{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:33:00Z","timestamp":1789651980872,"version":"4.0.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"General Research Fund"},{"name":"Research Grants Council"},{"name":"The Government of the Hong Kong Special Administrative Region"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 \u00d7 109 per liver and hepatocyte clone size of 2.41 \u00d7 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 \u00d7 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 \u00d7 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 \u00d7 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 \u00d7 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciac383","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T21:09:07Z","timestamp":1653080947000},"page":"e801-e809","source":"Crossref","is-referenced-by-count":57,"title":["Effect of Antiviral Treatment on Hepatitis B Virus Integration and Hepatocyte Clonal Expansion"],"prefix":"10.1093","volume":"76","author":[{"given":"Ning","family":"Chow","sequence":"first","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9078-5005","authenticated-orcid":false,"given":"Danny","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Lung","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung-Yi","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Fung","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi-Tang","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"Department of Pathology, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Wai","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Kay","family":"Seto","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Fung","family":"Yuen","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"},{"name":"State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"2023020817083598000_ciac383-B1","doi-asserted-by":"crossref","first-page":"e317","DOI":"10.1038\/oncsis.2017.22","article-title":"Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma","volume":"6","author":"Chauhan","year":"2017","journal-title":"Oncogenesis"},{"key":"2023020817083598000_ciac383-B2","doi-asserted-by":"crossref","first-page":"e02007-17","DOI":"10.1128\/JVI.02007-17","article-title":"Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via sodium taurocholate cotransporting polypeptide-dependent uptake of enveloped virus particles","volume":"92","author":"Tu","year":"2018","journal-title":"J Virol"},{"key":"2023020817083598000_ciac383-B3","doi-asserted-by":"crossref","first-page":"9710","DOI":"10.1128\/JVI.73.12.9710-9717.1999","article-title":"Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor","volume":"73","author":"Yang","year":"1999","journal-title":"J Virol"},{"key":"2023020817083598000_ciac383-B4","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1053\/j.gastro.2016.07.012","article-title":"HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant","volume":"151","author":"Mason","year":"2016","journal-title":"Gastroenterology"},{"key":"2023020817083598000_ciac383-B5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1093\/infdis\/155.1.64","article-title":"Sequences of hepatitis B virus DNA in the serum and liver of patients with acute benign and fulminant hepatitis","volume":"155","author":"Lugassy","year":"1987","journal-title":"J Infect Dis"},{"key":"2023020817083598000_ciac383-B6","doi-asserted-by":"crossref","first-page":"12992","DOI":"10.1038\/ncomms12992","article-title":"Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma","volume":"7","author":"Zhao","year":"2016","journal-title":"Nat Commun"},{"key":"2023020817083598000_ciac383-B7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/ng.2295","article-title":"Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma","volume":"44","author":"Sung","year":"2012","journal-title":"Nat Genet"},{"key":"2023020817083598000_ciac383-B8","doi-asserted-by":"crossref","first-page":"25075","DOI":"10.18632\/oncotarget.25308","article-title":"Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers","volume":"9","author":"Furuta","year":"2018","journal-title":"Oncotarget"},{"key":"2023020817083598000_ciac383-B9","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1101\/gr.133926.111","article-title":"The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients","volume":"22","author":"Jiang","year":"2012","journal-title":"Genome Res"},{"key":"2023020817083598000_ciac383-B10","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1186\/s12864-016-3029-z","article-title":"Global profiling of alternative RNA splicing events provides insights into molecular differences between various types of hepatocellular carcinoma","volume":"17","author":"Tremblay","year":"2016","journal-title":"BMC Genomics"},{"key":"2023020817083598000_ciac383-B11","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1111\/liv.12773","article-title":"Conceptual models for the initiation of hepatitis B virus-associated hepatocellular carcinoma","volume":"35","author":"Tu","year":"2015","journal-title":"Liver Int"},{"key":"2023020817083598000_ciac383-B12","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.7150\/jca.26052","article-title":"Molecular characterization of HBV DNA integration in patients with hepatitis and hepatocellular carcinoma","volume":"9","author":"Yang","year":"2018","journal-title":"J Cancer"},{"key":"2023020817083598000_ciac383-B13","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/apt.13895","article-title":"Effects of nucleoside analogue prescription for hepatitis B on the incidence of liver cancer in Hong Kong: a territory-wide ecological study","volume":"45","author":"Seto","year":"2017","journal-title":"Aliment Pharmacol Ther"},{"key":"2023020817083598000_ciac383-B14","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/jvh.13237","article-title":"A large real-world cohort study examining the effects of long-term entecavir on hepatocellular carcinoma and HBsAg seroclearance","volume":"27","author":"Ko","year":"2020","journal-title":"J Viral Hepat"},{"key":"2023020817083598000_ciac383-B15","first-page":"4984","article-title":"Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis","volume":"18","author":"Jin","year":"2019","journal-title":"Oncol Lett"},{"key":"2023020817083598000_ciac383-B16","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1056\/NEJMoa051285","article-title":"A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B","volume":"354","author":"Chang","year":"2006","journal-title":"N Engl J Med"},{"key":"2023020817083598000_ciac383-B17","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMoa051287","article-title":"Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B","volume":"354","author":"Lai","year":"2006","journal-title":"N Engl J Med"},{"key":"2023020817083598000_ciac383-B18","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1056\/NEJMoa066422","article-title":"Telbivudine versus lamivudine in patients with chronic hepatitis B","volume":"357","author":"Lai","year":"2007","journal-title":"N Engl J Med"},{"key":"2023020817083598000_ciac383-B19","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-term nucleos(t)ide analogue treatment in chronic hepatitis B","volume":"66","author":"Lai","year":"2017","journal-title":"J Hepatol"},{"key":"2023020817083598000_ciac383-B20","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.cgh.2013.01.026","article-title":"Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency","volume":"11","author":"Wong","year":"2013","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2023020817083598000_ciac383-B21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/978-1-4939-6700-1_9","volume-title":"Hepatitis B virus methods in molecular biology","author":"Tu","year":"2017"},{"key":"2023020817083598000_ciac383-B22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0925-4773(02)00338-6","article-title":"The role of hepatocytes and oval cells in liver regeneration and repopulation","volume":"120","author":"Fausto","year":"2003","journal-title":"Mech Dev"},{"key":"2023020817083598000_ciac383-B23","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1097\/MPG.0b013e3181e7ff55","article-title":"Hepatic progenitor cell proliferation and liver injury in alpha-1-antitrypsin deficiency","volume":"51","author":"Brunt","year":"2010","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"2023020817083598000_ciac383-B24","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1053\/jhep.2001.21900","article-title":"Heterogeneity and plasticity of hepatocyte lineage cells","volume":"33","author":"Sell","year":"2001","journal-title":"Hepatology"},{"key":"2023020817083598000_ciac383-B25","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","author":"Werle-Lapostolle","year":"2004","journal-title":"Gastroenterology"},{"key":"2023020817083598000_ciac383-B26","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1440-1711.2005.01346.x","article-title":"Liver inflammation and cytokine production, but not acute phase protein synthesis, accompany the adult liver progenitor (oval) cell response to chronic liver injury","volume":"83","author":"Knight","year":"2005","journal-title":"Immunol Cell Biol"},{"key":"2023020817083598000_ciac383-B27","doi-asserted-by":"crossref","first-page":"6059","DOI":"10.21873\/anticanres.11195","article-title":"Apoptosis of hepatitis B virus-expressing liver tumor cells induced by a high concentration of nucleos(t)ide analogue","volume":"36","author":"Tak","year":"2016","journal-title":"Anticancer Res"},{"key":"2023020817083598000_ciac383-B28","doi-asserted-by":"crossref","first-page":"16264","DOI":"10.1038\/s41598-020-73387-4","article-title":"Tax1BP1 limits hepatic inflammation and reduces experimental hepatocarcinogenesis","volume":"10","author":"Waidmann","year":"2020","journal-title":"Sci Rep"},{"key":"2023020817083598000_ciac383-B29","first-page":"568","article-title":"CUL4B, NEDD4, and UGT1As involve in the TGF-beta signalling in hepatocellular carcinoma","volume":"15","author":"Qu","year":"2016","journal-title":"Ann Hepatol"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciac383\/44329443\/ciac383.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/e801\/49125248\/ciac383.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/e801\/49125248\/ciac383.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T17:46:43Z","timestamp":1675878403000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/76\/3\/e801\/6589784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,20]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,5,20]]},"published-print":{"date-parts":[[2023,2,8]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciac383","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,5,20]]}}}