{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T18:18:40Z","timestamp":1785176320185,"version":"3.55.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Emerging evidence suggests a pivotal role for B-cell responses in the natural history of chronic hepatitis B. Serum levels of antibodies to hepatitis B core antigen (anti-HBc) vary across infection stages, but their role in predicting response to antiviral therapy is uncertain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Anti-HBc levels were assessed before peginterferon (PEG-IFN) therapy in patients with chronic hepatitis B who either started de novo PEG-IFN (n = 299; 195 hepatitis B e antigen [HBeAg] positive) or started PEG-IFN as add-on to an existing nucleo(s)tide analogue backbone (n = 91; all HBeAg-positive). Associations were explored between anti-HBc and (1) serum biomarkers, (2) liver histological findings, and (3) treatment response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We studied 390 patients. The hepatitis B virus (HBV) genotype were A, B, C, and D in 24%, 9%, 16%, and 49%, respectively; 72% of patients were Caucasian. Among currently untreated HBeAg-positive patients, anti-HBc was correlated with HBV DNA, hepatitis B core-related antigen (HBcrAg), hepatitis B surface antigen (HBsAg), and HBV RNA, but not with alanine aminotransferase (ALT). Higher anti-HBc was associated with more severe histological inflammatory activity (P &amp;lt; .001), irrespective of HBeAg status. After de novo PEG-IFN, higher anti-HBc levels were associated with HBeAg loss, sustained response, HBsAg decline, and HBsAg clearance (P &amp;lt; .050). Among patients treated with add-on PEG-IFN, higher anti-HBc was associated with HBeAg loss (P = .01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Serum anti-HBc levels correlate with histological inflammatory activity. Higher anti-HBc levels were associated with favorable treatment outcomes. These findings suggest that anti-HBc could be used to select patients most likely to respond to immunomodulatory therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trials Registration<\/jats:title><jats:p>NCT00114361, NCT00146705, NCT00877760, and NCT01532843.<\/jats:p><\/jats:sec>","DOI":"10.1093\/infdis\/jiac210","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T03:36:32Z","timestamp":1653276992000},"page":"113-122","source":"Crossref","is-referenced-by-count":20,"title":["Levels of Antibodies to Hepatitis B Core Antigen Are Associated With Liver Inflammation and Response to Peginterferon in Patients With Chronic Hepatitis B"],"prefix":"10.1093","volume":"227","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7687-4036","authenticated-orcid":false,"given":"Sylvia M","family":"Brakenhoff","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"de Knegt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemiek A","family":"van der Eijk","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke J","family":"van Vuuren","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina E","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry L A","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"de Man","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Boonstra","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan J","family":"Sonneveld","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center , Rotterdam , the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"2022122814515409900_jiac210-B1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cmi.2014.10.002","article-title":"Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection","volume":"21","author":"Song","year":"2015","journal-title":"Clin Microbiol Infect"},{"key":"2022122814515409900_jiac210-B2","doi-asserted-by":"crossref","first-page":"5497","DOI":"10.3390\/ijms22115497","article-title":"Immunopathology of chronic hepatitis B infection: role of innate and adaptive immune response in disease progression","volume":"22","author":"Khanam","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2022122814515409900_jiac210-B3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1002\/hep.27805","article-title":"Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells","volume":"62","author":"Vanwolleghem","year":"2015","journal-title":"Hepatology"},{"key":"2022122814515409900_jiac210-B4","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1111\/jvh.12428","article-title":"T- and B-cell responses and previous exposure to hepatitis B virus in \u2018anti-HBc alone\u2019 patients","volume":"22","author":"Wang","year":"2015","journal-title":"J Viral Hepat"},{"key":"2022122814515409900_jiac210-B5","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jhep.2020.01.024","article-title":"Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV","volume":"73","author":"Vanwolleghem","year":"2020","journal-title":"J Hepatol"},{"key":"2022122814515409900_jiac210-B6","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1111\/apt.16067","article-title":"Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis","volume":"52","author":"Sonneveld","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"2022122814515409900_jiac210-B7","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.jhep.2013.01.029","article-title":"Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B","volume":"58","author":"Sonneveld","year":"2013","journal-title":"J Hepatol"},{"key":"2022122814515409900_jiac210-B8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1136\/gutjnl-2014-308546","article-title":"Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues","volume":"65","author":"Fan","year":"2016","journal-title":"Gut"},{"key":"2022122814515409900_jiac210-B9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0140-6736(05)17701-0","article-title":"Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial","volume":"365","author":"Janssen","year":"2005","journal-title":"Lancet"},{"key":"2022122814515409900_jiac210-B10","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1038\/ajg.2010.186","article-title":"A randomized trial of peginterferon alpha-2a with or without ribavirin for HBeAg-negative chronic hepatitis B","volume":"105","author":"Rijckborst","year":"2010","journal-title":"Am J Gastroenterol"},{"key":"2022122814515409900_jiac210-B11","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1002\/hep.27586","article-title":"Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study)","volume":"61","author":"Brouwer","year":"2015","journal-title":"Hepatology"},{"key":"2022122814515409900_jiac210-B12","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1093\/infdis\/jix024","article-title":"Pegylated interferon alfa-2b add-on treatment in hepatitis B virus envelope antigen-positive chronic hepatitis B patients treated with nucleos(t)ide analogue: a randomized, controlled trial (PEGON)","volume":"215","author":"Chi","year":"2017","journal-title":"J Infect Dis"},{"key":"2022122814515409900_jiac210-B13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/hep.27381","article-title":"Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors","volume":"61","author":"van B\u00f6mmel","year":"2015","journal-title":"Hepatology"},{"key":"2022122814515409900_jiac210-B14","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/hep.29872","article-title":"Host and viral factors associated with serum hepatitis B virus RNA levels among patients in need for treatment","volume":"68","author":"van Campenhout","year":"2018","journal-title":"Hepatology"},{"key":"2022122814515409900_jiac210-B15","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1111\/jvh.13117","article-title":"Hepatitis B core-related antigen monitoring during peginterferon alfa treatment for HBeAg-negative chronic hepatitis B","volume":"26","author":"van Campenhout","year":"2019","journal-title":"J Viral Hepat"},{"key":"2022122814515409900_jiac210-B16","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J Hepatol"},{"key":"2022122814515409900_jiac210-B17","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0168-8278(02)00357-4","article-title":"Histopathological study of chronic hepatitis B and C: a comparison of two scoring systems","volume":"38","author":"Rozario","year":"2003","journal-title":"J Hepatol"},{"key":"2022122814515409900_jiac210-B18","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":"2022122814515409900_jiac210-B19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S2468-1253(19)30344-9","article-title":"Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad","volume":"5","author":"Ghany","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2022122814515409900_jiac210-B20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.3851\/IMP3251","article-title":"An easy-to-use baseline scoring system to predict response to peginterferon alfa-2a in patients with chronic hepatitis B in resource-limited settings","volume":"23","author":"Lampertico","year":"2018","journal-title":"Antivir Ther"},{"key":"2022122814515409900_jiac210-B21","doi-asserted-by":"crossref","first-page":"114226","DOI":"10.1016\/j.jviromet.2021.114226","article-title":"Quantitative serum HBV markers in predicting phases of natural history of chronic HBV infection","volume":"296","author":"Zhang","year":"2021","journal-title":"J Virol Methods"},{"key":"2022122814515409900_jiac210-B22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1128\/JVI.77.1.68-76.2003","article-title":"CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection","volume":"77","author":"Thimme","year":"2003","journal-title":"J Virol"},{"key":"2022122814515409900_jiac210-B23","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1182\/blood-2018-04-848044","article-title":"Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy","volume":"133","author":"Kusumoto","year":"2019","journal-title":"Blood"},{"key":"2022122814515409900_jiac210-B24","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1172\/JCI121957","article-title":"PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection","volume":"128","author":"Salimzadeh","year":"2018","journal-title":"J Clin Invest"},{"key":"2022122814515409900_jiac210-B25","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/apt.14376","article-title":"Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection","volume":"47","author":"Mak","year":"2018","journal-title":"Aliment Pharmacol Ther"},{"key":"2022122814515409900_jiac210-B26","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.jhep.2016.09.028","article-title":"Serum HBV pgRNA as a clinical marker for cccDNA activity","volume":"66","author":"Giersch","year":"2017","journal-title":"J Hepatol"},{"key":"2022122814515409900_jiac210-B27","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/jmv.24601","article-title":"Kinetics of serum HBsAg and intrahepatic cccDNA during pegylated interferon therapy in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B","volume":"89","author":"Chuaypen","year":"2017","journal-title":"J Med Virol"},{"key":"2022122814515409900_jiac210-B28","doi-asserted-by":"crossref","first-page":"218","DOI":"10.7150\/thno.10636","article-title":"Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon","volume":"5","author":"Hou","year":"2015","journal-title":"Theranostics"},{"key":"2022122814515409900_jiac210-B29","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1038\/s41598-017-03102-3","article-title":"Serum hepatitis B core antibody as a biomarker of hepatic inflammation in chronic hepatitis B patients with normal alanine aminotransferase","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci Rep"},{"key":"2022122814515409900_jiac210-B30","doi-asserted-by":"crossref","first-page":"e0156200","DOI":"10.1371\/journal.pone.0156200","article-title":"Remodeling of B-cell subsets in blood during pegylated IFN\u03b1-2a therapy in patients with chronic hepatitis B infection","volume":"11","author":"Aspord","year":"2016","journal-title":"PLoS One"},{"key":"2022122814515409900_jiac210-B31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1189\/jlb.3A0215-041RR","article-title":"IFN-\u03bb is able to augment TLR-mediated activation and subsequent function of primary human B cells","volume":"98","author":"de Groen","year":"2015","journal-title":"J Leukoc Biol"},{"key":"2022122814515409900_jiac210-B32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3851\/IMP3364","article-title":"The effects of nucleoside\/nucleotide analogues on host immune cells: the baseline for future immune therapy for HBV?","volume":"25","author":"Boeijen","year":"2020","journal-title":"Antivir Ther"},{"key":"2022122814515409900_jiac210-B33","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"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiac210\/44137004\/jiac210.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/227\/1\/113\/48438847\/jiac210.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/227\/1\/113\/48438847\/jiac210.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T01:13:40Z","timestamp":1700615620000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/227\/1\/113\/6590452"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,23]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,5,23]]},"published-print":{"date-parts":[[2022,12,28]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiac210","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,1,1]]},"published":{"date-parts":[[2022,5,23]]}}}