{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:02:01Z","timestamp":1776772921438,"version":"3.51.2"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2024JJ5457"],"award-info":[{"award-number":["2024JJ5457"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103861"],"award-info":[{"award-number":["82103861"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>There are no established recommendations for the most suitable treatment of children with immune-tolerant chronic hepatitis B (CHB).<\/jats:p>\n                  <jats:p>To evaluate the clinical outcome of combination therapy among treatment-na\u00efve children with immune-tolerant CHB, we conducted this study.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We retrospectively identified pediatric patients who were diagnosed with immune-tolerant CHB and who received combination therapy with interferon-alpha or peginterferon-alpha-2a plus entecavir at Hunan Children\u2019s Hospital between August 2014 and April 2023. A total of 106 patients were ultimately enrolled in the study. Complete clinical data were collected for all the enrolled patients. The associations between baseline characteristics and HBsAg loss were assessed using Cox proportional hazards regression. Restricted cubic spline (RCS) plots were constructed to portray the association between HBsAg loss and patient age.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>After a median follow-up of 87\u00a0weeks, 23.5% (25\/106) of the participants achieved sustained HBsAg loss, with a cumulative incidence of 44.9%. Proportional hazard regression indicated a significant association between achieving HBsAg loss and age, HBsAg level, and HBsAb level at baseline. The RCS plots suggested that, for pediatric patients, initiating antiviral therapy for immune-tolerant CHB might be most beneficial when they are less than 5\u00a0years old. Seventy-five (70.8%) patients experienced adverse events (AEs) following interferon therapy, with no severe AEs leading to treatment discontinuation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The combination therapy led to favorable clinical outcomes for children with immune-tolerant CHB. Moreover, young age and low HBsAg and high HBsAb levels at baseline are predictors of a clinical cure.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpids\/piaf083","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T18:22:29Z","timestamp":1758306149000},"source":"Crossref","is-referenced-by-count":1,"title":["Incidence and Predictors of HBsAg Loss in Treatment-Na\u00efve Children With Immune-Tolerant Chronic Hepatitis B After Antiviral Therapy"],"prefix":"10.1093","volume":"14","author":[{"given":"Yi","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"ShuangJie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatopathy Center, Hunan Children's Hospital , Changsha 410007 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingping","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sisi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1713-4120","authenticated-orcid":false,"given":"Songxu","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, Xiangya School of Public Health, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"2025100314481059500_ref1","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/s2468-1253(22)00124-8","article-title":"Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"7","year":"2022","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2025100314481059500_ref2","doi-asserted-by":"publisher","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":"2025100314481059500_ref3","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/s2468-1253(19)30042-1","article-title":"Hepatitis B virus infection in children and adolescents","volume":"4","author":"Indolfi","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2025100314481059500_ref4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/jvh.13154","article-title":"Long-term efficacy and safety of peginterferon in the treatment of children with HBeAg-positive chronic hepatitis B","volume":"26 Suppl 1","author":"Liu","year":"2019","journal-title":"J Viral Hepat"},{"key":"2025100314481059500_ref5","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/s0022-3476(86)80987-8","article-title":"Liver cirrhosis associated with chronic hepatitis B virus infection in childhood","volume":"108","author":"Bortolotti","year":"1986","journal-title":"J Pediatr"},{"key":"2025100314481059500_ref6","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"2017 Clinical Practice Guidelines on the management of hepatitis B virus infection","volume":"67","author":"EASL","year":"2017","journal-title":"J Hepatol"},{"key":"2025100314481059500_ref7","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1053\/j.gastro.2016.07.012","article-title":"HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant","volume":"151","author":"Mason","year":"2016","journal-title":"Gastroenterology"},{"key":"2025100314481059500_ref8","article-title":"Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022\u20132030","author":"World Health Organisation","year":"2022"},{"key":"2025100314481059500_ref9","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1097\/hep.0000000000000430","article-title":"Pathway to global elimination of hepatitis B: HBV cure is just the first step","volume":"78","author":"Howell","year":"2023","journal-title":"Hepatology"},{"key":"2025100314481059500_ref10","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/s1473-3099(15)00158-9","article-title":"Global elimination of mother-to-child transmission of hepatitis B: revisiting the current strategy","volume":"15","author":"Thio","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"2025100314481059500_ref11","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1111\/jvh.12007","article-title":"Cure for immune-tolerant hepatitis B in children: is it an achievable target with sequential combo therapy with lamivudine and interferon?","volume":"20","author":"Poddar","year":"2013","journal-title":"J Viral Hepat"},{"key":"2025100314481059500_ref12","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1002\/hep.30312","article-title":"Combination of entecavir\/peginterferon alfa-2a in children with hepatitis B e antigen-positive immune tolerant chronic hepatitis B virus infection","volume":"69","author":"Rosenthal","year":"2019","journal-title":"Hepatology"},{"key":"2025100314481059500_ref13","doi-asserted-by":"publisher","first-page":"10395","DOI":"10.3748\/wjg.v20.i30.10395","article-title":"Natural history of chronic hepatitis B: phases in a complex relationship","volume":"20","author":"Croagh","year":"2014","journal-title":"World J Gastroenterol"},{"key":"2025100314481059500_ref14","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/hep.28156","article-title":"AASLD guidelines for treatment of chronic hepatitis B","volume":"63","author":"Terrault","year":"2016","journal-title":"Hepatology"},{"key":"2025100314481059500_ref15","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.jceh.2021.08.023","article-title":"Should we treat immune tolerant chronic hepatitis B? Lessons from Asia","volume":"12","author":"Premkumar","year":"2022","journal-title":"J Clin Exp Hepatol"},{"key":"2025100314481059500_ref16","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1007\/s12664-018-0878-1","article-title":"Pegylated interferon-based sequential therapy for treatment of HBeAg reactive pediatric chronic hepatitis B-first study in children","volume":"37","author":"Lal","year":"2018","journal-title":"Indian J Gastroenterol"},{"key":"2025100314481059500_ref17","doi-asserted-by":"publisher","article-title":"Making child\u2019s play of tolerance: defining the immune-viral interplay during combination entecavir and pegylated interferon therapy for immune-tolerant hepatitis B infection","author":"Howell","DOI":"10.1002\/hep.32450"},{"key":"2025100314481059500_ref18","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1053\/j.gastro.2012.06.009","article-title":"Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B","volume":"143","author":"Kennedy","year":"2012","journal-title":"Gastroenterology"},{"key":"2025100314481059500_ref19","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.jpeds.2005.09.020","article-title":"Combined lamivudine\/interferon-alpha treatment in \"immunotolerant\" children perinatally infected with hepatitis B: a pilot study","volume":"148","author":"D'antiga","year":"2006","journal-title":"J Pediatr"},{"key":"2025100314481059500_ref20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3760\/cma.j.issn.1674-2397.2024.01.001","article-title":"Expert consensus on whole-population management of hepatitis B virus infetcion (2023)","volume":"17","author":"Lanjuan","year":"2024","journal-title":"Chinese J Clin Infect Dis"},{"key":"2025100314481059500_ref21","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1002\/hep.23934","article-title":"Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options","volume":"52","author":"Jonas","year":"2010","journal-title":"Hepatology"},{"key":"2025100314481059500_ref22","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1586\/17474124.2016.1139450","article-title":"An update on the strategies used for the treatment of chronic hepatitis B in children","volume":"10","author":"Clemente","year":"2016","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"2025100314481059500_ref23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1282922","article-title":"Efficacy of pegylated interferon \u03b1-2b plus entecavir therapy and predictors of treatment success in children with chronic hepatitis B","volume":"14","author":"Huang","year":"2023","journal-title":"Front Immunol"},{"key":"2025100314481059500_ref24","doi-asserted-by":"publisher","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":"2025100314481059500_ref25","doi-asserted-by":"publisher","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":"2025100314481059500_ref26","doi-asserted-by":"publisher","first-page":"657","DOI":"10.3390\/v14040657","article-title":"HBsAg loss as a treatment endpoint for chronic HBV infection: HBV cure","volume":"14","author":"Moini","year":"2022","journal-title":"Viruses"},{"key":"2025100314481059500_ref27","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1016\/j.jhep.2018.01.037","article-title":"Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: a pilot open-label randomized study","volume":"68","author":"Zhu","year":"2018","journal-title":"J Hepatol"},{"key":"2025100314481059500_ref28","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1097\/inf.0000000000004057","article-title":"Efficacy and safety of antiviral therapy for immune-tolerant hepatitis B viral infection in children: a systematic review and meta-analysis","volume":"42","author":"Zheng","year":"2023","journal-title":"Pediatr Infect Dis J"},{"key":"2025100314481059500_ref29","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1080\/14787210.2021.1845652","article-title":"Spontaneous loss of chronic HBV infection markers in treatment-na\u00efve children: a systematic review and pooled meta-analyses","volume":"19","author":"Yang","year":"2021","journal-title":"Expert Rev Anti-Infect Ther"},{"key":"2025100314481059500_ref30","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2570","article-title":"Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune-tolerant phase of chronic hepatitis B virus infection: a systematic review and meta-analysis","volume":"34","author":"Liu","year":"2024","journal-title":"Rev Med Virol"},{"key":"2025100314481059500_ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7326\/0003-4819-137-1-200207020-00006","article-title":"Updated definitions of healthy ranges for serum alanine aminotransferase levels","volume":"137","author":"Prati","year":"2002","journal-title":"Ann Intern Med"},{"key":"2025100314481059500_ref32","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/hep.28015","article-title":"Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen-positive chronic hepatitis B","volume":"63","author":"Jonas","year":"2016","journal-title":"Hepatology"},{"key":"2025100314481059500_ref33","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1111\/j.1440-1754.2004.00361.x","article-title":"Tolerance of interferon-alpha therapy in children with chronic hepatitis B","volume":"40","author":"Liberek","year":"2004","journal-title":"J Paediatr Child Health"},{"key":"2025100314481059500_ref34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.4161\/hv.34306","article-title":"Hepatitis B vaccination","volume":"11","author":"Roman\u00f2","year":"2015","journal-title":"Hum Vaccin Immunother"},{"key":"2025100314481059500_ref35","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jhep.2021.07.031","article-title":"Role of anti-HBs in functional cure of HBeAg+ chronic hepatitis B patients infected with HBV genotype A","volume":"76","author":"Xu","year":"2022","journal-title":"J Hepatol"},{"key":"2025100314481059500_ref36","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1111\/apt.14862","article-title":"A baseline tool for predicting response to peginterferon alfa-2a in HBeAg-positive patients with chronic hepatitis B","volume":"48","author":"Chan","year":"2018","journal-title":"Aliment Pharmacol Ther"},{"key":"2025100314481059500_ref37","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1111\/apt.17667","article-title":"Age at treatment initiation predicts response in children with chronic hepatitis B","volume":"58","author":"Wu","year":"2023","journal-title":"Aliment Pharmacol Ther"},{"key":"2025100314481059500_ref38","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.14218\/jcth.2023.00014","article-title":"Functional cure of chronic hepatitis B with antiviral treatment in children having high-level viremia and normal or mildly elevated serum aminotransferase","volume":"11","author":"Li","year":"2023","journal-title":"J Clin Transl Hepatol"},{"key":"2025100314481059500_ref39","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s12072-023-10631-9","article-title":"Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B","volume":"18","author":"Zhang","year":"2024","journal-title":"Hepatol Int"}],"container-title":["Journal of the Pediatric Infectious Diseases Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jpids\/advance-article-pdf\/doi\/10.1093\/jpids\/piaf083\/64261506\/piaf083.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpids\/article-pdf\/14\/10\/piaf083\/64261506\/piaf083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpids\/article-pdf\/14\/10\/piaf083\/64261506\/piaf083.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:48:21Z","timestamp":1759517301000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpids\/article\/doi\/10.1093\/jpids\/piaf083\/8253498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,13]]},"references-count":39,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jpids\/piaf083","relation":{},"ISSN":["2048-7207"],"issn-type":[{"value":"2048-7207","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,13]]},"article-number":"piaf083"}}