{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:40:05Z","timestamp":1790890805436,"version":"4.1.0"},"reference-count":153,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Hepatitis B virus (HBV) infection remains a serious public health concern worldwide despite the availability of an efficient vaccine and the major improvements in antiviral treatments. The aim of the present study is to analyze the mutational profile of the HBV whole genome in ETV non-responder chronic HBV patients, in order to investigate antiviral drug resistance, immune escape, and liver disease progression to Liver Cirrhosis (LC) or Hepatocellular Carcinoma (HCC). Blood samples were collected from five chronic hepatitis B patients. For each patient, two plasma samples were collected, before and during the treatment. Whole genome sequencing was performed using Sanger technology. Phylogenetic analysis comparing the studied sequences with reference ones was used for genotyping. The mutational profile was analyzed by comparison with the reference sequence M32138. Genotyping showed that the studied strains belong to subgenotypes D1, D7, and D8. The mutational analysis showed high genetic variability. In the RT region of the polymerase gene, 28 amino acid (aa) mutations were detected. The most significant mutations were the pattern rtL180M\u2009+\u2009rtS202G\u2009+\u2009rtM204V, which confer treatment resistance. In the S gene, 35 mutations were detected namely sP120T, sT126S, sG130R, sY134F, sS193L, sI195M, and sL216stop were previously described to lead to vaccine, immunotherapy, and\/or diagnosis escape. In the C gene, 34 mutations were found. In particular, cG1764A, cC1766G\/T, cT1768A, and cC1773T in the BCP; cG1896A and cG1899A in the precore region and cT12S, cE64D, cA80T, and cP130Q in the core region were associated with disease progression to LC and\/or HCC. Other mutations were associated with viral replication increase including cT1753V, cG1764A\/T, cC1766G\/T, cT1768A, and cC1788G in the BCP as well as cG1896A and cG1899A in the precore region. In the X gene, 30 aa substitutions were detected, of which substitutions xT36D, xP46S, xA47T, xI88F, xA102V, xI127T, xK130M, xV131I, and xF132Y were previously described to lead to LC and\/or HCC disease progression. In conclusion, our results show high genetic variability in the long-term treatment of chronic HBV patients causing several effects. This could contribute to guiding national efforts to optimize relevant HBV treatment management in order to achieve the global hepatitis elimination goal by 2030.<\/jats:p>","DOI":"10.3389\/fmicb.2022.1020147","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:08:46Z","timestamp":1665972526000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Whole genome analysis of hepatitis B virus before and during long-term therapy in chronic infected patients: Molecular characterization, impact on treatment and liver disease progression"],"prefix":"10.3389","volume":"13","author":[{"given":"Zeineb","family":"Belaiba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaouther","family":"Ayouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariem","family":"Gdoura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa","family":"Kammoun Rebai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henda","family":"Touzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel","family":"Sadraoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Hammemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"Yacoubi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa","family":"Abdelati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamine","family":"Hamzaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Msaddak Azzouz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anissa","family":"Chouikha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henda","family":"Triki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,17]]},"reference":[{"key":"ref1","author":"Abdel Hamid","year":"2018"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"105115","DOI":"10.18632\/oncotarget.22428","article-title":"Hepatitis B virus (HBV) X gene mutations and their association with liver disease progression in HBV-infected patients","volume":"8","author":"Al-Qahtani","year":"2017","journal-title":"Oncotarget"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"10238","DOI":"10.3748\/wjg.v20.i30.10238","article-title":"Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma","volume":"20","author":"Ali","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00355","article-title":"The correlation between Hepatitis B virus Precore\/Core mutations and the progression of severe liver disease","volume":"8","author":"Al-Qahtani","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.jhep.2009.04.022","article-title":"Prevalence, viral replication efficiency and antiviral drug susceptibility of rtQ215 polymerase mutations within the hepatitis B virus genome","volume":"51","author":"Amini-Bavil-Olyaee","year":"2009","journal-title":"J. Hepatol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1128\/JVI.01796-09","article-title":"Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains","volume":"84","author":"Amini-Bavil-Olyaee","year":"2010","journal-title":"J. Virol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1111\/j.1872-034X.2008.00392.x","article-title":"Occult hepatitis B virus infection in HIV-infected patients: evaluation of biochemical, virological and molecular parameters","volume":"38","author":"Araujo","year":"2008","journal-title":"Hepatol. Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.5454\/mi.10.1.2","article-title":"Detection of Hepatitis B virus X gene mutation from local clinical samples","volume":"10","author":"Artarini","year":"2016","journal-title":"Microbiol Indones."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.4274\/vhd.galenos.2019.2019.0015","article-title":"Molecular characterization of Hepatitis B virus strains isolated from chronic Hepatitis B patients in southeastern region of Turkey","volume":"25","author":"Ayd\u0131n","year":"2019","journal-title":"Viral Hepat. J."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.jinf.2006.05.013","article-title":"Hepatitis B virus genotypes and precore\/core-promoter mutations in Tunisian patients with chronic hepatitis B virus infection","volume":"54","author":"Ayed","year":"2007","journal-title":"J. Infect."},{"key":"ref11","article-title":"Epidemiology, risk factors, and molecular characterization of occult hepatitis B infection among anti-hepatitis B core antigen alone subjects","volume":"91","author":"Azarkar","year":"2018","journal-title":"J. Med. Virol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"5448","DOI":"10.3748\/wjg.14.5448","article-title":"Clinical, virologic and phylogenetic features of hepatitis B infection in Iranian patients","volume":"14","author":"Bahramali","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1002\/jmv.20554","article-title":"Hepatitis B genotypes, precore and core promoter mutants circulating in Tunisia","volume":"78","author":"Bahri","year":"2006","journal-title":"J. Med. Virol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"DD04","DOI":"10.7860\/JCDR\/2017\/26821.10498","article-title":"Hepatitis B core antibody negativity in a chronic hepatitis b infected patient: report of an unusual serological pattern","volume":"11","author":"Bajpai","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.15(5)2015.25749","article-title":"Efficacy of tenofovir disoproxil fumarate therapy in nucleoside-analogue naive Iranian patients treated for chronic hepatitis B","volume":"15","author":"Bakhshizadeh","year":"2015","journal-title":"Hepat. Mon."},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/212704","article-title":"Characterization of the occult hepatitis B virus variants circulating among the blood donors from eastern India","author":"Biswas","year":"2013","journal-title":"Sci. World J."},{"key":"ref17","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1093\/trstmh\/trz021","article-title":"Hepatitis B virus activity in untreated hepatitis B e antigen-negative human immunodeficiency virus-hepatitis B virus co-infected patients from sub-Saharan Africa","volume":"113","author":"Boyd","year":"2019","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1111\/jvh.12914","article-title":"Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co-infected patients from Western Africa","volume":"25","author":"Boyd","year":"2018","journal-title":"J. Viral Hepat."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3748\/wjg.v22.i1.145","article-title":"Overview of hepatitis B virus mutations and their implications in the management of infection","volume":"22","author":"Caligiuri","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1159\/000445894","article-title":"Naturally occurring surface antigen variants of Hepatitis B virus in Tunisian patients","volume":"59","author":"Chaouch","year":"2016","journal-title":"Intervirology"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1053\/j.gastro.2004.08.003","article-title":"Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter","volume":"127","author":"Chaudhuri","year":"2004","journal-title":"Gastroenterology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1099\/vir.0.018127-0","article-title":"A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV\/E strains","volume":"91","author":"Chekaraou","year":"2010","journal-title":"J. Gen. Virol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"6000","DOI":"10.1128\/JCM.43.12.6000-6006.2005","article-title":"Clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations affecting HBV e antigen expression in Taiwan","volume":"43","author":"Chen","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3390\/v12070731","article-title":"In Silico prediction of human leukocytes antigen (HLA) class II binding Hepatitis B virus (HBV) peptides in Botswana","volume":"12","author":"Choga","year":"2020","journal-title":"Viruses"},{"key":"ref25","doi-asserted-by":"publisher","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."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1002\/hep.20019","article-title":"Identification of HBV DNA Sequences That Are Predictive of Response to Lamivudine Therapy","volume":"39","author":"Ciancio","year":"2004","journal-title":"Hepatology"},{"key":"ref27","doi-asserted-by":"publisher","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."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s12879-018-3161-2","article-title":"Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe","volume":"18","author":"Colagrossi","year":"2018","journal-title":"BMC Infect. Dis."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.4254\/wjh.v7.i27.2729","article-title":"Clinical significance of hepatitis B surface antigen mutants","volume":"7","author":"Coppola","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110012","article-title":"Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma","volume":"9","author":"Datta","year":"2014","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/095632020101200101","article-title":"Resistance of hepatitis B virus to antiviral drugs: Current aspects and directions for future investigation","volume":"12","author":"Delaney","year":"2001","journal-title":"Antivir. Chem. Chemother."},{"key":"ref32","doi-asserted-by":"crossref","first-page":"80346","DOI":"10.1371\/journal.pone.0080346","article-title":"High Endemicity and Low Molecular Diversity of Hepatitis B Virus Infections in Pregnant Women in a Rural District of North Cameroon","volume":"8","author":"Ducancelle","year":"2013","journal-title":"PLoS One"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.1111\/jgh.13338","article-title":"Different precore\/core mutations of hepatitis B interact with, limit, or favor liver fibrosis severity","volume":"31","author":"Ducancelle","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref34","author":"Duda","year":"2020"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1440-1746.2008.05321.x","article-title":"Virological and clinical implication of core promoter C1752\/V1753 and T1764\/G1766 mutations in hepatitis B virus genotype D infection in Mongolia","volume":"23","author":"Elkady","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.meegid.2008.01.010","article-title":"Genotype determination in Moroccan hepatitis B chronic carriers","volume":"8","author":"Ezzikouri","year":"2008","journal-title":"Infect. Genet. Evol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2254","DOI":"10.1111\/j.1572-0241.2008.01974.x","article-title":"HBV A1762T, G1764A mutations are a valuable biomarker for identifying a subset of male HBsAG carriers at extremely high risk of hepatocellular carcinoma: a prospective study","volume":"103","author":"Fang","year":"2008","journal-title":"Am. J. Gastroenterol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/jmv.23513","article-title":"Reactivation of occult hepatitis B virus infection following cytotoxic lymphoma therapy in an anti-HBc negative patient","volume":"85","author":"Feeney","year":"2013","journal-title":"J. Med. Virol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1034\/j.1600-6143.2003.00149.x","article-title":"Characterization of Hepatitis B Virus Surface Antigen and Polymerase Mutations in Liver Transplant Recipients Pre- and Post-Transplant","volume":"3","author":"Germer","year":"2003","journal-title":"Am. J. Transplant."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"E412","DOI":"10.1111\/j.1469-0691.2012.03975.x","article-title":"Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection","volume":"18","author":"Ghosh","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"5883","DOI":"10.3748\/wjg.v25.i38.5883","article-title":"Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment","volume":"25","author":"Gil-Garc\u00eda","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"9294","DOI":"10.3748\/wjg.v19.i48.9294","article-title":"Hepatitis B virus subgenotype A1 predominates in liver disease patients from Kerala, India","volume":"19","author":"Gopalakrishnan","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/S0168-8278(99)80124-X","article-title":"Absence of mutations in the YMDD motif\/B region of the hepatitis B virus polymerase in famciclovir therapy failure","volume":"30","author":"G\u00fcnther","year":"1999","journal-title":"J. Hepatol."},{"key":"ref44","first-page":"9630","article-title":"Detection and analysis of resistance mutations of hepatitis B virus","volume":"8","author":"He","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"6096","DOI":"10.3748\/wjg.v18.i42.6096","article-title":"Quasispecies dynamics in main core epitopes of hepatitis B virus by ultra-deep-pyrosequencing","volume":"18","author":"Homs","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3851\/IMP1701","article-title":"HBV core region variability: effect of antiviral treatments on main epitopic regions","volume":"16","author":"Homs","year":"2011","journal-title":"Antivir. Ther."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/jmv.1890440118","article-title":"Differences in the entire nucleotide sequence between hepatitis B virus genomes from carriers positive for antibody to hepatitis B e antigen with and without active disease","volume":"44","author":"Horikita","year":"1994","journal-title":"J. Med. Virol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.aohep.2018.12.006","article-title":"Association of HBsAg mutation patterns with hepatitis B infection outcome: Asymptomatic carriers versus HCC\/cirrhotic patients","volume":"18","author":"Hosseini","year":"2019","journal-title":"Ann. Hepatol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1053\/j.gastro.2011.06.048","article-title":"Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21","volume":"141","author":"Huang","year":"2011","journal-title":"Gastroenterology"},{"key":"ref50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115743","article-title":"Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection","volume":"9","author":"Huang","year":"2014","journal-title":"PLoS One"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1159\/000323521","article-title":"Antiviral resistance mutations and genotype-associated amino acid substitutions in treatment-Na\u00efve Hepatitis B virus-infected individuals from the Indian subcontinent","volume":"55","author":"Ismail","year":"2011","journal-title":"Intervirology"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1099\/vir.0.83468-0","article-title":"Effect of basal core promoter and pre-core mutations on hepatitis B virus replication","volume":"89","author":"Jammeh","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5812\/hepatmon.100899","article-title":"Downregulation of gsk3\u03b2 and upregulation of urg7 in hepatitis b-related hepatocellular carcinoma","volume":"20","author":"Javanmard","year":"2020","journal-title":"Hepat. Mon."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1093\/jac\/dkg236","article-title":"The mechanisms of action of antivirals against hepatitis B virus infection","volume":"51","author":"Kamiya","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.jcv.2011.10.011","article-title":"Molecular characterization of a novel entecavir mutation pattern isolated from a multi-drug refractory patient with chronic hepatitis B infection","volume":"53","author":"Karatayli","year":"2012","journal-title":"J. Clin. Virol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"4114","DOI":"10.19082\/4114","article-title":"Prevalence and Characteristics of Precore Mutation in Iran and Its Correlation with Genotypes of Hepatitis B","volume":"9","author":"Kargar Kheirabad","year":"2017","journal-title":"Electron. Physician"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1002\/jmv.21499","article-title":"Molecular characterization of occult hepatitis B cases in Greek blood donors","volume":"81","author":"Katsoulidou","year":"2009","journal-title":"J. Med. Virol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3346\/jkms.2010.25.2.257","article-title":"Hepatitis B viral surface mutations in patients with adefovir resistant chronic hepatitis B with A181T\/V polymerase mutations","volume":"25","author":"Kim","year":"2010","journal-title":"J. Korean Med. Sci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"5467","DOI":"10.3748\/wjg.v22.i24.5467","article-title":"X region mutations of hepatitis B virus related to clinical severity","volume":"22","author":"Kim","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref60","doi-asserted-by":"publisher","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."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"e54486","DOI":"10.1371\/journal.pone.0084194","article-title":"Naturally occurring mutations in large surface genes related to occult Infection of Hepatitis B virus Genotype C. Blackard J, editor","volume":"8","author":"Kim","year":"2013","journal-title":"PLoS One"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"e42891","DOI":"10.1371\/journal.pone.0042891","article-title":"Variability in the Precore and Core Promoter Regions of HBV Strains in Morocco: Characterization and Impact on Liver Disease Progression","volume":"7","author":"Kitab","year":"2012","journal-title":"PLoS One"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1159\/000071456","article-title":"Precore wild-type hepatitis B virus with G1896 in the resolution of persistent hepatitis B virus infection","volume":"46","author":"Kobayashi","year":"2003","journal-title":"Intervirology"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets Downloaded from","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1128\/JVI.02701-12","article-title":"Impaired Virion secretion by Hepatitis B virus immune escape mutants and its rescue by wild-type envelope proteins or a second-site mutation","volume":"87","author":"Kwei","year":"2013","journal-title":"J. Virol."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"e92223","DOI":"10.1371\/journal.pone.0092223","article-title":"Analysis of Complete Nucleotide Sequences of Angolan Hepatitis B Virus Isolates Reveals the Existence of a Separate Lineage within Genotype E","volume":"9","author":"Lago","year":"2014","journal-title":"PLoS One"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"778","DOI":"10.3390\/v11090778","article-title":"Immune-escape hepatitis B virus mutations associated with viral reactivation upon immunosuppression","volume":"11","author":"Lazarevic","year":"2019","journal-title":"Viruses"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"5141","DOI":"10.3892\/mmr.2015.4072","article-title":"Biological characteristics of the A1762T\/G1764A mutant strain of hepatitis B virus in vivo","volume":"12","author":"Leng","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref69","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1743-422X-2-60","article-title":"HBx M130K and V131I (T-A) mutations in HBV genotype F during a follow-up study in chronic carriers","volume":"4","author":"Le\u00f3n","year":"2005","journal-title":"Virol. J."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1631\/jzus.2005.B0664","article-title":"Character of HBV (hepatitis B virus) polymerase gene rtM204V\/I and rtL180M mutation in patients with lamivudine resistance","volume":"6","author":"Li","year":"2005","journal-title":"J. Zhejiang Univ. Sci."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.3892\/mmr.2017.6362","article-title":"F221Y mutation in hepatitis B virus reverse transcriptase is associated with hepatocellular carcinoma prognosis following liver resection","volume":"15","author":"Li","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref72","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000013964","article-title":"The association between TNF-a 238A\/G and 308A\/G polymorphisms and juvenile idiopathic arthritis: An updated PRISMA-compliant meta-analysis","volume":"97","author":"Li","year":"2018","journal-title":"Medicine"},{"key":"ref73","doi-asserted-by":"publisher","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."},{"key":"ref74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038394","article-title":"Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis","volume":"7","author":"Liao","year":"2012","journal-title":"PLoS One"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"4703","DOI":"10.3748\/wjg.v11.i30.4703","article-title":"Biological impacts of \u201chot-spot\u201d mutations of hepatitis B virus X proteins are genotype B and C differentiated","volume":"11","author":"Lin","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref76","doi-asserted-by":"publisher","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."},{"key":"ref77","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1093\/jnci\/djp180","article-title":"Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis","volume":"101","author":"Liu","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.jhep.2005.11.036","article-title":"Cellular and virological mechanisms of HBV drug resistance","volume":"44","author":"Locarnini","year":"2006","journal-title":"J. Hepatol."},{"key":"ref79","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1055\/s-2003-37587","article-title":"The hepatitis B virus and common mutants","volume":"23","author":"Locarnini","year":"2003","journal-title":"Semin. Liver Dis."},{"key":"ref80","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.6712","article-title":"Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-na\u00efve chronic HBV patients","volume":"13","author":"Mahabadi","year":"2013","journal-title":"Hepat. Mon."},{"key":"ref81","doi-asserted-by":"publisher","DOI":"10.4103\/ijmm.IJMM_19_421","article-title":"Hepatitis B virus X protein: the X factor in chronic hepatitis B virus disease progression","author":"Mani","year":"2019","journal-title":"Indian J. Med. Microbiol."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1099\/vir.0.009738-0","article-title":"A novel hepatitis B virus subgenotype, D7, in Tunisian blood donors","volume":"90","author":"Meldal","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref83","first-page":"159","article-title":"Evaluation of sensitivity for wild type and mutant forms of hepatitis B surface antigen by four commercial HBsAg assays","volume":"50","author":"Moerman","year":"2004","journal-title":"Clin. Lab."},{"key":"ref84","first-page":"13","article-title":"The importance of hepatitis B virus genome diversity in basal core promoter region","volume":"3","author":"Mohamadkhani","year":"2011","journal-title":"Middle East J. Dig. Dis."},{"key":"ref85","doi-asserted-by":"publisher","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."},{"key":"ref86","author":"Mokaya","year":"2019"},{"key":"ref87","volume-title":"Hepatitis B virus resistance to tenofovir: fact or fiction? A systematic literature review and structural analysis of drug resistance mechanisms [version 1; peer review: awaiting peer review]","author":"Mokaya","year":"2020"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"710.e11","DOI":"10.1016\/j.cmi.2015.03.004","article-title":"Immune-driven adaptation of hepatitis B virus genotype D involves preferential alteration in B-cellepitopes and replicative attenuation-an insight from human immunodeficiency virus\/hepatitis B virus coinfection","volume":"21","author":"Mondal","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1093\/jac\/dkm187","article-title":"Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment","volume":"60","author":"Moriconi","year":"2007","journal-title":"J. Antimicrob. Chemother."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1128\/AAC.01061-09","article-title":"Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation","volume":"54","author":"Mukaide","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref91","doi-asserted-by":"crossref","first-page":"0673","DOI":"10.1371\/journal.pmed.0020163","article-title":"Host heterogeneous ribonucleoprotein K (hnRNP K) as a potential target to suppress hepatitis B virus replication","volume":"2","author":"Ng","year":"2005","journal-title":"PLoS Med."},{"key":"ref92","doi-asserted-by":"publisher","first-page":"2643","DOI":"10.1099\/jgv.0.000566","article-title":"Enhanced pregenomic RNA levels and lowered precore mRNA transcription efficiency in a genotype A hepatitis B virus genome with C1766T and T1768A mutations obtained from a fulminant hepatitis patient","volume":"97","author":"Nishizawa","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s00430-007-0050-5","article-title":"Hepatitis B virus genotype E surface antigen detection with different immunoassays and diagnostic impact of mutations in the preS\/S gene","volume":"196","author":"Olinger","year":"2007","journal-title":"Med. Microbiol. Immunol."},{"key":"ref94","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.001338","article-title":"Profiles of mutations in hepatitis B virus surface and polymerase genes isolated from treatment-na\u00efve Nigerians infected with genotype E","volume":"70","author":"Olusola","year":"2021","journal-title":"J. Med. Microbiol."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1002\/jmv.23394","article-title":"Frequency and clinical significance of core promoter and precore region mutations in Tunisian patients infected chronically with hepatitis B","volume":"84","author":"Ouneissa","year":"2012","journal-title":"J. Med. Virol."},{"key":"ref96","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.11781","article-title":"Evaluation of PCR-RFLP in the Pre-S Region as Molecular Method for Hepatitis B Virus Genotyping","volume":"13","author":"Ouneissa","year":"2013","journal-title":"Hepat. Mon."},{"key":"ref97","first-page":"70","article-title":"Hepatitis B virus core promoter and precore mutations and their relatedness to genotypes and disease pathogenesis","volume":"7","author":"Pahal","year":"2016","journal-title":"Pelagia Res. Lib. Adv. Appl. Sci. Res."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"6601","DOI":"10.1128\/JVI.77.12.6601-6612.2003","article-title":"Genome replication, Virion secretion, and e antigen expression of naturally occurring Hepatitis B virus Core promoter mutants","volume":"77","author":"Parekh","year":"2003","journal-title":"J. Virol."},{"key":"ref99","doi-asserted-by":"publisher","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."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1177\/135965350901400504","article-title":"Variability of reverse transcriptase and overlapping S gene in hepatitis B virus isolates from untreated and lamivudine-resistant chronic hepatitis B patients","volume":"14","author":"Pollicino","year":"2009","journal-title":"Antivir. Ther."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1002\/hep.21529","article-title":"Molecular and functional analysis of occult hepatitis B virus isolates from patients with hepatocellular carcinoma","volume":"45","author":"Pollicino","year":"2007","journal-title":"Hepatology"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1002\/jmv.23864","article-title":"Molecular characterization of hepatitis B virus (HBV) strains circulating in the northern coast of the Persian Gulf and its comparison with worldwide distribution of HBV subgenotype D1","volume":"86","author":"Pourkarim","year":"2014","journal-title":"J. Med. Virol."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1111\/j.1365-2893.2008.00998.x","article-title":"Clinical significance of precore and core promoter mutations in genotype D hepatitis B-related chronic liver disease","volume":"15","author":"Poustchi","year":"2008","journal-title":"J. Viral Hepat."},{"key":"ref104","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1159\/000096312","article-title":"A new algorithm for deduction of hepatitis B surface antigen subtype determinants from the amino acid sequence","volume":"50","author":"Purdy","year":"2006","journal-title":"Intervirology"},{"key":"ref105","first-page":"28","article-title":"Association between HBx variations and development of severe liver disease among indonesian patients","volume":"65","author":"Putri","year":"2019","journal-title":"Kobe J. Med. Sci."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1007\/s11434-013-5770-x","article-title":"Polymerase mutations rtN238R, rtT240Y and rtN248H of hepatitis B virus decrease susceptibility to adefovir","volume":"58","author":"Qin","year":"","journal-title":"Chin. Sci. Bull."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"12160","DOI":"10.5812\/hepatmon.12160","article-title":"Substitution Rtq267h of hepatitis B virus increases the weight of replication and lamivudine resistance","volume":"13","author":"Qin","year":"","journal-title":"Hepat. Mon."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"425","DOI":"10.3748\/wjg.v20.i2.425","article-title":"Core promoter: a critical region where the hepatitis B virus makes decisions","volume":"20","author":"Quarleri","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1177\/135965350801300315","article-title":"Evidence of long-term suppression of hepatitis B virus DNA by tenofovir as rescue treatment in patients coinfected by HIV","volume":"13","author":"Quiros-Roldan","year":"2008","journal-title":"Antivir. Ther."},{"key":"ref110","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1016\/j.jhep.2017.07.011","article-title":"How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach?","volume":"67","author":"Rajoriya","year":"2017","journal-title":"J. Hepatol."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"e0180447","DOI":"10.1371\/journal.pone.0180447","article-title":"Navas MC. Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia","volume":"12","author":"Rendon","year":"2017","journal-title":"PLoS One"},{"key":"ref112","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090432","article-title":"Molecular characterization of HBV strains circulating among the treatment-naive HIV\/HBV co-infected patients of eastern India","volume":"9","author":"Saha","year":"2014","journal-title":"PLoS One"},{"key":"ref113","doi-asserted-by":"crossref","first-page":"31","DOI":"10.18869\/acadpub.mlj.10.1.31","article-title":"Mutations at nucleotide 1762, 1764 and 1766 of Hepatitis B virus X gene in patients with chronic Hepatitis B and Hepatitis B-related cirrhosis","volume":"10","author":"Salarneia","year":"2016","journal-title":"Med. Lab. J"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"4533","DOI":"10.1128\/AAC.00840-07","article-title":"Novel lamivudine resistance [3]","volume":"51","author":"Schildgen","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1099\/vir.0.81023-0","article-title":"T1764G1766 core promoter double mutants are restricted to Hepatitis B virus strains with an A1757 and are common in genotype D","volume":"86","author":"Sendi","year":"2005","journal-title":"J. Gen. Virol."},{"key":"ref116","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.jhep.2006.01.001","article-title":"HBV drug resistance: mechanisms, detection and interpretation","volume":"44","author":"Shaw","year":"2006","journal-title":"J. Hepatol."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1093\/jac\/dkn014","article-title":"Soriano V. Hepatitis B virus escape mutants induced by antiviral therapy","volume":"61","author":"Sheldon","year":"2008","journal-title":"J. Antimicrob. Chemother."},{"key":"ref118","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1111\/j.1365-2893.2005.00713.x","article-title":"Mutations affecting the replication capacity of the hepatitis B virus [Internet]","volume":"13","author":"Sheldon","year":"2006","journal-title":"J. Viral Hepat."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1128\/JCM.42.6.2455-2460.2004","article-title":"Hepatitis B virus genotypes and precore and core mutants in Brazilian patients","volume":"42","author":"Sitnik","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref120","doi-asserted-by":"publisher","DOI":"10.2174\/1876517301103010007","article-title":"Hepatitis B virus genotypes in Latvia","volume":"3","author":"Sominskaya","year":"2011","journal-title":"Open Hepatol. J."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"5427","DOI":"10.3748\/wjg.v20.i18.5427","article-title":"Hepatitis B virus genotypes: global distribution and clinical importance","volume":"20","author":"Sunbul","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref122","first-page":"3113","article-title":"Overlapping Pol\/S gene analysis in chronic hepatitis B patients with coexisting Hbsag and Anti-HBs","volume":"35","author":"Suntur","year":"2019","journal-title":"Acta Medica Mediterranea."},{"key":"ref123","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.31490","article-title":"G1896A precore mutation and association with HBeAG status, genotype and clinical status in patients with chronic hepatitis B","volume":"15","author":"Suppiah","year":"2015","journal-title":"Hepat. Mon."},{"key":"ref124","doi-asserted-by":"publisher","first-page":"161","DOI":"10.5114\/ceh.2019.84781","article-title":"Comparison of pre-S1\/S2 variations of hepatitis B virus between asymptomatic carriers and cirrhotic\/hepatocellular carcinoma-affected individuals","volume":"5","author":"Taghiabadi","year":"2019","journal-title":"Clin Exp Hepatol."},{"key":"ref125","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1128\/AAC.48.9.3498-3507.2004","article-title":"Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine","volume":"48","author":"Tenney","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1002\/hep.23571","article-title":"Serum hepatitis B surface antigen and hepatitis B e antigen titers: Disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers","volume":"51","author":"Thompson","year":"2010","journal-title":"Hepatology"},{"key":"ref127","doi-asserted-by":"publisher","first-page":"514","DOI":"10.24953\/turkjped.2018.05.007","article-title":"Investigation of antiviral resistance and escape mutations in children with naive chronic hepatitis B patients and their parents","volume":"60","author":"Tokg\u00f6z","year":"2018","journal-title":"Turk. J. Pediatr."},{"key":"ref128","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1111\/j.1478-3231.2007.01585.x","article-title":"Basal core promoter T1762\/A1764 and precore A1896 gene mutations in hepatitis B surface antigen-positive hepatocellular carcinoma: a comparison with chronic carriers","volume":"27","author":"Tong","year":"2007","journal-title":"Liver Int."},{"key":"ref129","doi-asserted-by":"publisher","first-page":"2","DOI":"10.7150\/ijms.2.2","article-title":"Hepatitis B virus e antigen variants","volume":"2","author":"Tong","year":"2005","journal-title":"Int. J. Med. Sci."},{"key":"ref130","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/emi.2013.10","article-title":"Hepatitis B virus genetic variants: biological properties and clinical implications","volume":"2","author":"Tong","year":"2013","journal-title":"Emerg. Microbes Infect."},{"key":"ref131","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1006\/viro.2002.1448","article-title":"Restoration of replication phenotype of lamivudine-resistant hepatitis B virus mutants by compensatory changes in the \u201cfingers\u201d subdomain of the viral polymerase selected as a consequence of mutations in the overlapping S gene","volume":"299","author":"Torresi","year":"","journal-title":"Virology"},{"key":"ref132","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1006\/viro.2001.1246","article-title":"Reduced antigenicity of the Hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy","volume":"293","author":"Torresi","year":"","journal-title":"Virology"},{"key":"ref133","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1017\/S0950268899003921","article-title":"High circulation of hepatitis B virus (HBV) precore mutants in Tunisia, North Africa","volume":"125","author":"Triki","year":"2000","journal-title":"Epidemiol. Infect."},{"key":"ref134","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.jhep.2006.11.016","article-title":"Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient","volume":"46","author":"Villet","year":"2007","journal-title":"J. Hepatol."},{"key":"ref135","doi-asserted-by":"publisher","first-page":"727","DOI":"10.3855\/jidc.9021","article-title":"Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression","volume":"11","author":"Wang","year":"2017","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref136","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.3892\/mco.2016.847","article-title":"HBV X gene point mutations are associated with the risk of hepatocellular carcinoma: A systematic review and meta-analysis","volume":"4","author":"Wang","year":"2016","journal-title":"Mol. Clin. Oncol."},{"key":"ref137","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.canep.2011.11.006","article-title":"Analysis of hepatitis B virus X gene (HBx) mutants in tissues of patients suffered from hepatocellular carcinoma in China","volume":"36","author":"Wang","year":"2012","journal-title":"Cancer Epidemiol."},{"key":"ref138","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.virusres.2010.10.018","article-title":"Characterization of hepatitis virus B isolated from a multi-drug refractory patient","volume":"155","author":"Wei","year":"2011","journal-title":"Virus Res."},{"key":"ref139","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1053\/jhep.2003.50288","article-title":"Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B","volume":"38","author":"Westland","year":"2003","journal-title":"Hepatology"},{"key":"ref140","year":"2021"},{"key":"ref141","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115141","article-title":"Novel natural mutations in the Hepatitis B virus reverse transcriptase domain associated with hepatocellular carcinoma","volume":"9","author":"Wu","year":"2014","journal-title":"PLoS One"},{"key":"ref142","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1093\/infdis\/jit638","article-title":"The impact of hepatitis B virus precore\/core gene carboxyl terminal mutations on viral biosynthesis and the host immune response","volume":"209","author":"Wu","year":"2014","journal-title":"J Infect Dis"},{"key":"ref143","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3892\/br.2019.1239","article-title":"Association between host TNF-\u03b1, TGF-\u03b21, p53 polymorphisms, hbv x gene mutation, hbv viral load and the progression of hbv-associated chronic liver disease in indonesian patients","volume":"11","author":"Wungu","year":"2019","journal-title":"Biomed. Rep."},{"key":"ref144","doi-asserted-by":"publisher","first-page":"1810","DOI":"10.1002\/hep.21893","article-title":"Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma","volume":"46","author":"Xu","year":"2007","journal-title":"Hepatology"},{"key":"ref145","doi-asserted-by":"publisher","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."},{"key":"ref146","first-page":"5","article-title":"Deep sequencing of hepatitis B virus basal core promoter and precore mutants in HBeAg-positive chronic hepatitis B patients","volume":"9","author":"Yan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref147","article-title":"Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV","volume":"1359","author":"Yang","year":"2005","journal-title":"Antivir. Ther."},{"key":"ref148","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1053\/jhep.2002.34740","article-title":"Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks","volume":"36","author":"Yang","year":"2002","journal-title":"Hepatology"},{"key":"ref149","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/ajg.2010.399","article-title":"Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma","volume":"106","author":"Yin","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref150","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1158\/1055-9965.EPI-08-0966","article-title":"Prospective evaluation of hepatitis B 1762 T\/1764 a mutations on hepatocellular carcinoma development in Shanghai, China","volume":"18","author":"Yuan","year":"2009","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref151","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1111\/j.1478-3231.2012.02859.x","article-title":"Prevalence and significance of Hepatitis B reverse transcriptase mutants in different disease stages of untreated patients","volume":"32","author":"Zheng","year":"2012","journal-title":"Liver Int."},{"key":"ref152","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.prp.2008.05.001","article-title":"Hepatitis B virus mutations associated with in situ expression of hepatitis B core antigen, viral load and prognosis in chronic hepatitis B patients","volume":"204","author":"Zhu","year":"2008","journal-title":"Pathol. Res. Pract."},{"key":"ref153","doi-asserted-by":"publisher","first-page":"37806","DOI":"10.5812\/hepatmon.37806","article-title":"Genotyping and mutation pattern in the overlapping MHR region of HBV isolates in southern khorasan, eastern Iran","volume":"16","author":"Ziaee","year":"2016","journal-title":"Hepat. Mon."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1020147\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:09:10Z","timestamp":1665972550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.1020147\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,17]]},"references-count":153,"alternative-id":["10.3389\/fmicb.2022.1020147"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.1020147","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,17]]},"article-number":"1020147"}}