Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B-Report From the 2019 EASL-AASLD HBV Treatment Endpoints Conference
Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B-Report From the 2019 EASL-AASLD HBV Treatment Endpoints Conference
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DOI：
10.1002/hep.31030
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发表时间：
2020-03-01
期刊：
影响因子：
13.5
通讯作者：
Zoulim, Fabien
中科院分区：
文献类型：
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作者：
Cornberg, Markus;Lok, Anna Suk-Fong;Zoulim, Fabien
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，主要目标是就慢性B肝炎病毒（HBV）治疗终点达成一致，以指导旨在“治愈”HBV的临床试验。与会者就一些关键问题达成了一致意见。“功能性”但非灭菌性治愈是可以实现的，应定义为治疗后6个月除HBV DNA检测不到外，HBsAg持续丢失。III期临床试验的主要终点应该是功能性治愈;在这些试验中，HBsAg丢失≥ 30%的患者被认为是可接受的应答率。中期目标为停药后6个月持续病毒学抑制（血清HBV DNA检测不到）且无HBsAg丢失。证明预测持续HBsAg丢失的有效性被认为是批准新HBV检测以确定疗效终点的最适当标准。针对HBV功能性治愈的临床试验应首先关注HBeAg阳性或阴性的慢性肝炎患者，这些患者未经治疗或使用核苷（酸）类似物病毒抑制。与胆红素或国际标准化比值升高相关的肝炎发作应促使暂时或永久停止试验性治疗。新的治疗方法必须与现有的核苷（酸）类似物一样安全。HDV合并感染的III期试验的主要终点应该是停止治疗后6个月血清HDV RNA检测不到。在治疗中，HDV RNA抑制与丙氨酸氨基转移酶正常化相关被认为是一个中间目标。总之，关于HBV“功能性治愈”，主要目标是完成治疗后持续HBsAg丢失且HBV DNA不可检测，中间目标是停止治疗后持续HBV DNA不可检测且HBsAg丢失。
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 sterilising 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 III 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 for the prediction of 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 or negative chronic hepatitis, who are treatment-naive or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV "functional cure", the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.