{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:46:24Z","timestamp":1792514784811,"version":"4.5.0"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pegylated interferon-\u03b1 (PegIFN-\u03b1) is a cornerstone immunomodulatory therapy with the potential to achieve a functional cure for chronic hepatitis B (CHB). However, its clinical application is constrained by a high frequency of multisystem adverse reactions, which often lead to dose modifications or treatment discontinuation. These toxicities are not ancillary effects but rather direct consequences of the drug\u2019s therapeutic mechanism, arising from a broad and often dysregulated systemic immune activation. This review systematically delineates the clinical spectrum of these reactions and provides a unified framework for their underlying host immunopathological mechanisms. We dissect the interconnected network of host factors including cytokine-driven inflammation, hematopoietic suppression, loss of immune tolerance, and neuro-immune axis disruption that mediate common toxicities such as flu-like syndrome, cytopenias, autoimmunity, and neuropsychiatric symptoms. A focused analysis of ocular vascular injury is included. By synthesizing recent evidence, we discuss predictive biomarkers and contemporary management strategies designed to navigate this therapeutic dichotomy. Finally, we outline future directions for developing safer, mechanism-informed, and host-directed personalized therapies for CHB.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1801043","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:06:45Z","timestamp":1775801205000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanisms and management of pegylated interferon-\u03b1 toxicity in chronic hepatitis B"],"prefix":"10.3389","volume":"17","author":[{"given":"Liya","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital of Yangtze University","place":["Jingzhou, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital of Yangtze University","place":["Jingzhou, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingfang","family":"Pi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital of Yangtze University","place":["Jingzhou, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital of Yangtze University","place":["Jingzhou, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01468-4","article-title":"Hepatitis B","volume":"401","author":"Jeng","year":"2023","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1002\/hep.28280","article-title":"Antiviral therapy for chronic hepatitis B viral infection 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