Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
Antimicrob Agents Chemother. 2013 May;57(5):2054-65. doi: 10.1128/AAC.02494-12. Epub 2013 Feb 12.
Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α-RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.
达卡他韦（DCV；BMS-790052）是一种丙型肝炎病毒（HCV）NS5A 复制复合物抑制剂（RCI），在体外具有皮摩尔至低纳摩尔效力和广泛的基因型覆盖范围。在包括 DCV 在内的无干扰素-α-利巴韦林（IFN-α-RBV）和 IFN-RBV 方案的临床中，已经观察到病毒 RNA 下降。对在 14 天单药治疗研究中接受 DCV 治疗的选定受试者的随访标本（长达 6 个月）进行了基因型和表型分析。通过克隆测序在基线标本中检测到变异体，并且在病毒 RNA 突破和治疗后通过群体测序很容易检测到变异体。在体内产生耐药性的主要氨基酸取代发生在 1a 基因型（GT-1a）的 M28、Q30、L31 和 Y93 以及 1b 基因型的 L31 和 Y93，与体外复制子系统观察到的耐药性取代相似。在体外和体内观察到的耐药模式的主要区别是在临床标本中观察到的连锁变异组合的复杂性增加。在随访期间观察到个别变异体的百分比变化；然而，在总人群中，变异体的总体百分比持续到 6 个月。我们的研究结果表明，在 14 天单药治疗期间，DCV 几乎根除了所有野生型病毒。在 DCV 治疗结束后，病毒适应性而不是 DCV 耐药性可能决定哪些病毒变异成为群体中的优势。
