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标题: 乙型肝炎:新型抗病毒治疗的早期临床研究 [打印本页]

作者: StephenW    时间: 2018-3-21 21:37     标题: 乙型肝炎:新型抗病毒治疗的早期临床研究

Anna S. Lok, MD, FAASLD
Director, Clinical Hepatology
University of Michigan
1500 East Medical Center Drive
3110G Taubman Center, SPC 5362
Ann Arbor, MI 48109
Email: [email protected]
Hepatitis B: Early Phase Clinical Studies of Novel Antiviral Therapies
Currently approved treatments for hepatitis B are effective in suppressing but not in eliminating HBV; thus, most patients require long durations and often lifelong treatment. There are many barriers to eliminating HBV: (1) existence of covalent
ly closed circular HBV DNA(cccDNA) with long half-life serving as template for transcription of pregenomic RNA and translation of HBV proteins, (2) presence of integrated HBV DNA, and (3) impaired innate and adaptive host immune response to HBV. Thus, even in persons with serological recovery from transient HBV
infection, HBV persists in the liver and reactivation can occur with potent immunosuppression. With improved understanding of the biology of HBV and better in vitro and animal models, many new antiviral targets have been identified and novel antiviral therapies directed at these targets are being tested in preclinical and early phase clinical trials. Novel antiviral therapies in development include compounds that inhibit or modulate entry receptors; capsid assembly; RNA transcription and translation; cccDNA formation, replenishment, transcription and persistence; HBx protein, RNAseH, and HBV assembly and secretion. While the primary role of
these agents is to suppress HBV DNA replication and HBV protein expression, they may also facilitate recovery of immune response.
Among these novel antiviral approaches, several are being evaluated in early phase clinical trials and have shown promise. These include entry inhibitors such as Myrcludex, capsid assembly inhibitors such as NVR-3778, RNAi such as ARC
-520, and nucleic acid polymers targeting HBsAg secretion such as REP-2139.
These agents have been shown not only to reduce serum HBV DNA levels but also serum HBV RNA and HBsAg levels. Most of these agents have only been tested for short durations and some were evaluated in combination with interferon or nucleos/tide analogues, and the long term safety and durability of antiviral efficacy
of these agents remain unclear. Regardless, it is envisioned that a combination of antiviral agents targeting multiple steps in HBV lifecyle will be necessary to achieve sustained control of HBV replication, and additional immune modulatory therapy will likely be needed to restore immune control to allow safe withdrawal of antiviral therapy. As new therapies are developed and tested in clinical trials, a key question is whether HBV cure is possible. While sterilizing cure is unlikely to be feasible, functional cure defined as clearance of HBsAg in a higher proportion of patients
that can be achieved with currently available therapies, after a finite duration of treatment may be possible. Accomplishment of this goal will require
the collaboration of multiple stake holders: regulatory agencies, diagnostic and
therapeutic companies, scientists and clinical investigators. In addition to new antiviral drugs, new assays for novel biomarkers will also be necessary.

作者: StephenW    时间: 2018-3-21 21:37

安娜S.乐,医学博士,FAASLD
临床肝病学主任
密歇根大学
1500 East Medical Center Drive
3110G Taubman中心,SPC 5362
安阿伯,MI 48109
电子邮件:[email protected]
乙型肝炎:新型抗病毒治疗的早期临床研究
目前批准的乙肝治疗方法可有效抑制但不能消除HBV;因此,大多数患者需要长时间并且经常终身治疗。消除HBV有许多障碍:(1)共价存在
包括半衰期长的HBV DNA(cccDNA)作为前基因组RNA转录和HBV蛋白翻译的模板,(2)存在整合的HBV DNA,以及(3)先天性和适应性宿主对HBV的免疫应答受损。因此,即使在患有短暂HBV的血清学恢复的人中也是如此
感染,HBV持续存在于肝脏中,并且可以通过有效的免疫抑制进行再激活。随着对HBV生物学知识的进一步了解以及更好的体外和动物模型,已经确定了许多新的抗病毒靶点,针对这些靶点的新型抗病毒治疗正在临床前和早期临床试验中进行测试。正在开发的新型抗病毒疗法包括抑制或调节进入受体的化合物;衣壳组装; RNA转录和翻译; cccDNA形成,补充,转录和持久性; HBx蛋白,RNAseH和HBV组装和分泌。虽然主要作用
这些药物是抑制HBV DNA复制和HBV蛋白表达的,它们也可能促进免疫反应的恢复。
在这些新的抗病毒方法中,有几个正在早期阶段的临床试验中进行评估,并显示出前景。这些包括进入抑制剂如Myrcludex,衣壳组装抑制剂如NVR-3778,RNAi如ARC
-520,以及靶向HBsAg分泌的核酸聚合物如REP-2139。
已经显示这些药物不仅降低血清HBV DNA水平,而且降低血清HBV RNA和HBsAg水平。大多数这些药物只进行了短时间的检测,有些药物与干扰素或核苷/类似物结合使用进行了评估,并且抗病毒效力的长期安全性和持久性
这些代理人仍然不清楚。无论如何,可以想象的是,靶向HBV生命周期中的多个步骤的抗病毒剂的组合对于实现对HBV复制的持续控制是必需的,并且可能需要额外的免疫调节疗法来恢复免疫控制以允许安全撤回抗病毒疗法。随着新疗法在临床试验中的开发和测试,关键问题是HBV治愈是否可能。虽然杀菌治疗不太可行,但功能性治愈的定义是在较高比例的患者中清除HBsAg
这可以通过目前可用的疗法在有限的治疗持续时间之后实现。这个目标的完成将需要
多个利益相关者的合作:监管机构,诊断和治疗
治疗公司,科学家和临床研究人员。除了新的抗病毒药物之外,新型生物标志物的新测定也是必要的。
作者: hbv_challenger    时间: 2018-3-21 21:59

中肯的表达  不灰心,不盲目乐观




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