是否需要新的长效核苷酸类似物来治疗乙型肝炎感染？

StephenW

Editorial| Volume 74, ISSUE 5, P1011-1014, May 01, 2021
   
Is there any need for new, long-acting nucleos(t)ide analogues for the treatment of hepatitis B infection?

    David Durantel
    Cyril B. Dousson
    Pietro Lampertico

Published:March 11, 2021DOI:https://doi.org/10.1016/j.jhep.2021.01.038

Keywords

    Chronic hepatitis B
    Nucleos(t)ide analogues
    Long-lasting effect
    Covalently-closed-circular DNA
    HBV cure

See Article, pages 1075–1086
In worldwide clinical settings, several nucleos(t)ide analogues (NAs), including tenofovir disoproxil fumarate (TDF), entecavir (ETV), and tenofovir alafenamide fumarate (TAF) are used to treat patients chronically infected with HBV.[1],[2] NAs are easily administrated orally and have favorable pharmacologic profiles.[3]
Their use is generally preferred to that of the immune stimulator pegylated-interferon (Peg-IFN)-alpha, which induces more adverse effects (AEs) and less virological suppression (i.e. HBV DNA decline in serum), although it is associated with a higher rate of HBsAg loss.[1],[2],[4] Treatment indications for these NAs have been clearly defined by international societies, including EASL.[1]
Their efficacy to suppress/reduce HBV viremia and overall safety have been properly assessed in randomized controlled phase III clinical trials (i.e. registration trials) and in long-term real-world studies.[1],[2],[4] When “no virologic resistance” occurs, long-term treatments with 1 of the 3 most used NAs (TDF, ETV, TAF) are associated with a prolonged virologic responses (i.e. viremia below detection levels by qPCR) in most patients (>95%), normalized alanine aminotransferase levels, regression of fibrosis, and altogether with the prevention of disease progression, including hepatocellular carcinoma development (See Fig. 1).[1]Figure thumbnail gr1 Fig. 1Schematic representation of the effect of current and “ideal” NAs on various viral parameters.
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Yet, currently, NAs are to be taken daily and long-term, as treatment cessation is quasi-universally associated with virological rebound,[2],[5] except in selected patients for whom “NA stopping rules” have been applied with some success (note that this latter point will not be discussed here; please refer to the following references for recent discussions on this topic[6]). Moreover it is also well acknowledged that NAs generally have a limited impact on HBsAg levels[1],[2],[4]and that very long-term therapies are needed to reduce covalently closed circular DNA (cccDNA) levels.[7],[8]
As these viral parameters are instrumental to a proper HBV cure (at minima functional, and at maxima sterilizing), there is some room for improvement.

StephenW

社论|第74卷，第5期，P1011-1014,2021年5月1日
   
是否需要新的长效核苷酸类似物来治疗乙型肝炎感染？

    大卫·杜兰特尔（David Durantel）
    西里尔·道森
    彼得罗·兰佩蒂科（Pietro Lampertico）

发布时间：2021年3月11日DOI：https：//doi.org/10.1016/j.jhep.2021.01.038

关键字词

    慢性乙型肝炎
    核苷类似物
    效果持久
    共价闭合环状DNA
    乙肝病毒治疗

参见文章，第1075–1086页
在世界范围内的临床环境中，几种核苷酸（tside）类似物（NAs），包括替诺福韦二富马酸富马酸酯（TDF），恩替卡韦（ETV）和替诺福韦阿拉芬酰胺富马酸酯（TAF）用于治疗慢性感染HBV的患者。[1] [2] NAs易于口服且药理学特征良好。[3]
它们的使用通常优于免疫刺激剂聚乙二醇化干扰素（Peg-IFN）-α，尽管它与更高的浓度相关，但可引起更多的不良反应（AEs）和较少的病毒学抑制作用（即血清中HBV DNA下降）。 [1]，[2]，[4]这些NA的治疗适应症已由包括EASL在内的国际社会明确定义。[1]
在随机对照的III期临床试验（即注册试验）和长期的实际研究中，已正确评估了它们抑制/降低HBV病毒血症的功效和总体安全性。[1]，[2]，[4]当“ “没有病毒抗药性”发生，在大多数患者中，使用3种最常用的NAs（TDF，ETV，TAF）中的一种进行长期治疗与病毒学应答时间延长（即病毒血症低于qPCR检测水平）有关（> 95％）正常化的丙氨酸氨基转移酶水平，纤维化消退，以及与疾病进展的预防（包括肝细胞癌的发展）一起使用（见图1）。[1]图gr1图1当前和“理想” NA的作用示意图各种病毒参数。
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然而，目前，NAs是每天和长期服用的，因为停止治疗与病毒学反弹几乎是普遍相关的[2]，[5]，但在某些患者中应用了“ NA停止规则”的患者成功（请注意，此处将不讨论后一点；有关该主题的最新讨论，请参考以下参考文献[6]）。此外，众所周知的是，NAs通常对HBsAg水平的影响有限[1]，[2]，[4]，并且需要非常长期的治疗以降低共价闭合环状DNA（cccDNA）的水平。[7] ，[8]
由于这些病毒参数对正确的HBV治愈至关重要（在最小功能和最大消毒水平），因此仍有一些改进的空间。