停止HBeAg阴性慢性乙型肝炎核苷（酸）类似物治疗后乙型肝炎

StephenW

Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B
Author links open overlay panelFranziskaRinker13†Christine L.Zimmer2†ChristophHöner zu Siederdissen1Michael P.Manns134Anke R.M.Kraft1HeinerWedemeyer13Niklas K.Björkström2†MarkusCornberg134†

1
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

2
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

3
    German Center for Infection Research, Partner Site Hannover-Braunschweig, Germany

4
    Centre for Individualised Infection Medicine (CIIM), c/o CRC Hannover, Germany

Received 2 November 2017, Revised 2 May 2018, Accepted 3 May 2018, Available online 29 June 2018.
crossmark-logo
https://doi.org/10.1016/j.jhep.2018.05.004
Get rights and content
Highlights

•

    Discontinuation of NA therapy leads to higher HBsAg loss rates in HBeAg-negative CHB patients.
•

    T cells from patients with subsequent HBsAg loss show a less exhausted phenotype.
•

    These T cells also express higher levels of activation and proliferation markers at week 12 after discontinuation of therapy.
•

    Relapse of active HBV replication may trigger immunological environment that enhances responsiveness of HBV-specific T cells in vitro.

Background & Aims

Treatment with nucleos(t)ide analogues (NA) leads to hepatitis B virus (HBV) DNA suppression in most patients with chronic hepatitis B (CHB), but HBV surface antigen (HBsAg) loss rates are low. Upon NA discontinuation, HBV DNA can return rapidly with ensuing alanine aminotransferase flares and induction of cytokines. Several studies reported higher HBsAg loss rates after stopping therapy, but at present it is unclear if cell-mediated immune responses are altered after treatment discontinuation. The aim of this study was to characterise T cell responses during the early phase of virological relapse, following discontinuation of NA therapy in HBeAg-negative patients.
Methods

A total of 15 HBeAg-negative patients with CHB on long-term NA treatment were included in a prospective study and subjected to structured NA discontinuation. T cell responses were studied at the end of NA therapy and 4, 8 and 12 weeks thereafter.
Results

The T cell phenotype of patients with CHB on long-term NA therapy was markedly different compared to healthy individuals, but was only slightly altered after discontinuation of therapy. T cells from patients with HBsAg loss expressed low levels of KLRG1 and PD-1 at all time-points and high levels of Ki-67 and CD38 at week 12 after treatment cessation. In vitro peptide stimulated HBV-specific T cell responses were increased in several patients after NA cessation. Blocking of PD-L1 further enhanced HBV-specific T cell responses, especially after discontinuation of therapy.
Conclusion

Relapse of active HBV replication after stopping therapy may trigger an immunological environment that enhances the responsiveness of HBV-specific T cells in vitro. Together with other immune interventions, this approach might be of interest for the development of novel therapeutic options to induce HBsAg loss in CHB.
Lay summary

Relapse of hepatitis B virus replication after discontinuation of nucleos(t)ide analogue therapy in certain patients with chronic hepatitis B may alter the phenotype of T cells and enhance the responsiveness of hepatitis B virus-specific T cells to in vitro peptide stimulation. Blocking PD-L1 can further augment these hepatitis B virus-specific T cell responses. Interestingly, T cells of patients that subsequently achieve hepatitis B surface antigen loss are less exhausted at all time-points after stopping treatment and display a higher proliferative capacity 12-weeks after treatment discontinuation. These findings contribute to the understanding of the immunological events that occur during discontinuation of nucleos(t)ide analogue therapy.

StephenW

停止HBeAg阴性慢性乙型肝炎核苷（酸）类似物治疗后乙型肝炎病毒特异性T细胞反应
作者链接open overlay panelFranziskaRinker13†Christine L.Zimmer2†ChristophHönerzuSiederdissen1Michael P.Manns134AnkeR.M.Kraft1HeinerWedemeyer13NiklasK.Björkström2†MarkusCornberg134†

1
    德国汉诺威汉诺威医学院消化内科，肝脏病学和内分泌科

2
    瑞典斯德哥尔摩卡罗林斯卡大学医院卡罗林斯卡医学院Huddinge医学传染病中心

3
    德国感染研究中心，合作伙伴网站汉诺威 - 不伦瑞克，德国

4
    个体化感染医学中心（CIIM），c / o CRC汉诺威，德国

2017年11月2日收到，2018年5月2日修订，2018年5月3日接受，2018年6月29日在线提供。
CROSSMARK车标
https://doi.org/10.1016/j.jhep.2018.05.004
获取权利和内容
强调

•

    NA治疗的中止导致HBeAg阴性CHB患者的HBsAg丢失率升高。
•

    来自患有HBsAg后丢失的患者的T细胞表现出较少的表型。
•

    在停止治疗后第12周，这些T细胞也表达更高水平的活化和增殖标志物。
•

    活跃的HBV复制的复发可以引发免疫环境，其增强体外HBV特异性T细胞的响应性。

背景与目的

用核苷（酸）类似物（NA）治疗导致大多数慢性乙型肝炎（CHB）患者的乙型肝炎病毒（HBV）DNA抑制，但HBV表面抗原（HBsAg）丢失率低。在NA停止后，HBV DNA可迅速恢复，随后出现丙氨酸氨基转移酶突发和细胞因子的诱导。一些研究报告停止治疗后HBsAg的丢失率较高，但目前尚不清楚治疗中止后细胞介导的免疫反应是否会改变。本研究的目的是在HBeAg阴性患者中停止NA治疗后，在病毒学复发的早期阶段表征T细胞应答。
方法

一项前瞻性研究纳入了15名HBeAg阴性的长期NA治疗CHB患者，并进行了结构性NA停药。在NA治疗结束时和之后的4,8和12周研究T细胞应答。
结果

与健康个体相比，长期NA治疗的CHB患者的T细胞表型显着不同，但在停止治疗后仅略有改变。来自HBsAg丢失患者的T细胞在治疗停止后第12周在所有时间点表达低水平的KLRG1和PD-1，并且表达高水平的Ki-67和CD38。在NA停止后，几名患者体外肽刺激的HBV特异性T细胞应答增加。阻断PD-L1进一步增强了HBV特异性T细胞应答，特别是在停止治疗后。
结论

停止治疗后复发的活性HBV复制可能引发免疫环境，从而增强体外HBV特异性T细胞的反应性。与其他免疫干预一起，这种方法可能对开发诱导CHB中HBsAg丢失的新型治疗选择感兴趣。
放置摘要

在某些慢性乙型肝炎患者中停用核苷（酸）类似物治疗后乙型肝炎病毒复制的复发可能改变T细胞的表型并增强乙型肝炎病毒特异性T细胞对体外肽刺激的反应性。阻断PD-L1可以进一步增强这些乙型肝炎病毒特异性T细胞应答。有趣的是，随后实现乙型肝炎表面抗原丢失的患者的T细胞在停止治疗后的所有时间点都较少疲劳，并且在治疗中断后12周显示出更高的增殖能力。这些发现有助于理解在核苷（酸）类似物治疗中断期间发生的免疫事件。

StephenW