Pawlotsky Jean-Michel, Najera Isabel, Jacobson Ira
National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
Antivir Ther. 2012;17(3):411-23. doi: 10.3851/IMP2088. Epub 2012 Mar 8.
Mericitabine (RG7128), an orally administered prodrug of PSI-6130, is the most clinically advanced nucleoside analogue inhibitor of the RNA-dependent RNA polymerase (RdRp) of HCV. This review describes what has been learnt so far about the resistance profile of mericitabine. A serine to threonine substitution at position 282 (S282T) of the RdRp that reduces its replication capacity to approximately 15% of wild-type is the only variant that has been consistently generated in serial in vitro passage experiments. To date, no evidence of genotypic resistance to mericitabine has been detected by population or clonal sequence analysis in any baseline or on-treatment samples collected from >600 patients enrolled in Phase I/II trials of mericitabine administered as monotherapy, in combination with pegylated interferon/ribavirin, or in combination with the protease inhibitor, danoprevir, for 14 days in the proof-of-concept study of interferon-free therapy.
美西他滨（RG7128）是PSI-6130的口服前体药物，是丙型肝炎病毒（HCV）的RNA依赖性RNA聚合酶（RdRp）在临床上进展最为显著的核苷类似物抑制剂。本综述描述了目前关于美西他滨耐药情况的了解。RdRp第282位丝氨酸至苏氨酸的替代（S282T）将其复制能力降低至野生型的约15%，这是在连续体外传代实验中唯一持续产生的变体。迄今为止，在600多名参加美西他滨单药治疗、与聚乙二醇化干扰素/利巴韦林联合治疗或与蛋白酶抑制剂达诺普韦联合治疗的I/II期试验的患者中，收集的任何基线或治疗样本中，通过群体或克隆序列分析均未检测到对美西他滨的基因型耐药证据，该试验在无干扰素治疗的概念验证研究中持续14天。
