核潮类似物撤除后 HBsAg 消失的概率取决于 HBV 基因型和病毒

StephenW

肝病杂志

. 2022 年 1 月 26 日；S0168-8278(22)00020-4。
doi: 10.1016/j.jhep.2022.01.007。在印刷之前在线。
核潮类似物撤除后 HBsAg 消失的概率取决于 HBV 基因型和病毒抗原水平
MJ Sonneveld 1 , SM Chiu 2 , JY Park 3 , SM Brakenhoff 4 , A Kaewdech 5 , WK Seto 6 , Y Tanaka 7 , I Carey 8 , M Papatheodoridi 9 , F van Bömmel 10 , T Berg 11 , F Zoulim 12 , SH Ahn 13，GN Dalekos 14，NS Erler 15，C Höner Zu Siederdissen 16，H Wedemeyer 17，M Cornberg 18，MF Yuen 19，K Agarwal 20，A Boonstra 21，M Buti 22，T Piratvisuth 23，G Papatheodoridis 24，CH Chen 25 , B Maasoumy 26 , CREATE 学习小组
隶属关系
隶属关系

    1
    荷兰鹿特丹 Erasmus MC 大学医学中心胃肠病学和肝病学系。电子地址：[email protected]。
    2
    台湾高雄高雄长庚纪念医院内科。电子地址：[email protected]。
    3
    韩国首尔延世大学医学院内科。电子地址：[url=mailto[email protected]][email protected][/url]。
    4
    荷兰鹿特丹 Erasmus MC 大学医学中心胃肠病学和肝病学系。电子地址：[email protected]。
    5
    泰国合艾宋卡王子大学医学院。电子地址：[email protected]。
    6
    香港大学肝脏研究国家重点实验室医学系。电子地址：[email protected]。
    7
    日本熊本熊本大学胃肠病学和肝病学系。电子地址：[email protected]。
    8
    英国伦敦国王学院医院肝脏研究所。电子地址：[email protected]。
    9
    希腊雅典国立和 Kapodistrian 大学雅典“莱科”总医院消化内科。电子地址：[email protected]。
    10
    德国莱比锡大学诊所肝病科、肿瘤科、肠胃科、肝病科、传染病和肺病科。电子地址：[email protected]。
    11
    德国莱比锡大学诊所肝病科、肿瘤科、肠胃科、肝病科、传染病和肺病科。电子地址：[email protected]。
    12
    INSERM 单元 1052，法国里昂。电子地址：[email protected]。
    13
    韩国首尔延世大学医学院内科。电子地址：[email protected]。
    14
    内科医学和研究实验室，希腊国家自身免疫性肝病专家中心，拉里萨综合大学医院，希腊拉里萨。电子地址：[email protected]。
    15
    荷兰鹿特丹伊拉斯姆斯 MC 大学医学中心生物统计学系；荷兰鹿特丹伊拉斯姆斯 MC 大学医学中心流行病学系。电子地址：[email protected]。
    16
    德国汉诺威汉诺威医学院胃肠病学和肝病学系。电子地址：[email protected]。
    17
    德国汉诺威汉诺威医学院胃肠病学和肝病学系。电子地址：[email protected]。
    18
    荷兰鹿特丹伊拉斯姆斯 MC 大学医学中心流行病学系。电子地址：[email protected]。
    19
    香港大学肝脏研究国家重点实验室医学系。电子地址：[email protected]。
    20
    英国伦敦国王学院医院肝脏研究所。电子地址：[email protected]。
    21
    荷兰鹿特丹 Erasmus MC 大学医学中心胃肠病学和肝病学系。电子地址：[email protected]。
    22
    肝脏科，内科，Universitari Vall d'Hebron 和 Ciberehd del Intituto Carlos III de Barcelona，西班牙。电子地址：[email protected]。
    23
    泰国合艾宋卡王子大学医学院。电子地址：[email protected]。
    24
    希腊雅典国立和 Kapodistrian 大学雅典“莱科”总医院消化内科。电子地址：[email protected]。
    25
    台湾高雄高雄长庚纪念医院内科。电子地址：[email protected]。
    26
    德国汉诺威汉诺威医学院胃肠病学和肝病学系。电子地址：[email protected]。

    PMID：35092743 DOI：10.1016/j.jhep.2022.01.007



抽象的背景和目的：核潮汐类似物 (NUC) 退出可能会导致一部分患者的 HBsAg 清除，但预测因素仍然不明确。方法：我们研究了在停止长期 NUC 治疗的 HBeAg 阴性、HBV DNA 检测不到的全球队列中，NUC 退出后 HBsAg 消失的预测因素。治疗停止后需要再治疗的患者被认为是无反应者。结果：我们招募了 1216 名患者（991 名有基因型数据）； 98 人（8.1%）实现了 HBsAg 消失。非亚洲患者（调整后的风险比 (aHR) 8.26，p<0.001）以及 HBsAg 较低（aHR 0.243，p<0.001）和 HBcrAg（aHR 0.718，p=0.001）患者的 HBsAg 消失概率更高水平。结合 HBsAg（<10、10-100 或 >100 IU/mL）和 HBcrAg（<2log vs ≥2 log）水平可改善对 HBsAg 消失的预测，在 HBsAg >100 IU/mL 且可检测到 HBcrAg 的患者中观察到的比率极低. HBsAg 消失率也因 HBV 基因型而异。基因型 A 和 D 的发生率最高，并且没有 HBV 基因型 E 的患者出现 HBsAg 下降（基因型的总体比较 p<0.001；基因型 A/D 与基因型 B/C 的 p<0.001）。在亚洲患者中，与基因型 B 相比，HBV 基因型 C 与更高的 HBsAg 消失概率独立相关（aHR 2.494，95% CI：1.490 - 4.174，p=0.001）。结论：NUC 停止后 HBsAg 消失的可能性因患者种族、HBV 基因型和治疗结束病毒抗原水平而异。 HBsAg 低（<100 IU/ml）和/或检测不到 HBcrAg 水平的患者，尤其是非亚洲人或感染 HBV 基因 C 型的患者，似乎是停止治疗的最佳人选。总结：部分患者在停止核潮类似物治疗后可能实现 HBsAg 清除（所谓的功能性治愈）。在这项针对 1216 名停止抗病毒治疗的患者的多中心研究中，我们确定了非亚洲种族、HBV 基因 C 型以及乙型肝炎表面抗原和乙型肝炎核心相关抗原水平低是与 HBsAg 消失机会增加相关的因素。关键词：HBV基因型； HBcrAg；乙肝表面抗原； HBsAg 丢失。版权所有 © 2022 作者。由 Elsevier B.V. 出版。保留所有权利。

StephenW

J Hepatol

. 2022 Jan 26;S0168-8278(22)00020-4.
doi: 10.1016/j.jhep.2022.01.007. Online ahead of print.
Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels
M J Sonneveld  1 , S-M Chiu  2 , J Y Park  3 , S M Brakenhoff  4 , A Kaewdech  5 , W K Seto  6 , Y Tanaka  7 , I Carey  8 , M Papatheodoridi  9 , F van Bömmel  10 , T Berg  11 , F Zoulim  12 , S H Ahn  13 , G N Dalekos  14 , N S Erler  15 , C Höner Zu Siederdissen  16 , H Wedemeyer  17 , M Cornberg  18 , M F Yuen  19 , K Agarwal  20 , A Boonstra  21 , M Buti  22 , T Piratvisuth  23 , G Papatheodoridis  24 , C-H Chen  25 , B Maasoumy  26 , CREATE study group
Affiliations
Affiliations

    1
    Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].
    2
    Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: [email protected].
    3
    Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].
    4
    Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].
    5
    Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand. Electronic address: [email protected].
    6
    Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. Electronic address: [email protected].
    7
    Department of Gastroenterology & Hepatology, Kumamoto University, Kumamoto, Japan. Electronic address: [email protected].
    8
    Institute of Liver Studies, King's College Hospital, London, United Kingdom. Electronic address: [email protected].
    9
    Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece. Electronic address: [email protected].
    10
    Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany. Electronic address: [email protected].
    11
    Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany. Electronic address: [email protected].
    12
    INSERM Unit 1052, Lyon, France. Electronic address: [email protected].
    13
    Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].
    14
    Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece. Electronic address: [email protected].
    15
    Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].
    16
    Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: [email protected].
    17
    Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: [email protected].
    18
    Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].
    19
    Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. Electronic address: [email protected].
    20
    Institute of Liver Studies, King's College Hospital, London, United Kingdom. Electronic address: [email protected].
    21
    Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].
    22
    Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Ciberehd del Intituto Carlos III de Barcelona, Spain. Electronic address: [email protected].
    23
    Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand. Electronic address: [email protected].
    24
    Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece. Electronic address: [email protected].
    25
    Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: [email protected].
    26
    Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: [email protected].

    PMID: 35092743 DOI: 10.1016/j.jhep.2022.01.007

Abstract

Background & aims: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients, but predictors remain ill-defined.

Methods: We studied predictors of HBsAg loss after NUC withdrawal in a global cohort of HBeAg negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after therapy cessation were considered non-responders.

Results: We enrolled 1216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio (aHR) 8.26, p<0.001), and in patients with lower HBsAg (aHR 0.243, p<0.001) and HBcrAg (aHR 0.718, p=0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/mL) and HBcrAg (<2log vs ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/mL with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p<0.001 for the overall comparison across genotypes; p<0.001 for genotypes A/D versus genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494, 95% CI: 1.490 - 4.174, p=0.001).

Conclusions: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for therapy withdrawal.

Lay summary: A subset of patients may achieve clearance of HBsAg (so-called functional cure) after withdrawal of nucleo(s)tide analogue therapy. In this multicenter study of 1216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core related antigen levels as factors associated with an increased chance of HBsAg loss.

Keywords: HBV genotype; HBcrAg; HBsAg; HBsAg loss.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

StephenW

https://www.journal-of-hepatolog ... 8278(22)00020-4/pdf