HBV再激活相关肝衰竭的研究进展

施毓; 郑敏

doi:10.3969/j.issn.1001-5256.2021.04.002

HBV再激活相关肝衰竭的研究进展

DOI: 10.3969/j.issn.1001-5256.2021.04.002

施毓,
郑敏^,

浙江大学医学院附属第一医院传染病诊治国家重点实验室，杭州 310003

基金项目:

“十三五”国家传染病科技重大专项 (2018ZX10302206)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：郑敏、施毓对文章的思路有关键贡献；施毓参与起草文章；郑敏修改文章关键内容。

详细信息

作者简介:
施毓(1985—)，男，副主任医师，博士，主要从事终末期肝病及肝衰竭研究

通信作者:
郑敏，minzheng@zju.edu.cn

中图分类号: R512.62;R575.3
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- 被引次数: 0
出版历程
- 收稿日期: 2020-12-23
- 录用日期: 2021-03-01
- 出版日期: 2021-04-20

Research advances in liver failure associated with hepatitis B virus reactivation

Yu SHI,
Min ZHENG^,

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

摘要

摘要: HBV感染是全球重大公共问题。当前的抗病毒治疗药物能够有效的控制病毒复制，但无法清除HBV，在停用了抗HBV药物之后病毒仍然有再激活的可能。实验研究及临床研究表明在感染HBV以后，虽然95%的成人能够自发达到临床痊愈，但病毒基因组仍在宿主的肝细胞内持续存在，当使用免疫抑制剂或肿瘤化疗等药物治疗实体和血液系统恶性肿瘤、风湿免疫疾病、HCV感染等基础疾病时，HBV复制可能重新激活。HBV再激活可能导致严重的临床结局，部分患者可出现肝衰竭，甚至死亡。我国的回顾性研究表明有9%~30%乙型肝炎相关慢加急性肝衰竭是由HBV再激活引起。因此，识别HBV再激活的风险人群并制订合理的预防措施对于减少乙型肝炎相关慢加急肝衰竭的发生有着非常重要的意义。简述了HBV再激活的定义、发生基础，同时论述了HBV再激活引起肝衰竭的诱因及机理，最后总结了需预防人群及措施。
- 乙型肝炎病毒 /
- 肝功能衰竭 /
- 治疗学
Abstract: Hepatitis B virus (HBV) infection is a major public issue in the world. Although currently used antiviral drugs can effectively control virus replication, they cannot clear HBV and HBV reactivation is still observed after the withdrawal of anti-HBV drugs. Meanwhile, experimental studies and clinical research have shown that after HBV infection, although 95% of the adult patients can achieve clinical cure spontaneously, virus genome still exists in host hepatocytes, and when immunosuppressants or chemotherapeutic drugs are used for the treatment of underlying diseases such as solid tumor, hematological malignancies, rheumatic immune diseases, and HCV infection, HBV replication might be reactivated. HBV reactivation may lead to severe clinical outcomes, and some patients may experience liver failure or even death. Retrospective studies in China show that 9%-30% of the cases of acute-on-chronic hepatitis B liver failure are caused by HBV reactivation, and therefore, it is of great importance to identify the population at risk of HBV reactivation and develop reasonable preventive measures, which may help to reduce the development of acute-on-chronic hepatitis B liver failure. This article reviews the definition and basis of HBV reactivation, elaborates on the predisposing factors and mechanism of HBV reactivation in inducing liver failure, and summarizes the population requiring prevention and related preventive measures.
- Hepatitis B virus /
- Liver Failure /
- Therapeutics

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表 1 常见免疫抑制药物引起HBV再激活的可能机理及风险

类型	药物	可能治疗的疾病	可能的HBV再激活机制	HBV再激活风险
类型	药物	可能治疗的疾病	可能的HBV再激活机制	慢性感染	既往感染
B或T淋巴细胞靶向抗体
抗CD20抗体	利妥昔单抗、奥法木单抗、奥滨尤妥珠单抗、奥瑞珠单抗	B淋巴细胞恶性肿瘤、慢性淋巴细胞白血病、类风湿关节炎、自发性血小板减少性紫癜、多发性硬化	长期持久的B淋巴细胞耗竭	高	高
抗CD52抗体	阿仑单抗	难治性慢性淋巴细胞白血病、淋巴瘤，干细胞移植，实体器官移植，类风湿关节炎	长期持久的T淋巴细胞耗竭或控制HBV的关键的B淋巴细胞或T淋巴细胞耗竭	高	数据不足
癌症化疗药物	蒽环类(多柔比星和表柔比星)	系统性使用于实体肿瘤、血液恶性肿瘤，HCC的TACE治疗	细胞毒性和抑制淋巴细胞增殖	高	数据不足
	铂类化合物，抗代谢药、奥沙利铂/伊利替康	实体肿瘤	细胞毒性和抑制淋巴细胞增殖	高	中
生物制剂
细胞因子抑制剂
TNFα抑制剂	英夫利昔单抗、阿达木单抗、赛妥珠单抗、戈利木单抗	炎症性肠病、银屑病、强直性脊柱炎和类风湿性关节炎	阻断在控制HBV复制和cccDNA降解中发挥关键作用的TNFα	高	低
其他	苏金单抗	银屑病	结合并中和参与HBV清除的IL-17	高	中
	优特克单抗	银屑病、炎症性肠病	结合并中和T淋巴细胞激活和/或增殖所需的IL-12和IL-23	高	中
钙调磷酸酶抑制剂	环孢素、他克莫司	实体器官移植、类风湿性关节炎、银屑病和再生障碍性贫血	抑制T淋巴细胞激活信号转导所需的钙调磷酸酶活性，并抑制T淋巴细胞增殖所需的IL-2的转录	低	低
哺乳动物雷帕霉素靶蛋白(mTOR) 抑制剂	依维莫司	乳腺癌、肾细胞癌和神经内分泌肿瘤	通过抑制对生长因子的应答，阻断T淋巴细胞和B淋巴细胞的增殖	数据不足	数据不足
趋化因子抑制剂	Mogamulizumab	难治性成人T淋巴细胞白血病/淋巴瘤	阻断T淋巴细胞上的趋化因子受体CCR4，通过抑制活化的淋巴细胞向肝脏的趋化作用，从而破坏局部免疫对HBV复制的控制	数据不足	高
整合素抑制剂	那他珠单抗、维多珠单抗	银屑病、炎症性肠病和多发性硬化	抑制淋巴细胞上的细胞黏附分子α4整合素，从而阻止淋巴细胞与内皮细胞的粘附	低	低
共刺激抑制剂	阿巴西普、贝拉西普	银屑病、炎症性肠病	通过抑制CD80和CD86信号传导阻断T淋巴细胞的共刺激，从而抑制T淋巴细胞的激活	高	低
蛋白酶体抑制剂	硼替佐米	多发性骨髓瘤	抑制正常B淋巴细胞基本免疫功能所需的蛋白酶体	中	数据不足
酪氨酸激酶抑制剂	伊马替尼、尼洛替尼、达沙替尼、厄洛替尼、依鲁替尼	肺癌、肾细胞癌、胃肠道间质瘤、淋巴瘤、慢性淋巴细胞白血病	TKIs对T淋巴细胞或B淋巴细胞受体信号传导的脱靶免疫作用可抑制B淋巴细胞和T淋巴细胞的激活和增殖	中	低
JAK抑制剂	托法替尼、鲁索替尼	风湿性关节炎、骨髓纤维化和真性红细胞增多症	对抗病毒细胞因子的细胞内信号传导产生负向作用，如通过JAK/STAT信号通路发挥作用的IFN	高	低
传统免疫抑制剂	硫唑嘌呤、6-巯基嘌呤、甲氨蝶呤	炎症性肠病、银屑病、结节病、自身免疫性肝病和关节炎	抑制淋巴细胞增殖所需的DNA和RNA的合成	低	低
皮质类固醇类
系统性			抑制淋巴细胞激活，促进淋巴细胞凋亡，高浓度时抑制B淋巴细胞和T淋巴细胞的产生
≥3个月		炎症性肠病、血炎、结节病、自身免疫性疾病、哮喘、血液恶性肿瘤(间歇性)
中/高剂量				高	数据不足
低剂量				中	数据不足
吸入性		哮喘		中	数据不足
CART治疗	抗CD22和/或抗CD19 CART免疫治疗	难治的/复发的大B细胞淋巴瘤	B淋巴细胞耗竭的脱靶效应	数据不足	数据不足
注：表格授权引用并翻译自参考文献[1]。

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