Hepatitis C virus directly acting antivirals: current developments with NS3/4A HCV serine protease inhibitors
Hepatitis C virus directly acting antivirals: current developments with NS3/4A HCV serine protease inhibitors
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DOI：
10.1093/jac/dkq284
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发表时间：
2010-10-01
影响因子：
5.2
通讯作者：
McHutchison, John
中科院分区：
文献类型：
--
作者：
Naggie, Susanna;Patel, Keyur;McHutchison, John
慢性丙型肝炎病毒（HCV）感染是一个全球性的健康问题，但目前的治疗是有效的，在< 50%的患者感染基因型1。随着细胞培养系统在过去十年中的进步，开发直接作用于HCV的抗病毒药物（DAA）已成为可能。目前在该治疗领域有超过50项活跃的临床试验，NS 3/4A蛋白酶抑制剂目前正在进入III期研究。迄今为止，我们已经了解到DAA是HCV复制的有效抑制剂，导致血清HCV RNA水平快速下降，并有可能缩短治疗时间。然而，这些药物驱动了突变病毒的选择压力，这些突变病毒可以快速发展并降低对药物的敏感性。因此，目前，包括聚乙二醇干扰素α（pegIFN）和利巴韦林在内的现行标准治疗仍然是新药开发的关键部分。此外，早期DAA的不良事件特征增加了当前标准治疗中常见的耐受性问题。目前的问题包括治疗的最佳持续时间，如何以及何时联合联合收割机DAA，以及聚乙二醇干扰素和利巴韦林的长期作用。在这里，我们总结了目前关于蛋白酶抑制剂治疗慢性HCV的有效性的信息，并讨论了该领域目前面临的主要挑战。
Chronic hepatitis C virus (HCV) infection is a global health problem, but the current therapy is effective in < 50% of patients infected with genotype 1. With advances in cell culture systems over the past decade, the development of directly acting antivirals (DAAs) for HCV has become possible. There are currently > 50 active clinical trials in this therapeutic area and NS3/4A protease inhibitors are now entering Phase III study. To date, we have learned that DAAs are potent inhibitors of HCV replication, resulting in rapid declines in serum HCV RNA levels, and have the potential to allow shortening of therapy. However, these agents drive selective pressure for mutant viruses that can develop rapidly and have reduced susceptibility to the drug. Therefore, for now, the current standard of care including pegylated interferon alpha (pegIFN) and ribavirin remains a crucial part of new drug development. Furthermore, the adverse event profile for the early DAAs has added to the concerns of tolerability that are so common for the current standard of care. Ongoing issues include the optimal duration of therapy, how and when to combine DAAs, and the long-term role of pegIFN and ribavirin. Here, we summarize the current information regarding the effectiveness of protease inhibitors in treating chronic HCV and discuss the key challenges now facing the field.