title":"Hepatology"},{"issue":"Suppl. 1","key":"hep31240-bib-0019-20250905","first-page":"116","article-title":"Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance","volume":"33","year":"2013","journal-title":"Liver Int"},{"key":"hep31240-bib-0020-20250905","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1111\/j.1440-1746.2012.07198.x","article-title":"Prevention and management of drug resistant hepatitis B virus infections","volume":"27","year":"2012","journal-title":"J Gastroenterol Hepatol"},{"key":"hep31240-bib-0021-20250905","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/jgh.12835","article-title":"Randomized, three\u2010arm study to optimize lamivudine efficacy in hepatitis B e antigen\u2010positive chronic hepatitis B patients","volume":"30","year":"2015","journal-title":"J Gastroenterol Hepatol"},{"key":"hep31240-bib-0022-20250905","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1002\/hep.30325","article-title":"Serum hepatitis B virus RNA: a new potential biomarker for chronic hepatitis B virus infection","volume":"69","year":"2019","journal-title":"Hepatology"},{"key":"hep31240-bib-0023-20250905","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.jhep.2016.09.028","article-title":"Serum HBV pgRNA as a clinical marker for cccDNA activity","volume":"66","year":"2017","journal-title":"J Hepatol"},{"key":"hep31240-bib-0024-20250905","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jhep.2016.05.029","article-title":"Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep31240-bib-0025-20250905","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1093\/infdis\/jiv397","article-title":"Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa\u20102a and nucleos(t)ide analogues","volume":"213","year":"2016","journal-title":"J Infect Dis"},{"key":"hep31240-bib-0026-20250905","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/hep.27381","article-title":"Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep31240-bib-0027-20250905","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1002\/hep.26885","article-title":"The 104\u2010week efficacy and safety of telbivudine\u2010based optimization strategy in chronic hepatitis B patients: a randomized, controlled study","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep31240-bib-0028-20250905","doi-asserted-by":"crossref","first-page":"17123","DOI":"10.1038\/srep17123","article-title":"Composition and interactions of hepatitis B virus quasispecies defined the virological response during telbivudine therapy","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"hep31240-bib-0029-20250905","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/j.1365-2036.2011.04750.x","article-title":"Randomised clinical trial: efficacy of peginterferon alfa\u20102a in HBeAg positive chronic hepatitis B patients with lamivudine resistance","volume":"34","year":"2011","journal-title":"Aliment Pharmacol Ther"},{"key":"hep31240-bib-0030-20250905","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.cgh.2019.07.046","article-title":"Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy","volume":"18","year":"2020","journal-title":"Clin Gastroenterol Hepatol"},{"key":"hep31240-bib-0031-20250905","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.virol.2010.07.013","article-title":"The persistence in the liver of residual duck hepatitis B virus covalently closed circular DNA is not dependent upon new viral DNA synthesis","volume":"406","year":"2010","journal-title":"Virology"},{"key":"hep31240-bib-0032-20250905","first-page":"e01117","article-title":"T5 exonuclease hydrolysis of hepatitis B virus replicative intermediates allows reliable quantification and fast drug efficacy testing of covalently closed circular DNA by PCR","volume":"92","year":"2018","journal-title":"J Virol"},{"key":"hep31240-bib-0033-20250905","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1126\/science.284.5415.825","article-title":"Viral clearance without destruction of infected cells during acute HBV infection","volume":"284","year":"1999","journal-title":"Science"},{"key":"hep31240-bib-0034-20250905","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1073\/pnas.0308478100","article-title":"Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees","volume":"101","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31240-bib-0035-20250905","doi-asserted-by":"crossref","first-page":"17780","DOI":"10.1073\/pnas.0508913102","article-title":"Dynamics of hepatitis B virus clearance in chimpanzees","volume":"102","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31240-bib-0036-20250905","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1128\/JVI.74.3.1495-1505.2000","article-title":"Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections","volume":"74","year":"2000","journal-title":"J Virol"},{"key":"hep31240-bib-0037-20250905","doi-asserted-by":"crossref","first-page":"11652","DOI":"10.1073\/pnas.1635109100","article-title":"Hepatocyte turnover during resolution of a transient hepadnaviral infection","volume":"100","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31240-bib-0038-20250905","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1073\/pnas.0409332102","article-title":"Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection","volume":"102","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep31240-bib-0039-20250905","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1128\/JVI.01587-08","article-title":"The amount of hepatocyte turnover that occurred during resolution of transient hepadnavirus infections was lower when virus replication was inhibited with entecavir","volume":"83","year":"2009","journal-title":"J Virol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.31240","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31240","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31240","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31240","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T16:06:39Z","timestamp":1757088399000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31240"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31240","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,1]]},"assertion":[{"value":"2019-09-20","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-10","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}