Duke Clinical Research Institute, Durham, NC, USA.
J Antimicrob Chemother. 2010 Oct;65(10):2063-9. doi: 10.1093/jac/dkq284. Epub 2010 Aug 4.
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 α (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.
慢性丙型肝炎病毒 (HCV) 感染是一个全球性的健康问题，但目前的治疗方法对感染基因型 1 的患者的有效率不足 50%。在过去十年中，随着细胞培养系统的进步，开发直接作用抗病毒药物 (DAA) 治疗 HCV 成为可能。目前，该治疗领域有超过 50 项正在进行的临床试验，NS3/4A 蛋白酶抑制剂现已进入 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 水平迅速下降，并有可能缩短治疗时间。然而，这些药物会导致对药物敏感性降低的突变病毒产生选择压力，这些病毒会迅速出现。因此，目前包括聚乙二醇干扰素 α (pegIFN) 和利巴韦林在内的标准护理仍然是新药开发的重要组成部分。此外，早期 DAA 的不良事件谱增加了对当前标准护理中常见的耐受性问题的担忧。目前仍存在一些问题，包括治疗的最佳持续时间、如何以及何时联合使用 DAA，以及 pegIFN 和利巴韦林的长期作用。在这里，我们总结了蛋白酶抑制剂治疗慢性 HCV 的有效性的最新信息，并讨论了该领域目前面临的关键挑战。
