{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:17:54Z","timestamp":1792642674885,"version":"4.5.0"},"reference-count":91,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"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>Despite the availability of effective vaccines and antiviral therapy over the past two to three decades, chronic hepatitis B virus (HBV) infection remains a major global health threat as a leading cause of cirrhosis and liver cancer. Functional HBV cure defined as hepatitis B surface antigen (HBsAg) loss and undetectable serum HBV DNA is associated with improved clinical outcomes in patients with chronic HBV infection. However, spontaneous loss of HBsAg is rare and occurs in only 1% of all HBsAg-positive individuals annually. Furthermore, the rate of functional cure with currently available antiviral therapy is even lower, &lt;1% patients on treatment per year. Nonetheless, HBsAg loss has become the new target or therapeutic endpoint for antiviral treatment. Recently, there has been much excitement surrounding the development of novel antiviral agents such as small interfering RNA (siRNA), core assembly modulators (CAMs), nucleic acid polymers (NAPs) among others, which may be used in combination with nucleos(t)ide analogs and possibly immunomodulatory therapies to achieve functional cure in a significant proportion of patients with chronic hepatitis B. Novel assays with improved sensitivity for detection of very low levels of HBsAg and to determine the source of HBsAg production will also be required to measure efficacy of newer antiviral treatments for HBV cure. In this narrative review, we will define HBV cure, discuss various sources of HBsAg production, evaluate rates of HBsAg loss with current and future antiviral agents, review clinical factors associated with spontaneous HBsAg loss, and explore clinical implications of functional cure.<\/jats:p>","DOI":"10.3390\/v14040657","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T23:20:55Z","timestamp":1647991255000},"page":"657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["HBsAg Loss as a Treatment Endpoint for Chronic HBV Infection: HBV Cure"],"prefix":"10.3390","volume":"14","author":[{"given":"Maryam","family":"Moini","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Ottawa, Ottawa, ON K1Y 4E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Fung","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"ref_1","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","author":"Gamkrelidze","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1016\/S0140-6736(14)60220-8","article-title":"Hepatitis B virus infection","volume":"384","author":"Chan","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.jhep.2012.05.021","article-title":"Minimization of hepatitis B infection by a 25-year universal vaccination program","volume":"57","author":"Ni","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1093\/jnci\/djp288","article-title":"Decreased Incidence of Hepatocellular Carcinoma in Hepatitis B Vaccinees: A 20-Year Follow-up Study","volume":"101","author":"Chang","year":"2009","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_5","first-page":"1","article-title":"Surveillance for acute viral hepatitis\u2014United States, 2006","volume":"57","author":"Wasley","year":"2008","journal-title":"Morb. Mortal. Wkly. Rep. Surveill. Summ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/hep.23464","article-title":"Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus","volume":"51","author":"Simonetti","year":"2010","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1053\/j.gastro.2008.07.008","article-title":"HBsAg Seroclearance in Chronic Hepatitis B in Asian Patients: Replicative Level and Risk of Hepatocellular Carcinoma","volume":"135","author":"Yuen","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.jhep.2015.01.002","article-title":"Risk of hepatocellular carcinoma in chronic hepatitis B: Assessment and modification with current antiviral therapy","volume":"62","author":"Papatheodoridis","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.jhep.2016.08.009","article-title":"The role of quantitative hepatitis B surface antigen revisited","volume":"66","author":"Cornberg","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_10","first-page":"E263","article-title":"Analysis of hepatitis B surface antigen (HBsAg) using high-sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays","volume":"48","author":"Ozeki","year":"2017","journal-title":"Hepatol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1002\/hep.29323","article-title":"Hepatitis B cure: From discovery to regulatory approval","volume":"66","author":"Lok","year":"2017","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e02007-17","DOI":"10.1128\/JVI.02007-17","article-title":"Hepatitis B Virus DNA Integration Occurs Early in the Viral Life Cycle in an In Vitro Infection Model via Sodium Taurocholate Cotransporting Polypeptide-Dependent Uptake of Enveloped Virus Particles","volume":"92","author":"Tu","year":"2018","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/mt.2010.20","article-title":"Zinc-finger Nucleases as a Novel Therapeutic Strategy for Targeting Hepatitis B Virus DNAs","volume":"18","author":"Cradick","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.omtn.2020.03.005","article-title":"Permanent Inactivation of HBV Genomes by CRISPR\/Cas9-Mediated Non-cleavage Base Editing","volume":"20","author":"Yang","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1136\/gut.2005.065136","article-title":"Prognostic determinants for chronic hepatitis B in Asians: Therapeutic implications","volume":"54","author":"Yuen","year":"2005","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1002\/hep.22977","article-title":"Endpoints of therapy in chronic hepatitis B","volume":"49","author":"Feld","year":"2009","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1056\/NEJMoa013215","article-title":"Hepatitis B e Antigen and the Risk of Hepatocellular Carcinoma","volume":"347","author":"Yang","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/07853890310021580","article-title":"Seropositivity of hepatitis B e antigen and hepatocellular carcinoma","volume":"36","author":"You","year":"2004","journal-title":"Ann. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1053\/jhep.2002.33638","article-title":"Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B","volume":"35","author":"Hsu","year":"2002","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/hep.21758","article-title":"Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients","volume":"46","author":"Hui","year":"2007","journal-title":"Hepatology"},{"key":"ref_21","first-page":"374","article-title":"Antiviral therapy leads to histological improvement of HBeAg-negative chronic hepatitis B patients","volume":"28","author":"Papachrysos","year":"2015","journal-title":"Ann. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/jama.295.1.65","article-title":"Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level","volume":"295","author":"Chen","year":"2006","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1111\/apt.15499","article-title":"Tenofovir disoproxil fumarate reduces hepatocellular carcinoma, decompensation and death in chronic hepatitis B patients with cirrhosis","volume":"50","author":"Liu","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/S0140-6736(12)61425-1","article-title":"Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study","volume":"381","author":"Marcellin","year":"2013","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1136\/gutjnl-2013-305517","article-title":"HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: Clinical outcomes and durability","volume":"63","author":"Kim","year":"2014","journal-title":"Gut"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jhep.2018.10.014","article-title":"HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues","volume":"70","author":"Yip","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1053\/j.gastro.2018.10.027","article-title":"Factors Associated With Rates of HBsAg Seroclearance in Adults with Chronic HBV Infection: A Systematic Review and Meta-analysis","volume":"156","author":"Yeo","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jhep.2017.09.018","article-title":"Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients","volume":"68","author":"Yip","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.jhep.2020.05.042","article-title":"Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance","volume":"73","author":"Mak","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jhep.2019.11.003","article-title":"Guidance for design and endpoints of clinical trials in chronic hepatitis B\u2013Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference","volume":"72","author":"Cornberg","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1111\/liv.14155","article-title":"Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection","volume":"39","author":"Marcellin","year":"2019","journal-title":"Liver Int."},{"key":"ref_33","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_34","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_35","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/hep.30474","article-title":"The Role of Hepatitis B Surface Antigen in Nucleos(t)ide Analogues Cessation Among Asian Patients With Chronic Hepatitis B: A Systematic Review","volume":"70","author":"Liu","year":"2019","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1053\/j.gastro.2021.11.002","article-title":"Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study)","volume":"162","author":"Hirode","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3851\/IMP1497","article-title":"Hepatitis B surface antigen seroclearance during chronic HBV infection","volume":"15","author":"Chu","year":"2010","journal-title":"Antivir. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S2468-1253(18)30308-X","article-title":"Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: A systematic review and pooled meta-analyses","volume":"4","author":"Zhou","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/00000441-197901000-00002","article-title":"The Liver Histology and Frequency of Clearance of the Hepatitis B Surface Antigen (HBsAg) in Chronic Carriers","volume":"277","author":"Sampliner","year":"1979","journal-title":"Am. J. Med Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/hep.1840130403","article-title":"Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: A prospective study","volume":"13","author":"Liaw","year":"1991","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/hep.21612","article-title":"HBsAg seroclearance in asymptomatic carriers of high endemic areas: Appreciably high rates during a long-term follow-up","volume":"45","author":"Chu","year":"2007","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1053\/j.gastro.2009.08.061","article-title":"Factors That Predict Response of Patients With Hepatitis B e Antigen\u2013Positive Chronic Hepatitis B to Peginterferon-Alfa","volume":"137","author":"Buster","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1053\/j.gastro.2015.09.043","article-title":"Combination of Tenofovir Disoproxil Fumarate and Peginterferon \u03b1-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B","volume":"150","author":"Marcellin","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/hep4.1436","article-title":"Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B","volume":"4","author":"Lok","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.cgh.2019.07.018","article-title":"Durability of Spontaneous and Treatment-Related Loss of Hepatitis B s Antigen","volume":"18","author":"Alawad","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Fung, S., Choi, H.S.J., Gehring, A., and Janssen, H.L.A. (2022). Getting to HBV cure: The promising paths forward. Hepatology.","DOI":"10.1002\/hep.32314"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/liv.14851","article-title":"HBV 2021: New therapeutic strategies against an old foe","volume":"41","author":"Testoni","year":"2021","journal-title":"Liver Int."},{"key":"ref_48","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 Na\u00efve to Nucleos(t)ide Therapy","volume":"158","author":"Bazinet","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1002\/hep.31920","article-title":"Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients with Chronic Hepatitis B","volume":"74","author":"Gane","year":"2021","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/hep.25718","article-title":"A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance","volume":"56","author":"Seto","year":"2012","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1093\/infdis\/jir283","article-title":"Viral Determinants of Hepatitis B Surface Antigen Seroclearance in Hepatitis B e Antigen\u2013Negative Chronic Hepatitis B Patients","volume":"204","author":"Chan","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/hep.24615","article-title":"Determinants of spontaneous surface antigen loss in hepatitis B e antigen-negative patients with a low viral load","volume":"55","author":"Tseng","year":"2012","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1093\/infdis\/jiy272","article-title":"Incidence and Predictors of HBsAg Loss After Peginterferon Therapy in HBeAg-Negative Chronic Hepatitis B: A Multicenter, Long-term Follow-up Study","volume":"218","author":"Lee","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12876-020-01263-6","article-title":"HBsAg quantification predicts off-treatment response to interferon in chronic hepatitis B patients: A retrospective study of 250 cases","volume":"20","author":"Wu","year":"2020","journal-title":"BMC Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/hep.29213","article-title":"A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha","volume":"66","author":"Cao","year":"2017","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1002\/hep.24221","article-title":"Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir","volume":"53","author":"Lee","year":"2011","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/jmv.22089","article-title":"Correlation of serum hepatitis B surface antigen level with response to entecavir in na\u00efve patients with chronic hepatitis B","volume":"83","author":"Lee","year":"2011","journal-title":"J. Med. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7686","DOI":"10.3748\/wjg.v20.i24.7686","article-title":"Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues","volume":"20","author":"Chen","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1093\/infdis\/jis439","article-title":"Hepatitis B Surface Antigen Declines and Clearance During Long-Term Tenofovir Therapy in Patients Coinfected With HBV and HIV","volume":"206","author":"Zoutendijk","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.jhep.2014.07.019","article-title":"Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate","volume":"61","author":"Marcellin","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1053\/j.gastro.2010.10.011","article-title":"Three-Year Efficacy and Safety of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B","volume":"140","author":"Heathcote","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1002\/hep.26436","article-title":"Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels","volume":"58","author":"Sonneveld","year":"2013","journal-title":"Hepatology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1002\/hep.22760","article-title":"Hepatitis B virus surface antigen levels: A guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B","volume":"49","author":"Brunetto","year":"2009","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/(SICI)1096-9071(199601)48:1<8::AID-JMV2>3.0.CO;2-E","article-title":"Analysis of hepatitis B virus genotypes and pre-core region variability during interferon treatment of HBe antigen negative chronic hepatitis B","volume":"48","author":"Zhang","year":"1996","journal-title":"J. Med. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/S0168-8278(00)80135-X","article-title":"Hepatitis B genotypes and the response to interferon therapy","volume":"33","author":"Kao","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_66","first-page":"1425","article-title":"HBV genotype B is associated with better response to interferon therapy in HBeAg( + ) chronic hepatitis than genotype C","volume":"36","author":"Wai","year":"2002","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1053\/jhep.2003.50458","article-title":"Determinants for sustained HBeAg response to lamivudine therapy","volume":"38","author":"Chien","year":"2003","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.3748\/wjg.v9.i12.2695","article-title":"Hepatitis B virus genotype has no impact on hepatitis B e antigen seroconversion after lamivudine treatment","volume":"9","author":"Chan","year":"2003","journal-title":"World J. Gastroenterol."},{"key":"ref_69","doi-asserted-by":"crossref","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":"ref_70","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1177\/135965350801300217","article-title":"Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence","volume":"13","author":"Wiegand","year":"2008","journal-title":"Antivir. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"29605","DOI":"10.1038\/srep29605","article-title":"Predictors of response to pegylated interferon in chronic hepatitis B: A real-world hospital-based analysis","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1053\/jhep.2003.50208","article-title":"Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: Analysis and review of the literature","volume":"37","author":"Mondou","year":"2003","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"383","DOI":"10.7150\/ijms.39775","article-title":"HBV DNA and HBsAg: Early Prediction of Response to Peginterferon \u03b1-2a in HBeAg-Negative Chronic Hepatitis B","volume":"17","author":"Zhang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.jfma.2013.02.001","article-title":"Hepatitis B viral factors and treatment responses in chronic hepatitis B","volume":"112","author":"Lin","year":"2013","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.4103\/0366-6999.160488","article-title":"Baseline Hepatitis B Virus DNA Level is a Promising Factor for Predicting the 3 (rd) Month Virological Response to Entecavir Therapy: A Study of Strict Defined Hepatitis B virus Induced Cirrhosis","volume":"128","author":"Xu","year":"2015","journal-title":"Chin. Med. J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.jhep.2017.07.012","article-title":"Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients\u2014FINITE study","volume":"67","author":"Berg","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/hep.510300313","article-title":"Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B","volume":"30","author":"Chien","year":"1999","journal-title":"Hepatology"},{"key":"ref_78","first-page":"1","article-title":"Preliminary results from a phase 2 study evaluationg VIR-2218 alone and in combination with pegylated interferon alpha-2a in participants with chronic hepatitis B infection. Oral Abstracts","volume":"74","author":"Yuen","year":"2021","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1002\/hep.30246","article-title":"Advancing Age and Comorbidity in a US Insured Population-Based Cohort of Patients With Chronic Hepatitis B","volume":"69","author":"Nguyen","year":"2018","journal-title":"Hepatology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1111\/apt.16595","article-title":"Systematic review with meta-analysis: Prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B","volume":"54","author":"Zheng","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.clinre.2015.12.011","article-title":"Chronic hepatitis B and fatty liver: Issues in clinical management","volume":"40","author":"Kumar","year":"2016","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.1200\/JCO.2008.16.1075","article-title":"Body-Mass Index and Progression of Hepatitis B: A Population-Based Cohort Study in Men","volume":"26","author":"Yu","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1111\/apt.12658","article-title":"Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B\u2014A prospective cohort study with paired transient elastography examinations","volume":"39","author":"Wong","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/hep.30857","article-title":"Nonalcoholic Steatohepatitis Is Associated With Liver-Related Outcomes and All-Cause Mortality in Chronic Hepatitis B","volume":"71","author":"Choi","year":"2020","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/infdis\/jiaa739","article-title":"Association Between Fatty Liver and Cirrhosis, Hepatocellular Carcinoma, and Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B","volume":"224","author":"Li","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_86","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_87","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1002\/hep.31610","article-title":"Comparison of Long-Term Clinical Outcomes Between Spontaneous and Therapy-Induced HBsAg Seroclearance","volume":"73","author":"Choi","year":"2021","journal-title":"Hepatology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1136\/gutjnl-2013-305785","article-title":"Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma","volume":"63","author":"Liu","year":"2014","journal-title":"Gut"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/jvh.13471","article-title":"Durability of hepatitis B surface antigen seroclearance and subsequent risk for hepatocellular carcinoma: A meta-analysis","volume":"28","author":"Song","year":"2021","journal-title":"J. Viral Hepat."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.jhep.2014.11.031","article-title":"Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: A need for surveillance","volume":"62","author":"Kim","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/cld.983","article-title":"Life After s Loss: Impact of Hepatitis B s Antigen Loss on Future Patient Outcomes","volume":"16","author":"Huang","year":"2020","journal-title":"Clin. 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