慢性乙型肝炎临床试验设计和终点指南-2019年EASL-AASLD HBV治疗

StephenW

Hepatology. 2019 Nov 12. doi: 10.1002/hep.31030. [Epub ahead of print]
Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference.
Cornberg M1,2,3, Lok AS4, Terrault NA5, Zoulim F6; 2019 EASL-AASLD HBV Treatment Endpoints Conference Faculty.
Collaborators (23)
Author information

1
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
2
    German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
3
    Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
4
    Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
5
    Division of Gastrointestinal and Liver Diseases, Keck Medicine at University of Southern California, Los Angeles, CA, USA.
6
    Hepatology Department, Hospices Civils de Lyon, INSERM U1052, University of Lyon, France.

Abstract

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilizing cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase 3 trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss, 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity in predicting sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive and HBeAg-negative chronic hepatitis, treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with increase in bilirubin or INR should prompt temporary or permanent cessation of investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase 3 trials for hepatitis D virus (HDV) co-infection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalization of ALT is considered an intermediate goal. CONCLUSION: For HBV 'functional cure', sustained HBsAg loss with undetectable HBV DNA after completion of treatment is the primary goal and sustained undetectable HBV DNA without HBsAg loss after stopping treatment an intermediate goal.

© 2019 by the American Association for the Study of Liver Diseases.
KEYWORDS:

Hepatitis D; antiviral therapy; hepatitis B surface antigen; immune modulatory therapy; nucleos(t)ide analogues

PMID:
    31713892
DOI:
    10.1002/hep.31030

StephenW

肝病学。 2019年11月12日.doi：10.1002 / hep.31030。 [Epub提前发布]
慢性乙型肝炎临床试验设计和终点指南-2019年EASL-AASLD HBV治疗终点会议的报告。
Cornberg M1,2,3，Lok AS4，Terrault NA5，Zoulim F6； 2019 EASL-AASLD HBV治疗终点会议教授。
合作者（23）
作者信息

1个
    德国汉诺威汉诺威医学院胃肠病学，肝病学和内分泌学系。
2
    德国感染研究中心（DZIF），德国汉诺威-不伦瑞克的合作伙伴。
3
    德国汉诺威，个体感染医学中心（CiiM）。
4
    密歇根大学胃肠病学和肝病学系，美国密西根州安娜堡。
5
    美国加利福尼亚州南加利福尼亚大学，凯克医学胃肠道和肝病科。
6
    法国里昂大学INSERM U1052里昂市民医院肝病科。

抽象

来自学术界，行业，监管机构和患者团体的代表于2019年3月召开会议，其主要目标是就慢性乙型肝炎病毒（HBV）治疗终点达成协议，以指导旨在``治愈''HBV的临床试验。会议与会者在一些关键点上达成了共识。可以实现“功能性”治疗，而不是无菌治疗，并且应定义为治疗后6个月中除了检测不到HBV DNA外，持续的HBsAg丢失。 3期试验的主要终点应该是功能性治疗。在这些试验中，建议将≥30％的患者HBsAg丢失作为可接受的缓解率。停止治疗后6个月，持续的病毒学抑制（血清HBV DNA不可检测）而无HBsAg丢失是中间目标。被证明在预测持续的HBsAg丢失方面的有效性被认为是批准新的HBV检测以确定疗效终点的最合适标准。旨在进行HBV功能治愈的临床试验应首先关注于未接受过治疗或被核苷类似物病毒抑制的HBeAg阳性和HBeAg阴性的慢性肝炎患者。与胆红素或INR升高相关的肝炎发作应促使暂时或永久停止研究治疗。新疗法必须与现有的核苷酸类似物一样安全。停止治疗6个月后，无法检测到的D型肝炎病毒（HDV）共感染的3期试验的主要终点是血清HDV RNA。在治疗中，与ALT正常化相关的HDV RNA抑制被认为是中间目标。结论：对于HBV“功能性治愈”，治疗完成后持续的HBsAg丢失和无法检测的HBV DNA是主要目标，而停止治疗后持续的HBsDNA持续检测到HBsAg丢失是中间目标。

©2019美国肝病研究协会版权所有。
关键字：

丁型肝炎；抗病毒治疗；乙型肝炎表面抗原；免疫调节疗法；核苷（核苷酸）类似物

PMID：
    31713892
DOI：
    10.1002 / hep.31030