Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
J Antimicrob Chemother. 2010 Feb;65(2):202-12. doi: 10.1093/jac/dkp388. Epub 2009 Nov 10.
Promising results have been observed with an investigational drug class for hepatitis C (HCV), the specifically targeted antiviral therapies for hepatitis C (STAT-Cs), when combined with peginterferon plus ribavirin (Peg-IFN/RBV). This class has the potential to increase sustained virological response (SVR) rates and reduce therapy duration in genotype 1 chronic HCV patients compared with Peg-IFN/RBV alone. However, because of the remarkable sequence variation in HCV (resulting from the high viral replication rate and intrinsically error-prone nature of HCV polymerase), variants with reduced susceptibility to STAT-Cs can occur naturally before treatment, usually at low levels, and can be selected in patients not responding to potent STAT-C treatment. This review first describes how resistance to a STAT-C can develop and then provides an overview of mutations that confer varying levels of resistance to STAT-Cs, which have been identified and characterized using both genotypic and phenotypic tools. We will discuss why an understanding of the selection of variants with reduced susceptibility to a treatment regimen may be important in optimizing the use of this new class of HCV therapy. Strategies for optimizing treatment regimens to increase response rates, and thereby minimize resistance, will be discussed. Finally, although resistance can be a consequence of not achieving an SVR on an initial regimen, there may be alternative treatment options for patients to achieve an SVR in the future. Future potential therapeutic strategies to address patients who do develop resistance to STAT-Cs are discussed, including combination therapy with multiple STAT-Cs with non-overlapping resistance profiles.
研究性丙型肝炎（HCV）药物类别（即针对 HCV 的特异性抗病毒治疗药物，简称 STAT-Cs）与聚乙二醇干扰素加利巴韦林（Peg-IFN/RBV）联合使用时，在慢性 HCV 基因型 1 患者中具有提高持续病毒学应答率（SVR）和缩短治疗时间的潜力，与 Peg-IFN/RBV 单药治疗相比。然而，由于 HCV 的序列变异显著（这是由 HCV 聚合酶的高病毒复制率和固有易错性质引起的），在治疗前，通常在低水平下，针对 STAT-Cs 的敏感性降低的变体就可能自然发生，并且在对强效 STAT-C 治疗无反应的患者中可以选择这些变体。本综述首先描述了针对 STAT-C 的耐药性如何发展，然后概述了导致对 STAT-C 产生不同水平耐药性的突变，这些突变已经使用基因型和表型工具进行了鉴定和特征描述。我们将讨论为什么了解对治疗方案敏感性降低的变体的选择可能对优化这种新型 HCV 治疗方法的应用很重要。我们将讨论优化治疗方案以提高应答率从而最大限度减少耐药性的策略。最后，尽管耐药性可能是初始治疗方案未达到 SVR 的结果，但将来可能会有替代治疗方案供患者实现 SVR。还讨论了针对对 STAT-Cs 耐药的患者的未来潜在治疗策略，包括联合使用具有非重叠耐药谱的多种 STAT-Cs 的治疗方案。
