{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:30:22Z","timestamp":1790069422398,"version":"4.0.1"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T00:00:00Z","timestamp":1489017600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:p>The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti\u2010HBV reagents; it has a very low resistance rate and is used as the first\u2010line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV\u2010refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare\u2010up) and assessed ETV resistance using replication\u2010competent 1.38\u2010fold HBV genome\u2010length molecular clones. The full genome sequences of infected HBVs in ETV\u2010refractory patients were determined. The HBV molecular clones were generated with the patient\u2010derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core\u2010particle\u2010associated HBV DNA using Southern blotting and real\u2010time polymerase chain reaction. Among these cases, ETV\u2010resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV\u2010resistant mutation was detected in the other cases. The identified ETV\u2010resistant mutations did not confer resistance to tenofovir disoproxil fumarate. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The HBV replication model with patient\u2010derived sequences is useful for assessing replication efficiency, susceptibility to anti\u2010HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment\u2010failure cases of chronic hepatitis B. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2017;1:110\u2010121)<\/jats:p>","DOI":"10.1002\/hep4.1022","type":"journal-article","created":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T12:33:01Z","timestamp":1489062781000},"page":"110-121","source":"Crossref","is-referenced-by-count":17,"title":["Resistance mutations of hepatitis B virus in entecavir\u2010refractory patients"],"prefix":"10.1097","volume":"1","author":[{"given":"Norie","family":"Yamada","sequence":"first","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"},{"name":"Department of Internal Medicine,Center for Liver Diseases, Seizankai Kiyokawa Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayuri","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"},{"name":"Department of Gastroenterology and Hepatology,Tokyo Medical and Dental University,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Center for Liver Diseases, Seizankai Kiyokawa Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Okuse","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine,Kanagawa,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine,Kanagawa,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyomi","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Center for Liver Diseases, Seizankai Kiyokawa Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yotsuyanagi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases,Advanced Clinical Research Center, Institute of Medical Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoji","family":"Moriya","sequence":"additional","affiliation":[{"name":"Department of Infection Control and Prevention,Graduate School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,Graduate School of Medicine, The University of Tokyo,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaji","family":"Wakita","sequence":"additional","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Virology II,National Institute of Infectious Diseases,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,3,9]]},"reference":[{"key":"hep41022-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1053\/j.gastro.2007.02.039","article-title":"Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B","volume":"132","year":"2007","journal-title":"Gastroenterology"},{"key":"hep41022-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.biocel.2012.04.006","article-title":"Antiviral therapies: focus on hepatitis B reverse transcriptase","volume":"44","year":"2012","journal-title":"Int J Biochem Cell Biol"},{"key":"hep41022-bib-0003-20240114","first-page":"1129","article-title":"Hepatocellular carcinoma and hepatitis B virus. 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