J. W. Goethe-University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
Gastroenterology. 2010 Feb;138(2):447-62. doi: 10.1053/j.gastro.2009.11.055. Epub 2009 Dec 16.
Chronic hepatitis C virus (HCV) infection is one of the major causes of cirrhosis, hepatocellular carcinoma, and liver failure that leads to transplantation. The current standard treatment, a combination of pegylated interferon alfa and ribavirin, eradicates the virus in only about 50% of patients. Directly acting antiviral (DAA) agents, which inhibit HCV replication, are in phase 1, 2, and 3 trials; these include reagents that target the nonstructural (NS)3 protease, the NS5A protein, the RNA-dependent RNA-polymerase NS5B, as well as compounds that directly inhibit HCV replication through interaction with host cell proteins. Because of the high genetic heterogeneity of HCV and its rapid replication, monotherapy with DAA agents poses a high risk for selection of resistant variants. We review the parameters that determine resistance, genotypic and phenotypic resistance profiles of DAA agents, and strategies to avoid the selection of resistant variants.
慢性丙型肝炎病毒（HCV）感染是导致肝硬化、肝细胞癌和肝衰竭的主要原因之一，这些疾病最终可能导致患者需要进行肝移植。目前的标准治疗方法是聚乙二醇干扰素 alfa 与利巴韦林联合治疗，但该方法只能使约 50%的患者体内的病毒得到清除。直接作用抗病毒（DAA）药物正在进行 1 期、2 期和 3 期临床试验，这些药物包括靶向非结构（NS）3 蛋白酶、NS5A 蛋白、RNA 依赖的 RNA 聚合酶 NS5B 的试剂，以及通过与宿主细胞蛋白相互作用直接抑制 HCV 复制的化合物。由于 HCV 的高度遗传异质性及其快速复制，DAA 药物的单药治疗存在选择耐药变异体的高风险。我们回顾了决定耐药性的参数、DAA 药物的基因型和表型耐药谱，以及避免选择耐药变异体的策略。
