Yeo Y.H.TAI-CHUNG TSENGHosaka T.Cunningham C.Fung J.Y.Y.Ho H.J.Kwak M.-S.Trinh H.N.Ungtrakul T.Yu M.-L.Kobayashi M.Le A.K.Henry L.Li J.Zhang J.Sriprayoon T.Jeong D.Tanwandee T.Gane E.Cheung R.C.Wu C.-Y.Lok A.S.Lee H.-S.Suzuki F.Yuen M.-F.JIA-HORNG KAOYang H.-I.Nguyen M.H.2021-09-042021-09-0420202155-384Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85094684370&doi=10.14309%2fctg.0000000000000196&partnerID=40&md5=ab1dff59d468133ba82592c5cf5d01a7https://scholars.lib.ntu.edu.tw/handle/123456789/581739INTRODUCTION: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics. METHODS: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (?2 undetectable HBsAg ?6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed. RESULTS: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ?55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state. DISCUSSION: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).[SDGs]SDG3hepatitis B surface antigen; hepatitis B(e) antigen; adolescent; adult; age; blood; chronic hepatitis B; female; follow up; genetics; Hepatitis B virus; human; immunology; male; middle aged; molecular typing; remission; sex factor; virology; young adult; Adolescent; Adult; Age Factors; Female; Follow-Up Studies; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Molecular Typing; Remission, Spontaneous; Sex Factors; Young Adultjournal article10.14309/ctg.0000000000000196330949532-s2.0-85094684370