{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:24:29Z","timestamp":1790033069299,"version":"4.0.1"},"reference-count":161,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This \u201cfunctional cure\u201d of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.<\/jats:p>","DOI":"10.3390\/v13050745","type":"journal-article","created":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T02:12:57Z","timestamp":1619316777000},"page":"745","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure"],"prefix":"10.3390","volume":"13","author":[{"given":"Andrew","family":"Vaillant","sequence":"first","affiliation":[{"name":"Replicor Inc., 6100 Royalmount Avenue, Montreal, QC H4P 2R2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra031087","article-title":"Hepatitis B virus infection--natural history and clinical consequences","volume":"350","author":"Ganem","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/02648725.2018.1474324","article-title":"Hepatitis B virus lymphotropism: Emerging details and challenges","volume":"34","author":"Joshi","year":"2018","journal-title":"Biotechnol. Genet. Eng. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1743-422X-4-36","article-title":"Infection of hepatitis B virus in extrahepatic endothelial tissues mediated by endothelial progenitor cells","volume":"4","author":"Rong","year":"2007","journal-title":"Virol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1038\/nm1096-1104","article-title":"The hepatitis B virus persists for decades after patients\u2019 recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response","volume":"2","author":"Rehermann","year":"1996","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1053\/j.gastro.2017.02.009","article-title":"Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions","volume":"152","author":"Loomba","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1177\/1060028018800501","article-title":"Pharmacotherapy-Induced Hepatitis B Reactivation Among Patients With Prior Functional Cure: A Systematic Review","volume":"53","author":"Bath","year":"2019","journal-title":"Ann. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S2468-1253(18)30056-6","article-title":"Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study","volume":"3","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_8","unstructured":"WHO (2019). Hepatitis B Fact Sheet, WHO."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Vaillant, A. (2020). HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect. Dis.","DOI":"10.1021\/acsinfecdis.0c00638"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jhep.2009.05.022","article-title":"Control of cccDNA function in hepatitis B virus infection","volume":"51","author":"Levrero","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tu, T., Budzinska, M.A., Shackel, N.A., and Urban, S. (2017). HBV DNA Integration: Molecular Mechanisms and Clinical Implications. Viruses, 9.","DOI":"10.3390\/v9040075"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mason, W.S., Jilbert, A.R., and Litwin, S. (2021). Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver. Viruses, 13.","DOI":"10.3390\/v13020210"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Freitas, N., Lukash, T., Gunewardena, S., Chappell, B., Slagle, B.L., and Gudima, S.O. (2018). Relative Abundance of Integrant-Derived Viral. RNAs in Infected Tissues Harvested from Chronic Hepatitis B Virus Carriers. J. Virol., 92.","DOI":"10.1128\/JVI.02221-17"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.coviro.2018.01.011","article-title":"Impact of integrated viral DNA on the goal to clear hepatitis B surface antigen with different therapeutic strategies","volume":"30","author":"Lindh","year":"2018","journal-title":"Curr. Opin Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nrgastro.2017.185","article-title":"Hepatitis: No cure for hepatitis B and D without targeting integrated viral DNA?","volume":"15","author":"Cornberg","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1586\/eri.09.57","article-title":"Chronic hepatitis B: Back to the future with HBsAg","volume":"7","author":"Moucari","year":"2009","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_17","first-page":"439","article-title":"Emerging Therapies Toward a Functional Cure for Hepatitis B Virus Infection","volume":"14","author":"Kim","year":"2018","journal-title":"Gastroenterol. Hepatol. (N. Y.)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1053\/j.gastro.2019.01.015","article-title":"Hepatitis B Surface Antigen Loss: Too Little, Too Late and the Challenge for the Future","volume":"156","author":"Dusheiko","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.cgh.2019.08.033","article-title":"How Do We Determine Whether a Functional Cure for HBV Infection Has Been Achieved?","volume":"18","author":"Yip","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.cgh.2020.05.041","article-title":"Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-analysis","volume":"19","author":"Anderson","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1136\/jcp.29.2.94","article-title":"Distribution patterns of hepatitis B surface antigen (HBsAg) in the liver of hepatitis patients","volume":"29","author":"Ray","year":"1976","journal-title":"J. Clin. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6685","DOI":"10.1073\/pnas.80.21.6685","article-title":"Detection of hepatitis B virus DNA in hepatocytes, bile duct epithelium, and vascular elements by in situ hybridization","volume":"80","author":"Blum","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","first-page":"493","article-title":"Expression of HBsAg and HBcAg in liver tissue: Correlation with disease activity","volume":"7","author":"Nakopoulou","year":"1992","journal-title":"Histol. Histopathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/j.1440-1746.1991.tb00889.x","article-title":"Hepatocyte hepatitis B surface antigen expression in chronic hepatitis B virus carriers in Singapore: Correlation with viral replication and liver pathology","volume":"6","author":"Wee","year":"1991","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/hep.1840080408","article-title":"Correlation of hepatocyte HBsAg expression with virus replication and liver pathology","volume":"8","author":"Hsu","year":"1988","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0166-0934(92)90023-7","article-title":"Simultaneous detection of HBV-specific antigens and DNA in paraffin-embedded liver tissue by immunohistochemistry and in situ hybridization using a digoxigenin-labeled probe","volume":"37","author":"Han","year":"1992","journal-title":"J. Virol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.3748\/wjg.v22.i12.3404","article-title":"Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma","volume":"22","author":"Safaie","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1172\/JCI83339","article-title":"In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection","volume":"126","author":"Zhang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0168-8278(05)80572-0","article-title":"Identification of hepatitis B virus-DNA in the liver by in situ hybridization using a biotinylated probe. Relation to HBcAg expression and histology","volume":"19","author":"Naoumov","year":"1993","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1590\/S0074-02762002000100018","article-title":"Detection of hepatitis B virus antigens in paraffin-embedded liver specimens from the Amazon region, Brazil","volume":"97","author":"Simonetti","year":"2002","journal-title":"Mem. Inst. Oswaldo Cruz."},{"key":"ref_31","first-page":"565","article-title":"Distribution of hepatitis B surface and core antigens in human liver cell carcinoma and surrounding nontumorous liver","volume":"69","author":"Hirohashi","year":"1982","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1099\/0022-1317-64-6-1229","article-title":"Patterns of single- and double-stranded hepatitis B virus DNA and viral antigen accumulation in infected liver cells","volume":"64 Pt 6","author":"Gowans","year":"1983","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1136\/jcp.44.11.905","article-title":"Rapid detection of hepatitis B virus DNA in liver tissue by in situ hybridisation and its combination with immunohistochemistry for simultaneous detection of HBV antigens","volume":"44","author":"Lau","year":"1991","journal-title":"J. Clin. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/jmv.10432","article-title":"Distribution of hepatitis B virus in the liver of chronic hepatitis C patients with occult hepatitis B virus infection","volume":"70","author":"Mariscal","year":"2003","journal-title":"J. Med. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5503","DOI":"10.1128\/JVI.77.9.5503-5506.2003","article-title":"Hepatitis B virus-mediated changes of apolipoprotein mRNA abundance in cultured hepatoma cells","volume":"77","author":"Norton","year":"2003","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/1476-511X-10-207","article-title":"HBV inhibits apoB production via the suppression of MTP expression","volume":"10","author":"Wang","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12944-016-0232-5","article-title":"The mechanism of apoliprotein A1 down-regulated by Hepatitis B virus","volume":"15","author":"Wang","year":"2016","journal-title":"Lipids Health Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12944-017-0607-2","article-title":"Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3","volume":"16","author":"Zhu","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jhep.2007.06.021","article-title":"Expression of hepatitis B virus proteins in transgenic mice alters lipid metabolism and induces oxidative stress in the liver","volume":"48","author":"Yang","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/hep.27159","article-title":"Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism","volume":"60","author":"Oehler","year":"2014","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/hep.22740","article-title":"Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma","volume":"49","author":"Na","year":"2009","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.3748\/wjg.v19.i14.2262","article-title":"Hepatitis B virus induces expression of cholesterol metabolism-related genes via TLR2 in HepG2 cells","volume":"19","author":"Li","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8421","DOI":"10.1038\/srep08421","article-title":"The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment","volume":"5","author":"Li","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lamontagne, J., Mell, J.C., and Bouchard, M.J. (2016). Transcriptome-Wide Analysis of Hepatitis B Virus-Mediated Changes to Normal Hepatocyte Gene Expression. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005438"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.metabol.2018.01.007","article-title":"A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways","volume":"83","author":"Lamontagne","year":"2018","journal-title":"Metabolism"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"15460","DOI":"10.1074\/jbc.M309280200","article-title":"Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells","volume":"279","author":"Lee","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1128\/JVI.02196-09","article-title":"The hepatitis B virus X protein modulates hepatocyte proliferation pathways to stimulate viral replication","volume":"84","author":"Gearhart","year":"2010","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.virusres.2010.09.023","article-title":"The hepatitis B virus HBx protein modulates cell cycle regulatory proteins in cultured primary human hepatocytes","volume":"155","author":"Gearhart","year":"2011","journal-title":"Virus Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1073\/pnas.0911373107","article-title":"The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication","volume":"107","author":"Sir","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","first-page":"1696","article-title":"HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation","volume":"128","author":"Inoue","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lazar, C., Macovei, A., Petrescu, S., and Branza-Nichita, N. (2012). Activation of ERAD pathway by human hepatitis B virus modulates viral and subviral particle production. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034169"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1128\/JVI.02590-08","article-title":"Hepatitis B virus X protein modulates apoptosis in primary rat hepatocytes by regulating both NF-kappaB and the mitochondrial permeability transition pore","volume":"83","author":"Clippinger","year":"2009","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.4049\/jimmunol.1800732","article-title":"Hepatitis B Virus Surface Antigen Enhances the Sensitivity of Hepatocytes to Fas-Mediated Apoptosis via Suppression of AKT Phosphorylation","volume":"201","author":"Jing","year":"2018","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1006\/geno.2002.6722","article-title":"cDNA cloning, genomic structure, chromosomal mapping, and functional expression of a novel human alanine aminotransferase","volume":"79","author":"Yang","year":"2002","journal-title":"Genomics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.abb.2007.07.023","article-title":"Isoforms of alanine aminotransferases in human tissues and serum--differential tissue expression using novel antibodies","volume":"466","author":"Lindblom","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_56","first-page":"35","article-title":"Catalytic enzyme activity concentration in tissues of man, dog, rabbit, guinea pig, rat and mouse. Approach to a quantitative diagnostic enzymology, III. Communication","volume":"24","author":"Lindena","year":"1986","journal-title":"J. Clin. Chem. Clin. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"621","DOI":"10.3892\/ijmm_00000173","article-title":"Detection of the mitochondrial and catalytically active alanine aminotransferase in human tissues and plasma","volume":"23","author":"Glinghammar","year":"2009","journal-title":"Int. J. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0009-9120(90)80062-N","article-title":"Aspartate aminotransferase isoenzymes","volume":"23","author":"Panteghini","year":"1990","journal-title":"Clin. Biochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0009-8981(80)90397-6","article-title":"The (iso)enzyme activities of lactate dehydrogenase, alpha-hydroxybutyrate dehydrogenase, creatine kinase and aspartate aminotransferase in human myocardial biopsies and autopsies","volume":"104","author":"Dijkshoorn","year":"1980","journal-title":"Clin. Chim. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1093\/clinchem\/24.11.1971","article-title":"Aspartate aminotransferase activity and isoenzyme proportions in human liver tissues","volume":"24","author":"Rej","year":"1978","journal-title":"Clin. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1089\/ars.2012.4997","article-title":"Human GGT2 does not autocleave into a functional enzyme: A cautionary tale for interpretation of microarray data on redox signaling","volume":"19","author":"West","year":"2013","journal-title":"Antioxid Redox Signal."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/clinchem\/31.6.797","article-title":"Gamma-glutamyltransferase and its isoenzymes: Progress and problems","volume":"31","author":"Nemesanszky","year":"1985","journal-title":"Clin. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1177\/44.10.8813074","article-title":"Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue","volume":"44","author":"Hanigan","year":"1996","journal-title":"J. Histochem. Cytochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1111\/j.1872-034X.2007.00151.x","article-title":"Hepatic expression of gamma-glutamyltranspeptidase in the human liver of patients with alcoholic liver disease","volume":"37","author":"Irie","year":"2007","journal-title":"Hepatol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/hep.1840110425","article-title":"Plasma membrane bleb formation and rupture: A common feature of hepatocellular injury","volume":"11","author":"Gores","year":"1990","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/0016-5085(95)90032-2","article-title":"Liver cell necrosis: Cellular mechanisms and clinical implications","volume":"108","author":"Rosser","year":"1995","journal-title":"Gastroenterology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"733 e719","DOI":"10.1016\/j.cmi.2016.05.009","article-title":"Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection","volume":"22","author":"Ghosh","year":"2016","journal-title":"Clin. Microbiol Infect."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1093\/infdis\/jiy097","article-title":"Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss","volume":"217","author":"Zimmer","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S22","DOI":"10.1002\/hep.22976","article-title":"Evaluation of the patient with hepatitis B","volume":"49","author":"Rotman","year":"2009","journal-title":"Hepatology"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2017). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol., 67, 370\u2013398.","DOI":"10.1016\/j.jhep.2017.03.021"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12072-015-9675-4","article-title":"Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update","volume":"10","author":"Sarin","year":"2016","journal-title":"Hepatol. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1002\/hep.29800","article-title":"Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"411","DOI":"10.5152\/tjg.2014.3693","article-title":"The relation between liver histopathology and GGT levels in viral hepatitis: More important in hepatitis B","volume":"25","author":"Eminler","year":"2014","journal-title":"Turk. J. Gastroenterol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1053\/j.gastro.2004.06.021","article-title":"Natural history of chronic HBV carriers in northern Italy: Morbidity and mortality after 30 years","volume":"127","author":"Manno","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"9957","DOI":"10.3748\/wjg.v21.i34.9957","article-title":"Association of serum gamma-glutamyl transferase with treatment outcome in chronic hepatitis B patients","volume":"21","author":"Huang","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1503\/cmaj.1040752","article-title":"Liver enzyme alteration: A guide for clinicians","volume":"172","author":"Giannini","year":"2005","journal-title":"CMAJ"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0168-8278(90)90069-4","article-title":"Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology","volume":"10","author":"Lok","year":"1990","journal-title":"J. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/hep.23424","article-title":"Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage","volume":"51","author":"Wu","year":"2010","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1111\/jgh.13377","article-title":"Flares during long-term entecavir therapy in chronic hepatitis B","volume":"31","author":"Chi","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1111\/liv.13716","article-title":"ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B","volume":"38","author":"Wong","year":"2018","journal-title":"Liver Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1600-0676.1994.tb00071.x","article-title":"Fluctuations in viremia, aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations","volume":"14","author":"Mels","year":"1994","journal-title":"Liver"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Brahmania, M., Lombardero, M., Hansen, B.E., Terrault, N.A., Lok, A.S., Perrillo, R.P., Belle, S.H., Di Bisceglie, A.M., Feld, J.J., and Lee, W.M. (2019). Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection. Clin. Gastroenterol. Hepatol.","DOI":"10.1016\/j.cgh.2019.02.005"},{"key":"ref_83","first-page":"445","article-title":"The relationship of hepatitis B e antigen, DNA polymerase activity, and titer of hepatitis B surface antigen with ongoing liver injury in chronic hepatitis B virus infection","volume":"77","author":"Perrillo","year":"1982","journal-title":"Am. J. Gastroenterol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/hep.1840070106","article-title":"Acute exacerbation in chronic type B hepatitis: Comparison between HBeAg and antibody-positive patients","volume":"7","author":"Liaw","year":"1987","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1053\/j.gastro.2009.01.011","article-title":"Spontaneous increases in alanine aminotransferase levels in asymptomatic chronic hepatitis B virus-infected patients","volume":"136","author":"Kumar","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0168-8278(85)80050-7","article-title":"Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis. A clinicopathological study","volume":"1","author":"Liaw","year":"1985","journal-title":"J. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/hep.1840070102","article-title":"Changes of serum hepatitis B virus DNA in two types of clinical events preceding spontaneous hepatitis B e antigen seroconversion in chronic type B hepatitis","volume":"7","author":"Liaw","year":"1987","journal-title":"Hepatology"},{"key":"ref_88","first-page":"948","article-title":"Immunohistochemical studies on intrahepatic lymphocyte infiltrates in chronic type B hepatitis, with special emphasis on the activation status of the lymphocytes","volume":"83","author":"Yang","year":"1988","journal-title":"Am. J. Gastroenterol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1172\/JCI115590","article-title":"Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion","volume":"89","author":"Tsai","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1023\/A:1023366013858","article-title":"HBcAg-specific CD8 T cells play an important role in virus suppression, and acute flare-up is associated with the expansion of activated memory T cells","volume":"23","author":"Shimada","year":"2003","journal-title":"J. Clin. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1136\/gutjnl-2018-316644","article-title":"Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection","volume":"68","author":"Hoogeveen","year":"2019","journal-title":"Gut"},{"key":"ref_92","first-page":"123","article-title":"Extrahepatic manifestations of acute hepatitis B virus infection","volume":"9","author":"Kappus","year":"2013","journal-title":"Gastroenterol. Hepatol. (N. Y.)"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.cgh.2010.02.023","article-title":"Hepatitis B virus DNA level predicts hepatic decompensation in patients with acute exacerbation of chronic hepatitis B","volume":"8","author":"Jeng","year":"2010","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1136\/gut.52.3.416","article-title":"A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: Implications for antiviral therapy","volume":"52","author":"Yuen","year":"2003","journal-title":"Gut"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Suslov, A., Meier, M.A., Ketterer, S., Wang, X., Wieland, S., and Heim, M.H. (2020). Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity. J. Hepatol.","DOI":"10.1016\/j.jhep.2020.11.003"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s12072-020-10125-y","article-title":"Liver damage favors the eliminations of HBV integration and clonal hepatocytes in chronic hepatitis B","volume":"15","author":"Hu","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"582292","DOI":"10.3389\/fimmu.2020.582292","article-title":"The Multiple Functions of B Cells in Chronic HBV Infection","volume":"11","author":"Cai","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/nrm1489","article-title":"Liver regeneration: From myth to mechanism","volume":"5","author":"Taub","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1002\/hep.22791","article-title":"Locating the stem cell niche and tracing hepatocyte lineages in human liver","volume":"49","author":"Fellous","year":"2009","journal-title":"Hepatology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.jhep.2012.04.016","article-title":"Liver regeneration","volume":"57","author":"Fausto","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s41232-016-0025-2","article-title":"Liver regeneration and fibrosis after inflammation","volume":"36","author":"Tanaka","year":"2016","journal-title":"Inflamm. Regen."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"8308","DOI":"10.1128\/JVI.00833-10","article-title":"Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection","volume":"84","author":"Mason","year":"2010","journal-title":"J. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/jvh.12380","article-title":"Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection","volume":"22","author":"Tu","year":"2015","journal-title":"J. Viral. Hepat."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/cld.161","article-title":"Hepatitis B virus treatment: Which patients should be treated with nucleos(t)ide analogue?","volume":"2","author":"Vigano","year":"2013","journal-title":"Clin. Liver Dis. (Hoboken)"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"6646","DOI":"10.1073\/pnas.0631696100","article-title":"Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7","volume":"100","author":"Lee","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejphar.2005.11.037","article-title":"Purine P1 receptor-dependent immunostimulatory effects of antiviral acyclic analogues of adenine and 2,6-diaminopurine","volume":"530","author":"Kmonickova","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ejphar.2006.04.018","article-title":"Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives","volume":"540","author":"Potmesil","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/QAI.0b013e3182185276","article-title":"Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12\/IL-10 balance in human primary cells","volume":"57","author":"Melchjorsen","year":"2011","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/intimm\/dxv062","article-title":"Guanosine and its modified derivatives are endogenous ligands for TLR7","volume":"28","author":"Shibata","year":"2016","journal-title":"Int. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1136\/gutjnl-2016-312653","article-title":"Induction of IFN-lambda3 as an additional effect of nucleotide, not nucleoside, analogues: A new potential target for HBV infection","volume":"67","author":"Murata","year":"2018","journal-title":"Gut"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3851\/IMP3196","article-title":"The association between serum cytokine and chemokine levels and antiviral response by entecavir treatment in chronic hepatitis B patients","volume":"23","author":"Kurihara","year":"2018","journal-title":"Antivir. Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/eji.201948151","article-title":"Deoxyguanosine is a TLR7 agonist","volume":"50","author":"Davenne","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1053\/j.gastro.2003.09.033","article-title":"Long-term safety of lamivudine treatment in patients with chronic hepatitis B","volume":"125","author":"Lok","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e252","DOI":"10.1111\/j.1365-2893.2011.01448.x","article-title":"Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B","volume":"18","author":"Zhang","year":"2011","journal-title":"J. Viral. Hepat."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1002\/hep.22841","article-title":"Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy","volume":"49","author":"Tenney","year":"2009","journal-title":"Hepatology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/hep.24078","article-title":"No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus","volume":"53","author":"Chappell","year":"2011","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Cathcart, A.L., Chan, H.L., Bhardwaj, N., Liu, Y., Marcellin, P., Pan, C.Q., Buti, M., Cox, S., and Parhy, B. (2018). No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection. Antimicrob. Agents Chemother., 62.","DOI":"10.1128\/AAC.01064-18"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1517\/14740338.2012.653340","article-title":"Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901","volume":"11","author":"Manns","year":"2012","journal-title":"Expert Opin Drug Saf."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3350\/cmh.2016.0067","article-title":"Clinical impact of the early alanine amininotransferase flare during tenofovir monotherapy in treatment-naive patients with chronic hepatitis B","volume":"23","author":"Seo","year":"2017","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/jvh.12833","article-title":"Great and rapid HBsAg decline in patients with on-treatment hepatitis flare in early phase of potent antiviral therapy","volume":"25","author":"Jeng","year":"2018","journal-title":"J. Viral. Hepat."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.jhep.2008.10.017","article-title":"Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: The case for continuous antiviral therapy","volume":"50","author":"Shouval","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/apt.13272","article-title":"Systematic review: Cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B","volume":"42","author":"Chang","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1053\/jhep.2000.16333","article-title":"Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy","volume":"32","author":"Honkoop","year":"2000","journal-title":"Hepatology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1136\/gut.51.4.597","article-title":"Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B","volume":"51","author":"Lim","year":"2002","journal-title":"Gut"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1093\/infdis\/jix690","article-title":"Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy","volume":"217","author":"Su","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1136\/gutjnl-2019-318981","article-title":"Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: Results from a randomised controlled trial (Toronto STOP study)","volume":"68","author":"Liem","year":"2019","journal-title":"Gut"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"100112","DOI":"10.1016\/j.jhepr.2020.100112","article-title":"Rebound of HBV DNA after cessation of nucleos\/tide analogues in chronic hepatitis B patients with undetectable covalently closed","volume":"2","author":"Lai","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/liv.14330","article-title":"The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B","volume":"40","author":"Wong","year":"2020","journal-title":"Liver Int."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1172\/JCI58847","article-title":"IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome","volume":"122","author":"Belloni","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Gill, U.S., Peppa, D., Micco, L., Singh, H.D., Carey, I., Foster, G.R., Maini, M.K., and Kennedy, P.T. (2016). Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral. Load Suppression In Vivo. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005788"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jhep.2012.09.029","article-title":"Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B","volume":"58","author":"Micco","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nri3806","article-title":"Regulation of antiviral T cell responses by type I interferons","volume":"15","author":"Crouse","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1136\/gut.2004.062208","article-title":"Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy","volume":"54","author":"Flink","year":"2005","journal-title":"Gut"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jcv.2008.02.007","article-title":"ALT and viral load decline during PEG-IFN alpha-2b treatment for HBeAg-positive chronic hepatitis B","volume":"42","author":"Hansen","year":"2008","journal-title":"J. Clin. Virol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/cid\/cis859","article-title":"Close monitoring of hepatitis B surface antigen levels helps classify flares during peginterferon therapy and predicts treatment response","volume":"56","author":"Sonneveld","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_136","first-page":"E89","article-title":"Hepatic flares promote rapid decline of serum hepatitis B surface antigen (HBsAg) in patients with HBsAg seroclearance: A long-term follow-up study","volume":"46","author":"Nagaoka","year":"2016","journal-title":"Hepatol. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3892\/br.2017.944","article-title":"Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective?","volume":"7","author":"Yano","year":"2017","journal-title":"Biomed. Rep."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1002\/hep.30050","article-title":"Efficacy and Safety of Peginterferon Alfa-2a (40KD) in Children With Chronic Hepatitis B: The PEG-B-ACTIVE Study","volume":"68","author":"Wirth","year":"2018","journal-title":"Hepatology"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Choi, H.J., Farag, M., Brouwer, W.P., Sonneveld, M.J., Feld, J.J., De Man, R.A., Hansen, B., and Janssen, H. (2020). Early PEG-interferon-related ALT Flares of High Magnitude Lead to HBsAg Decline and Loss. A Study of 639 Chronic Hepatitis B Patients. J. Hepatol., 73.","DOI":"10.1016\/S0168-8278(20)32175-9"},{"key":"ref_140","first-page":"27","article-title":"Thymosins: Structure, function and therapeutic applications","volume":"6","author":"Low","year":"1984","journal-title":"Thymus"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1159\/000171570","article-title":"Thymus-derived peptides in the treatment of viral chronic hepatitis","volume":"14","author":"Naylor","year":"1996","journal-title":"Dig. Dis."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/jvh.12807","article-title":"Immunotherapy for hepatitis B in the direct acting antiviral era: Reevaluating the thymosin alpha1 efficacy trials in the light of a combination therapy approach","volume":"25","author":"Naylor","year":"2018","journal-title":"J. Viral. Hepat."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1365-2893.2005.00633.x","article-title":"The efficacy and safety of thymosin alpha-1 in Japanese patients with chronic hepatitis B; results from a randomized clinical trial","volume":"12","author":"Iino","year":"2005","journal-title":"J. Viral. Hepat."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1002\/hep.510270527","article-title":"Efficacy of thymosin alpha1 in patients with chronic hepatitis B: A randomized, controlled trial","volume":"27","author":"Chien","year":"1998","journal-title":"Hepatology"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41598-020-80594-6","article-title":"Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection","volume":"11","author":"Kadelka","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Yuen, M.F., Wong, D.K., Schluep, T., Lai, C.L., Ferrari, C., Locarnini, S., Lo, R.C., Gish, R.G., Hamilton, J., and Wooddell, C.I. (2021). Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut.","DOI":"10.1136\/gutjnl-2020-323445"},{"key":"ref_147","unstructured":"Yuen, M.F. (2020, January 11\u201316). HBV RNAi inhibitor RG6346 in Phase 1b-2a trial was safe, well tolerated, and resulted in subatantial and durable reductions in serum HBsAg levels. Proceedings of the AASLD 2020 Late Breakong Oral Presentation."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1021\/acsinfecdis.8b00156","article-title":"REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection","volume":"5","author":"Vaillant","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Boulon, R., Blanchet, M., Lemasson, M., Vaillant, A., and Labonte, P. (Antiviral Res., 2019). Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro, Antiviral Res.","DOI":"10.1016\/j.antiviral.2020.104853"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.antiviral.2019.02.009","article-title":"Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15cells","volume":"164","author":"Blanchet","year":"2019","journal-title":"Antiviral Res."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Al-Mahtab, M., Bazinet, M., and Vaillant, A. (2016). Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156667"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S2468-1253(17)30288-1","article-title":"Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): A non-randomised, open-label, phase 2 trial","volume":"2","author":"Bazinet","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1053\/j.gastro.2020.02.058","article-title":"Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy","volume":"158","author":"Bazinet","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Bazinet, M., Pantea, V., Placinta, G., Moscalu, I., Cebotarescu, V., Cojuhari, L., Jimbei, P., Iarovoi, L., Smesnoi, V., and Musteata, T. (2021). Benefit of transaminase elevations in establishing functional cure of HBV infection during NAP-based combination therapy. J. Viral. Hepat.","DOI":"10.1111\/jvh.13483"},{"key":"ref_155","first-page":"505A","article-title":"Interferon free clearance of HDV RNA and HBsAg seroconversion in a cirrhotic subject with chronic HBV\/HDV co-infection with TDF and REP 2165-Mg","volume":"72","author":"Bazinet","year":"2020","journal-title":"Hepatology"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1097\/MEG.0000000000000341","article-title":"Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: A 10-year follow-up of 673 patients","volume":"27","author":"Poh","year":"2015","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1111\/j.1478-3231.2012.02831.x","article-title":"HBeAg-positive hepatitis delta: Virological patterns and clinical long-term outcome","volume":"32","author":"Heidrich","year":"2012","journal-title":"Liver Int."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.jhep.2013.07.005","article-title":"Prevalence and clinical course of hepatitis delta infection in Greece: A 13-year prospective study","volume":"59","author":"Manesis","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/0016-5085(93)90281-G","article-title":"Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B","volume":"104","author":"Hoofnagle","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1016\/j.cgh.2020.01.018","article-title":"Hepatitis Flares Are Associated With Better Outcomes Than No Flare in Patients With Decompensated Cirrhosis and Chronic Hepatitis B Virus Infection","volume":"18","author":"Chang","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1473-3099(18)30663-7","article-title":"Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): A randomised, placebo controlled, phase 2 trial","volume":"19","author":"Wedemeyer","year":"2019","journal-title":"Lancet Infect. Dis."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/745\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:52:10Z","timestamp":1760161930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":161,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["v13050745"],"URL":"https:\/\/doi.org\/10.3390\/v13050745","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]}}}