病毒和免疫因素与HBeAg阴性慢性乙型肝炎患者成功退出治疗有

StephenW

Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients
Mireia García-López  1 , Sabela Lens  1 , Laura J Pallett  2 , Barbara Testoni  3 , Sergio Rodríguez-Tajes  1 , Zoe Mariño  1 , Concepción Bartres  1 , Ester García-Pras  1 , Thais Leonel  1 , Elena Perpiñán  1 , Juan José Lozano  4 , Francisco Rodríguez-Frías  5 , George Koutsoudakis  1 , Fabien Zoulim  3 , Mala K Maini  2 , Xavier Forns  6 , Sofía Pérez-Del-Pulgar  7
Affiliations
Affiliations

    1
    Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
    2
    Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
    3
    Cancer Research Center of Lyon (CRCL), University of Lyon, UMR_S1052, UCBL, INSERM, U1052, Lyon, France.
    4
    Bioinformatics Platform, CIBERehd, Barcelona, Spain.
    5
    Liver Pathology Unit, Department of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain.
    6
    Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: [email protected].
    7
    Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: [email protected].

    PMID: 33278456 DOI: 10.1016/j.jhep.2020.11.043

Abstract

Background aims: Factors associated with a successful outcome upon nucleos(t)ide analog (NA) treatment withdrawal in chronic hepatitis B (CHB) HBeAg-negative patients have yet to be clarified. The objective of this study was to analyze the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation.

Methods: Twenty-seven non-cirrhotic patients with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analyzed at baseline and longitudinally throughout follow-up.

Results: After a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses.

Conclusions: Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal.

Keywords: Antiviral therapy discontinuation; Chronic hepatitis B (CHB); Covalently closed circular DNA (cccDNA); HBV-RNA; HBV-specific T cells; HBcrAg; HBsAg; Hepatitis B virus (HBV); Immune response; Nucleos(t)ide analog (NA).

Copyright © 2020. Published by Elsevier B.V.

StephenW

病毒和免疫因素与HBeAg阴性慢性乙型肝炎患者成功退出治疗有关
MireiaGarcía-López1，Sabela Lens 1，Laura J Pallett 2，Barbara Testoni 3，SergioRodríguez-Tajes1，ZoeMariño1，ConcepciónBartres 1，EsterGarcía-Pras1，Thais Leonel 1，ElenaPerpiñán1，JuanJoséLoz 4，弗朗西斯科·罗德里格斯·弗里亚斯5，乔治·库特索达基斯1，法比恩·祖利姆3，玛拉·缅因州2，泽维尔·福恩斯6，索非亚·佩雷斯·德尔-普尔加7
隶属关系
隶属关系

    1个
    西班牙巴塞罗那，IDIBAPS，CIBERehd，巴塞罗那大学，医院，肝病科。
    2
    英国伦敦大学学院免疫与移植研究所感染与免疫科。
    3
    里昂大学里昂癌症研究中心（CRCL），UMR_S1052，UCBL，INSERM，U1052，法国里昂。
    4
    生物信息平台，CIBERehd，西班牙巴塞罗那。
    5
    西班牙巴塞罗那大学巴塞罗那分校，UniversitéVall d'Hebron大学生物化学与微生物学系，肝病理学科。
    6
    西班牙巴塞罗那，IDIBAPS，巴塞罗那大学，医院诊所，肝病科。电子地址：[email protected]。
    7
    西班牙巴塞罗那，IDIBAPS，巴塞罗那大学，医院诊所，肝病科。电子地址：[email protected]。

    PMID：33278456 DOI：10.1016 / j.jhep.2020.11.043

抽象

背景目标：慢性乙型肝炎（CHB）HBeAg阴性患者中与核苷酸类似物（NA）治疗撤药成功结果相关的因素尚待阐明。这项研究的目的是分析NA停药患者的HBV特异性T细胞反应，以及外周和肝内病毒参数。

方法：前瞻性研究了27例HBeAg阴性CHB且完全抑制病毒（> 3年）的非肝硬化患者。在基线时定量肝内HBV-DNA（iHBV-DNA），肝内HBV-RNA（iHBV-RNA）和共价闭合环状DNA（cccDNA）。此外，在整个随访过程中，在基线和纵向分析了血清标志物（HBV-DNA，HBsAg，HBV核心相关抗原[HBcrAg]和HBV-RNA）和HBV特异性T细胞反应。

结果：中位随访34个月后，仍有22/27例患者（占82％）停止治疗，其中8例患者（占总队列的30％）失去了HBsAg。基线HBsAg与iHBV-DNA和iHBV-RNA显着相关，并且这些参数在丢失HBsAg的患者中较低。无论临床结果如何，所有患者的可检测cccDNA水平均相似。达到功能治愈的患者基线HBsAg水平≤1000IU / ml。同样，基线时功能性HBV特异性CD8 + T细胞的频率增加与持续的病毒控制关闭治疗相关。停药后，这些HBV特异性T细胞反应持续存在，但没有增加。对于HBV特异性CD4 + T细胞反应，观察到类似但无统计学意义的趋势。

结论：HBeAg阴性CHB患者NA终止后，cccDNA转录水平降低和HBsAg水平降低与HBsAg丢失有关。基线时功能性HBV特异性T细胞的存在与停药后的成功预后相关。

关键词：抗病毒治疗中止；慢性乙型肝炎（CHB）；共价封闭的环状DNA（cccDNA）；乙肝病毒RNA HBV特异性T细胞； HBcrAg;乙肝表面抗原乙型肝炎病毒（HBV）；免疫反应;核苷酸类似物（NA）。

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