{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,4,3]],"date-time":"2022-04-03T16:35:14Z","timestamp":1649003714519},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Foundation Project for Science and Technology of Huzhou City","award":["2019GY02","2020GY02"],"award-info":[{"award-number":["2019GY02","2020GY02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The reverse transcriptase (RT) region of the hepatitis B virus (HBV) is the target of antiviral treatment. However, the discrepancy in RT mutations between nucleos(t)ide analogue (NA)-treated and -untreated chronic hepatitis B (CHB) patients is un clear.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Serum samples were collected from 119 NA-treated and 135 NA-untreated patients. The sampling time was decided by the clinician. Full-length HBV RT regions were amplified using nest polymerase chain reaction. The mutations within the RT region were analysed by direct sequencing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The incidence of RT mutations in treated patients was higher than that in untreated patients (p&amp;lt;0.05). The classic drug-resistant mutations were detected in 44.5% (53\/119) of treated patients, which was significantly higher than in untreated patients (6.7% [9\/135]) (p&amp;lt;0.05). The non-classical mutations showed their complexity and diversity in both patient groups. Multiple mutations (three or more) were more frequent in treated patients than in untreated patients (p&amp;lt;0.05). Several novel mutations might be related to NA resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The selection pressures of NAs accelerated the development of RT mutations, especially within the functional domain. Mutations in the RT region occurred not only at classical sites, but also at other non-classical sites, which might be related to drug resistance and\/or viral replication. The biological function and fitness of HBV isolates harbouring these novel mutations need further in vitro and in vivo verification experiments.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/trstmh\/traa142","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T12:15:11Z","timestamp":1604664911000},"page":"870-877","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of mutations in the reverse transcriptase region of hepatitis B virus in treated and untreated chronic hepatitis B patients"],"prefix":"10.1093","volume":"115","author":[{"given":"Weihua","family":"Zou","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuchu","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"},{"name":"Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"},{"name":"Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"},{"name":"Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"},{"name":"Huzhou Key Laboratory of Molecular Medicine, 1558 Sanhuan North Road, Huzhou, Zhejiang Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"issue":"8","key":"2021080207533871600_bib1","doi-asserted-by":"crossref","first-page":"953","DOI":"10.3851\/IMP2654","article-title":"Mortality due to viral hepatitis in the Global Burden of Disease Study 2010: new evidence of an urgent global public health priority demanding action","volume":"18","author":"Cowie","year":"2013","journal-title":"Antivir Ther"},{"issue":"9859","key":"2021080207533871600_bib2","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"issue":"4","key":"2021080207533871600_bib3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jhep.2006.05.013","article-title":"The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide","volume":"45","author":"Perz","year":"2006","journal-title":"J Hepatol"},{"issue":"10003","key":"2021080207533871600_bib4","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/S0140-6736(15)61412-X","article-title":"Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013","volume":"386","author":"Schweitzer","year":"2015","journal-title":"Lancet"},{"issue":"7","key":"2021080207533871600_bib5","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S2468-1253(19)30119-0","article-title":"A global scientific strategy to cure hepatitis B","volume":"4","author":"Revill","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"issue":"2","key":"2021080207533871600_bib6","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection","volume":"67","author":"European Association for the Study of the Liver","year":"2017","journal-title":"J Hepatol"},{"issue":"4","key":"2021080207533871600_bib7","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1001\/jamaoncol.2016.5688","article-title":"Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study","volume":"3","author":"Fitzmaurice","year":"2017","journal-title":"JAMA Oncol"},{"issue":"1","key":"2021080207533871600_bib8","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/hep.21698","article-title":"Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management","volume":"46","author":"Lok","year":"2007","journal-title":"Hepatology"},{"issue":"6","key":"2021080207533871600_bib9","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1002\/hep.24318","article-title":"Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice","volume":"53","author":"Hongthanakorn","year":"2011","journal-title":"Hepatology"},{"issue":"4","key":"2021080207533871600_bib10","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1111\/j.1365-2893.2010.01360.x","article-title":"Genotypic resistance profile of hepatitis B virus (HBV) in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection","volume":"18","author":"Liu","year":"2011","journal-title":"J Viral Hepat"},{"issue":"3","key":"2021080207533871600_bib11","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.antiviral.2009.12.006","article-title":"Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-na\u00efve Chinese patients","volume":"85","author":"Liu","year":"2010","journal-title":"Antiviral Res"},{"issue":"2","key":"2021080207533871600_bib12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/jmv.23182","article-title":"Discrepancy of potential antiviral resistance mutation profiles within the HBV reverse transcriptase between nucleos(t)ide analogue-untreated and -treated patients with chronic hepatitis B in a hospital in China","volume":"84","author":"Li","year":"2012","journal-title":"J Med Virol"},{"issue":"8","key":"2021080207533871600_bib13","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3851\/IMP1677","article-title":"Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside\/nucleotide analogue treatment among Chinese chronic hepatitis B patients","volume":"15","author":"Yang","year":"2010","journal-title":"Antivir Ther"},{"issue":"4","key":"2021080207533871600_bib14","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1089\/mdr.2016.0093","article-title":"Comparison of detection rate and mutational pattern of drug-resistant mutations between a large cohort of genotype B and genotype C hepatitis B virus-infected patients in north China","volume":"23","author":"Li","year":"2017","journal-title":"Microb Drug Resist"},{"key":"2021080207533871600_bib15","doi-asserted-by":"crossref","first-page":"8078","DOI":"10.1038\/s41598-019-44604-6","article-title":"Potential resistant mutations within HBV reverse transcriptase sequences in nucleos(t)ide analogues-experienced patients with hepatitis B virus infection","volume":"9","author":"Zhang","year":"2019","journal-title":"Sci Rep"},{"issue":"1","key":"2021080207533871600_bib16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.diagmicrobio.2014.01.005","article-title":"Analysis of potential antiviral resistance mutation profiles within the HBV reverse transcriptase in untreated chronic hepatitis B patients using an ultra-deep pyrosequencing method","volume":"79","author":"Ciftci","year":"2014","journal-title":"Diagn Microbiol Infect Dis"},{"issue":"6","key":"2021080207533871600_bib17","doi-asserted-by":"crossref","first-page":"647","DOI":"10.7883\/yoken.JJID.2017.078","article-title":"Profile of mutations in the reverse transcriptase and overlapping surface genes of hepatitis B virus (HBV) in treatment-na\u00efve Indonesian HBV carriers","volume":"70","author":"Yamani","year":"2017","journal-title":"Jpn J Infect Dis"},{"issue":"12","key":"2021080207533871600_bib18","first-page":"888","article-title":"[The guidelines of prevention and treatment for chronic hepatitis B (2015 version)]","volume":"23","author":"Chinese Society of Infectious Diseases, Chinese Society of Hepatology","year":"2015","journal-title":"Zhonghua Gan ZangBing Za Zhi"},{"issue":"9","key":"2021080207533871600_bib19","doi-asserted-by":"crossref","first-page":"996","DOI":"10.3855\/jidc.8020","article-title":"Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou, China","volume":"10","author":"Qian","year":"2016","journal-title":"J Infect Dev Ctries"},{"issue":"23","key":"2021080207533871600_bib20","doi-asserted-by":"crossref","first-page":"4222","DOI":"10.3748\/wjg.v23.i23.4222","article-title":"Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-na\u00efve Korean patients infected with genotype C2","volume":"23","author":"Kim","year":"2017","journal-title":"World J Gastroenterol"},{"issue":"16","key":"2021080207533871600_bib21","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.3748\/wjg.v24.i16.1708","article-title":"Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression","volume":"24","author":"Choi","year":"2018","journal-title":"World J Gastroenterol"},{"issue":"3","key":"2021080207533871600_bib22","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.antiviral.2012.09.014","article-title":"Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy","volume":"96","author":"Mirandola","year":"2012","journal-title":"Antiviral Res"},{"issue":"Pt 3","key":"2021080207533871600_bib23","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1099\/jgv.0.000010","article-title":"Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients","volume":"96","author":"Fan","year":"2015","journal-title":"J Gen Virol"},{"issue":"2","key":"2021080207533871600_bib24","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s13337-018-00510-5","article-title":"Hepatitis B virus reverse transcriptase polymorphisms between treated and treatment-na\u00efve chronically infected patients","volume":"30","author":"Rezanezhadi","year":"2019","journal-title":"Virus Dis"},{"issue":"2","key":"2021080207533871600_bib25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s12072-008-9048-3","article-title":"Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure","volume":"2","author":"Locarnini","year":"2008","journal-title":"Hepatol Int"},{"issue":"5","key":"2021080207533871600_bib26","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","author":"Zoulim","year":"2009","journal-title":"Gastroenterology"},{"issue":"3","key":"2021080207533871600_bib27","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jcv.2014.03.018","article-title":"Viral evolutionary changes during tenofovir treatment in a chronic hepatitis B patient with sequential nucleos(t)ide therapy","volume":"60","author":"Lee","year":"2014","journal-title":"J Clin Virol"},{"key":"2021080207533871600_bib28","doi-asserted-by":"crossref","first-page":"104548","DOI":"10.1016\/j.jcv.2020.104548","article-title":"Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: an observational case series of South African adults","volume":"129","author":"Mokaya","year":"2020","journal-title":"J Clin Virol"},{"issue":"1","key":"2021080207533871600_bib29","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jcv.2012.02.003","article-title":"The rtL229 substitutions in the reverse transcriptase region of hepatitis B virus (HBV) polymerase are potentially associated with lamivudine resistance as a compensatory mutation","volume":"54","author":"Ji","year":"2012","journal-title":"J Clin Virol"},{"issue":"6","key":"2021080207533871600_bib30","doi-asserted-by":"crossref","first-page":"9678","DOI":"10.3892\/mmr.2017.7778","article-title":"Substitutions of rtL228 and\/or L229 are involved in the regulation of replication and HBsAg secretion in hepatitis B virus, and do not affect susceptibility to nucleos(t)ide analogs","volume":"16","author":"Qin","year":"2017","journal-title":"Mol Med Rep"},{"key":"2021080207533871600_bib31","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1743-422X-10-56","article-title":"Characterization of antiviral resistance mutations among the Eastern Indian Hepatitis B virus infected population","volume":"10","author":"Panigrahi","year":"2013","journal-title":"Virol J"},{"issue":"1","key":"2021080207533871600_bib32","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3851\/IMP3170","article-title":"Impacts of HBV rtH55R polymerase substitution on viral replication and rtM204I\/V resistance to nucleoside\/nucleotide antiviral drugs","volume":"23","author":"Xiang","year":"2018","journal-title":"Antivir Ther"},{"issue":"6","key":"2021080207533871600_bib33","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jhep.2019.02.006","article-title":"Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients","volume":"70","author":"Park","year":"2019","journal-title":"J Hepatol"},{"issue":"3","key":"2021080207533871600_bib34","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.jhep.2015.03.020","article-title":"Characterization of novel entecavir resistance mutations","volume":"63","author":"Hayashi","year":"2015","journal-title":"J Hepatol"},{"key":"2021080207533871600_bib35","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.antiviral.2019.02.012","article-title":"Prevalence of the entecavir-resistance-inducing mutation rtA186T in a large cohort of Chinese hepatitis B virus patients","volume":"164","author":"Liu","year":"2019","journal-title":"Antiviral Res"},{"issue":"3","key":"2021080207533871600_bib36","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1053\/jhep.2001.22166","article-title":"Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region","volume":"33","author":"Stuyver","year":"2001","journal-title":"Hepatology"},{"issue":"7","key":"2021080207533871600_bib37","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1128\/AAC.01499-06","article-title":"The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro","volume":"51","author":"Warner","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"2021080207533871600_bib38","first-page":"E1","article-title":"Different variants in reverse transcriptase domain determined by ultra-deep sequencing in treatment-na\u00efve and treated Indonesian patients infected with hepatitis B virus","volume":"62","author":"Wasityastuti","year":"2016","journal-title":"Kobe J Med Sci"},{"issue":"4","key":"2021080207533871600_bib39","doi-asserted-by":"crossref","first-page":"e35052","DOI":"10.1371\/journal.pone.0035052","article-title":"Dynamics of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by ultra-deep sequencing","volume":"7","author":"Nishijima","year":"2012","journal-title":"PLoS One"},{"issue":"8","key":"2021080207533871600_bib40","doi-asserted-by":"crossref","first-page":"e00119","DOI":"10.1128\/JCM.00119-19","article-title":"Characterization and clinical significance of natural variability in hepatitis B virus reverse transcriptase in treatment-naive Chinese patients by Sanger sequencing and next-generation sequencing","volume":"57","author":"Fu","year":"2019","journal-title":"J Clin Microbiol"}],"container-title":["Transactions of The Royal Society of Tropical Medicine and Hygiene"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/trstmh\/article-pdf\/115\/8\/870\/39520524\/traa142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/trstmh\/article-pdf\/115\/8\/870\/39520524\/traa142.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T07:55:14Z","timestamp":1627890914000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/trstmh\/article\/115\/8\/870\/6000684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,11,24]]},"published-print":{"date-parts":[[2021,8,2]]}},"URL":"https:\/\/doi.org\/10.1093\/trstmh\/traa142","relation":{},"ISSN":["0035-9203","1878-3503"],"issn-type":[{"value":"0035-9203","type":"print"},{"value":"1878-3503","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,8]]},"published":{"date-parts":[[2020,11,24]]}}}