Chronic hepatitis B: what should be the goal for new therapies?
Chronic hepatitis B: what should be the goal for new therapies?
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DOI：
10.1016/j.antiviral.2013.01.006
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发表时间：
2013-04
影响因子：
7.6
通讯作者：
Guo, Ju-Tao
中科院分区：
文献类型：
--
作者：
Block, Timothy M.;Gish, Robert;Guo, Haitao;Mehta, Anand;Cuconati, Andrea;London, W. Thomas;Guo, Ju-Tao
慢性B型肝炎目前可用聚乙二醇干扰素-α（pegIFN-α）或抑制B型肝炎病毒（HBV）DNA聚合酶的五种核苷（酸）类似物直接作用抗病毒剂（DAA）之一进行医学治疗。虽然pegIFN-α在约三分之一的治疗患者中有效，但聚合酶抑制剂可显著降低绝大多数治疗患者的病毒载量。然而，无论是pegIFN-α还是核苷（t）e类似物都不能可靠地消除病毒并实现治愈。此外，干扰素和聚合酶抑制剂被美国、欧洲和亚洲专业学会实践指南推荐仅用于HBV感染者的子集。该亚组是具有最高水平的循环病毒DNA和肝功能异常的人群。虽然这是肝硬化和肝癌风险最高的人群，但那些不符合治疗指南的人，病毒复制水平低，血清ALT正常，也可能从抗病毒治疗中受益。因此，问题是：是否需要新的药物类别来管理慢性B型肝炎？有可能治愈吗？有必要治疗吗？因此，重要的是要定义治愈的含义，并确定新疗法的目标应该是什么。在这篇文章中，我们解决这些问题，并提出了两个可操作的定义医学上可达到的治愈。第一种是基于临床结果的“功能性治愈”，其中患者的预期寿命与未经治疗而解决HBV感染的个体的预期寿命相同。由于这种结果不能在短期内测量，我们还定义了一个“明显的病毒学治愈”，基于稳定的停药抑制HBV病毒血症和抗原血症和ALT和其他实验室检查的正常化。我们认为这种病毒学治愈应该是所有慢性B型肝炎患者未来治疗的目标。病毒学治愈预测功能性治愈的程度只能通过长期随访来确定。
Chronic hepatitis B can currently be medically managed with either pegylated interferon-alpha (pegIFN-α) or one of the five nucleos(t)ide analogue Direct Acting Antivirals (DAAs) that inhibit the hepatitis B virus (HBV) DNA polymerase. While pegIFN-α is effective in approximately one-third of the treated patients, the polymerase inhibitors significantly reduce viral load in the vast majority of those treated. However, neither pegIFN-α nor nucleosid(t)e analogues are capable of reliably eliminating the virus and achieving a cure. Moreover, the interferons and polymerase inhibitors are recommended by US, European and Asian professional society practice guidelines for use in only a subset of those infected with HBV. This subset is the population with the greatest levels of circulating viral DNA and abnormal liver function. Although this is the population at the highest risk for cirrhosis and liver cancer, those who fall outside the treatment guidelines, with low levels of viral replication and normal serum ALTs, may also benefit from antiviral therapy. The questions are thus: are new classes of drugs needed to manage chronic hepatitis B? Is a cure possible? Is a cure even necessary? It is therefore important to define the meaning of a cure and determine what the goals of new therapies should be. In this article, we address those questions and propose two operational definitions of medically attainable cures. The first is a “functional cure” based on the clinical outcome, in which the patient’s life expectancy becomes the same as that of an individual who has resolved his HBV infection without therapy. Because such an outcome cannot be measured over the short term, we also define an “apparent virological cure,” based on the stable off-drug suppression of HBV viremia and antigenemia and the normalization of ALTs and other laboratory tests. We suggest that such a virological cure should be the goal of future therapeutics in all patients with chronic hepatitis B. The extent to which a virological cure predicts a functional cure will only be determined by long-term follow-up.
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