{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T04:28:14Z","timestamp":1783830494227,"version":"3.55.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The stoppage of nucleoside analog (NA) can lead to immune flare and loss of HBsAg in a proportion of HBeAg-negative chronic hepatitis B (CHB) patients. HBsAg loss could be improved by instituting Peg-Interferon therapy in those who show an immune flare after the stoppage of NA. We investigated the immune drivers of HBsAg loss in NA-treated HBeAg-negative CHB patients after stopping NAs and administration of Peg-IFN-\u03b12b therapy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Fifty-five NA-treated eAg-ve, HBV DNA not detected CHB patients were subjected to stopping NA therapy. Twenty-two (40%) patients relapsed (REL-CHBV) within 6 months (HBV DNA \u22652000\u00a0IU\/mL, ALT \u22652XULN) and were started on Peg-IFN-\u03b12b (1.5\u00a0mcg\/kg) for 48 weeks (PEG-CHBV). Cytokine levels, immune responses, and T-cell functionality were assessed.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Only 22 (40%) of 55 patients clinically relapsed, of which 6 (27%) cleared HBsAg. None of the 33 (60%) nonrelapsers cleared HBsAg. REL-CHBV patients had significantly increased IL-6 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.035), IFN-\u03b3 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.049), Th1\/17 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.005), CD4 effector memory (EM) (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.01), Tfh1\/17 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.005), and mature B cells (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.04) compared with CHBV. Six months after Peg-IFN therapy, immune resetting with a significant increase in CXCL10 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.042), CD8 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.01), CD19 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.001), and mature B cells (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.001) was observed. HBV-specific T-cell functionality showed increased Tfh-secreting IFN-\u03b3 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.001), IL-21 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.001), and TNF-\u03b1 (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.005) in relapsers and IFN-\u03b3\u2013secreting CD4 T cell (<jats:italic toggle=\"yes\">p<\/jats:italic>=0.03) in PEG-CHBV.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Stopping NA therapy induces flare in about 40% of HBeAg-negative patients. Peg-IFN therapy given to such patients causes immune restoration with HBsAg loss in one fourth of them.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/hc9.0000000000000098","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T14:00:42Z","timestamp":1682604042000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":16,"title":["Immune drivers of HBsAg loss in HBeAg-negative CHB patients after stopping nucleotide analog and administration of Peg-IFN"],"prefix":"10.1097","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7219-9686","authenticated-orcid":false,"given":"Mojahidul","family":"Islam","sequence":"first","affiliation":[{"name":"Departments of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4382-9831","authenticated-orcid":false,"given":"Karan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2725-5516","authenticated-orcid":false,"given":"Jayesh K.","family":"Sevak","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5582-7759","authenticated-orcid":false,"given":"Ankur","family":"Jindal","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6333-0195","authenticated-orcid":false,"given":"Ashish K.","family":"Vyas","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4345-294X","authenticated-orcid":false,"given":"Gayatri","family":"Ramakrishna","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-0812","authenticated-orcid":false,"given":"Shyamasundaran","family":"Kottilil","sequence":"additional","affiliation":[{"name":"Infectious Diseases Department, Institute of Human Virology, University of Maryland, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3448-8334","authenticated-orcid":false,"given":"Manoj K.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0544-5610","authenticated-orcid":false,"given":"Shiv K.","family":"Sarin","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6109-0033","authenticated-orcid":false,"given":"Nirupama","family":"Trehanpati","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2023,5]]},"reference":[{"key":"R1-20240826","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"key":"R2-20240826","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jceh.2014.12.004","article-title":"Tackling the hepatitis B disease burden in India","volume":"4","author":"Puri","year":"2014","journal-title":"J Clin Exp Hepatol"},{"key":"R3-20240826","doi-asserted-by":"crossref","DOI":"10.1016\/S2468-1253(17)30083-3","article-title":"Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial","author":"de Niet","year":"2017","journal-title":"The Lancet Gastroenterology and Hepatology"},{"key":"R4-20240826","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":"R5-20240826","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1002\/hep.31525","article-title":"Hepatitis B flare after cessation of nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B: to retreat or not to retreat","volume":"73","author":"Liaw","year":"2021","journal-title":"Hepatology"},{"key":"R6-20240826","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":"R7-20240826","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s12072-008-9080-3","article-title":"Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update","volume":"2","author":"Liaw","year":"2008","journal-title":"Hepatol Int"},{"key":"R8-20240826","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":"R9-20240826","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection","volume":"67","year":"2017","journal-title":"J Hepatol"},{"key":"R10-20240826","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/hep.29821","article-title":"Less can be more: a finite treatment approach for HBeAg-negative chronic hepatitis B","volume":"68","author":"Lampertico","year":"2018","journal-title":"Hepatology"},{"key":"R11-20240826","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/S2468-1253(17)30217-0","article-title":"Peg-interferon plus nucleotide analogue in patients with chronic hepatitis B with low viral load","volume":"2","author":"Jindal","year":"2017","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"R12-20240826","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/hep.29640","article-title":"Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B","volume":"68","author":"Jeng","year":"2018","journal-title":"Hepatology"},{"key":"R13-20240826","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1053\/j.gastro.2012.05.039","article-title":"Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir","volume":"143","author":"Hadziyannis","year":"2012","journal-title":"Gastroenterology"},{"key":"R14-20240826","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1093\/infdis\/jiw412","article-title":"Viral and host responses after stopping long-term nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B","volume":"214","author":"Honer Zu Siederdissen","year":"2016","journal-title":"J Infect Dis"},{"key":"R15-20240826","doi-asserted-by":"crossref","first-page":"e228","DOI":"10.1016\/j.cgh.2021.04.031","article-title":"Switching to or add-on peginterferon in patients on nucleos(t)ide analogues for chronic hepatitis B: the SWAP RCT","volume":"20","author":"Lim","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"R16-20240826","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.jhep.2021.04.040","article-title":"The times they are a-changing\u2014a refined proposal for finite HBV nucleos(t)ide analogue therapy","volume":"75","author":"Berg","year":"2021","journal-title":"J Hepatol"},{"key":"R17-20240826","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.clim.2018.08.005","article-title":"Th1\/17 cells, a subset of Th17 cells, are expanded in patients with active systemic lupus erythematosus","volume":"195","author":"Tsanaktsi","year":"2018","journal-title":"Clin Immunol"},{"key":"R18-20240826","article-title":"Immune predictors of hepatitis B surface antigen seroconversion in patients with hepatitis B reactivation","author":"Islam","year":"2022","journal-title":"Aliment Pharmacol Ther"},{"key":"R19-20240826","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/35073080","article-title":"A weak signal for strong responses: interferon-alpha\/beta revisited","volume":"2","author":"Taniguchi","year":"2001","journal-title":"Nat Rev Mol Cell Biol"},{"key":"R20-20240826","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3389\/fimmu.2017.00304","article-title":"Type I interferons and natural killer cell regulation in cancer","volume":"8","author":"Muller","year":"2017","journal-title":"Front Immunol"},{"key":"R21-20240826","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.molimm.2018.11.015","article-title":"A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders","volume":"105","author":"Kamali","year":"2019","journal-title":"Mol Immunol"},{"key":"R22-20240826","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cellimm.2017.07.003","article-title":"Atypical memory B cells in human chronic infectious diseases: an interim report","volume":"321","author":"Portugal","year":"2017","journal-title":"Cell Immunol"},{"key":"R23-20240826","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1002\/eji.201040391","article-title":"IL-6: regulator of Treg\/Th17 balance","volume":"40","author":"Kimura","year":"2010","journal-title":"Eur J Immunol"},{"key":"R24-20240826","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s12072-019-09989-6","article-title":"Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift","volume":"13","author":"Liaw","year":"2019","journal-title":"Hepatol Int"},{"key":"R25-20240826","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":"R26-20240826","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nri778","article-title":"Effector and memory T-cell differentiation: implications for vaccine development","volume":"2","author":"Kaech","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"R27-20240826","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.jhep.2009.12.015","article-title":"A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B","volume":"52","author":"Tan","year":"2010","journal-title":"J Hepatol"},{"key":"R28-20240826","doi-asserted-by":"crossref","first-page":"915","DOI":"10.3851\/IMP1866","article-title":"Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside\/nucleotide analogues","volume":"16","author":"Jaroszewicz","year":"2011","journal-title":"Antivir Ther"},{"key":"R29-20240826","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jhep.2013.08.023","article-title":"Changes of HBsAg and interferon-inducible protein 10 serum levels in naive HBeAg-negative chronic hepatitis B patients under 4-year entecavir therapy","volume":"60","author":"Papatheodoridis","year":"2014","journal-title":"J Hepatol"},{"key":"R30-20240826","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.micinf.2011.10.003","article-title":"XCL1 and XCR1 in the immune system","volume":"14","author":"Lei","year":"2012","journal-title":"Microbes Infect"},{"key":"R31-20240826","first-page":"121","article-title":"CXCL10\/IP-10 in infectious diseases pathogenesis and potential therapeutic implications","volume":"22","author":"Liu","year":"2011","journal-title":"Cytokine Growth Factor Rev"},{"key":"R32-20240826","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/JVI.02844-06","article-title":"Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection","volume":"81","author":"Boni","year":"2007","journal-title":"J Virol"},{"key":"R33-20240826","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.3389\/fimmu.2017.01597","article-title":"PD-1\/PD-L1 blockade: have we found the key to unleash the antitumor immune response?","volume":"8","author":"Xu-Monette","year":"2017","journal-title":"Front Immunol"},{"key":"R34-20240826","doi-asserted-by":"crossref","first-page":"629","DOI":"10.7326\/0003-4819-114-8-629","article-title":"Long-term remission of chronic hepatitis B after alpha-interferon therapy","volume":"114","author":"Korenman","year":"1991","journal-title":"Ann Intern Med"},{"key":"R35-20240826","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1056\/NEJM199605303342202","article-title":"Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B","volume":"334","author":"Niederau","year":"1996","journal-title":"N Engl J Med"},{"key":"R36-20240826","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1053\/jhep.2001.25273","article-title":"Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications","volume":"34","author":"Yuen","year":"2001","journal-title":"Hepatology"},{"key":"R37-20240826","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1002\/hep.23568","article-title":"Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B","volume":"51","author":"Wong","year":"2010","journal-title":"Hepatology"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000098","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T15:09:23Z","timestamp":1724684963000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/HC9.0000000000000098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023]]}},"URL":"https:\/\/doi.org\/10.1097\/hc9.0000000000000098","relation":{},"ISSN":["2471-254X"],"issn-type":[{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]},"assertion":[{"value":"2022-08-03","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-12","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}