电子版] REP 2139-Ca治疗HBeAg阳性慢性HBV感染时乙型肝炎表面抗

StephenW

J Viral Hepat. 2019 Jul 19. doi: 10.1111/jvh.13180. [Epub ahead of print]
Kinetics of hepatitis B surface antigen quasispecies during REP 2139-Ca therapy in HBeAg positive chronic HBV infection.
Usman Z1, Mijočević H2, Karimzadeh H2,3, Däumer M4, Mamun AM5, Bazinet M6, Frishman D1,7, Vaillant A6, Roggendorf M2.
Author information

1
    Department of Bioinformatics, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.
2
    Institute of Virology, Technische Universität München, Munich, Germany.
3
    Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany.
4
    Institute of Immunology and Genetics, Kaiserslautern, Germany.
5
    Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.
6
    Replicor Inc. Montreal, Canada.
7
    Laboratory of Bioinformatics, RASA research center, St Petersburg State Polytechnical University, Russia.

Abstract

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca; whereas 3 of 12 patients did not show responses (>1log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the "pre-S/S" open reading frame including the "a" determinant in responders and non-responders of the REP 102 study and 4 untreated matched controls. HBV QS complexity at baseline varied slightly between responders and non-responders (P=0.28). However, these responders showed significant decline in viral complexity (P=0.001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the non-responders (P=0.99). The MHR mutations were more frequently observed in responders than in non-responders and matched controls. No mutations were observed in "a" determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.
KEYWORDS:

HBsAg; Major hydrophilic region (MHR); Nucleic acid polymer (NAP); Quasispecies (QS)

PMID:
    31323705
DOI:
    10.1111/jvh.13180

StephenW

病毒肝病。 2019年7月19日.doi：10.1111 / jvh.13180。 [印刷前的电子版]
REP 2139-Ca治疗HBeAg阳性慢性HBV感染时乙型肝炎表面抗原准种的动态变化。
Usman Z1，MijočevićH2，Karimzadeh H2,3，DäumerM4，Mamun AM5，Bazinet M6，Frishman D1,7，Vaillant A6，Roggendorf M2。
作者信息

1
    慕尼黑工业大学生物信息学系，Wisnsnschaftszentrum Weihenstephan，Freising，德国。
2
    德国慕尼黑工业大学病毒学研究所。
3
    慕尼黑大学医院II医学系 - 德国慕尼黑Grosshadern。
4
    德国凯泽斯劳滕免疫学和遗传学研究所。
五
    Bangabandhu Sheikh Mujib医科大学，孟加拉国达卡。
6
    Replicor Inc.加拿大蒙特利尔。
7
    生物信息学实验室，RASA研究中心，俄罗斯圣彼得堡国立技术大学。

抽象

由于不同水平的免疫应答，慢性HBV感染导致各种临床表现。近年来，通过长期施用核苷（t）ide类似物（NUC）和peg-干扰素，乙型肝炎治疗得到改善。核酸聚合物（NAPs; REP 2139-Ca和REP 2139-Mg）是阻断亚病毒颗粒组装的新型抗病毒药物，因此当与各种免疫疗法结合时，阻止HBsAg的释放并允许其清除并恢复感染的功能控制。在REP 102研究（NCT02646189）中，12名患者中的9名显示出响应REP 2139-Ca的HBsAg和血清转化为抗HBs的显着减少;而12名患者中有3名未显示反应（HBsAg和HBV DNA从基线降低> 1log）。我们描述了HBV准种（QS）在“pre-S / S”开放阅读框架的主要亲水区（MHR）内的动态变化，包括REP 102研究的响应者和非响应者中的“a”决定因子和4未经处理的匹配对照。基线时HBV QS复杂性在应答者和非应答者之间略有不同（P = 0.28）。然而，随着REP 2139-Ca治疗的进展，这些应答者显示病毒复杂性显着下降（P = 0.001），但在无应答者中没有观察到复杂性的显着变化（P = 0.99）。在应答者中比在非应答者和匹配的对照中更频繁地观察到MHR突变。在主要QS群体的“a”决定簇中未观察到突变，其可能通过诊断测定干扰HBsAg的检测。在MHR中未发现特异性突变，这可以解释REP 2139-Ca治疗期间患者的HBsAg反应差。本文受版权保护。版权所有。

本文受版权保护。版权所有。
关键词：

乙肝表面抗原;主要亲水区（MHR）;核酸聚合物（NAP）;准种（QS）

结论：
    31323705
DOI：
    10.1111 / jvh.13180

齐欢畅

在REP 102研究（NCT02646189）中，12名患者中的9名显示出响应REP 2139-Ca的HBsAg和血清转化为抗HBs的显着减少;而12名患者中有3名未显示反应（HBsAg和HBV DNA从基线降低> 1log）。