Bartolini Barbara, Lionetti Raffaella, Giombini Emanuela, Sias Catia, Taibi Chiara, Montalbano Marzia, D'Offizi Gianpiero, McPhee Fiona, Hughes Eric A, Zhou Nannan, Ippolito Giuseppe, Garbuglia Anna Rosa, Capobianchi Maria R
"L. Spallanzani" National Institute for Infectious Diseases, Rome, Italy.
Research & Development, Bristol-Myers Squibb, Wallingford, CT, United States.
J Clin Virol. 2015 May;66:38-43. doi: 10.1016/j.jcv.2015.02.001. Epub 2015 Feb 16.
Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype.
Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV+DCV, as assessed by ultra-deep sequencing.
Five treatment-naïve GT4 patients (GT4a [n = 1], GT4d [n = 3], GT4o [n = 1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV±DCV.
Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and <0.6% at Wk4, 8 and 9).
This is the first report to describe DCV-resistance in patients infected with GT4d, supporting a possible role for a recently described RAV (L28S), and presenting the dynamics of HCV quasispecies during therapy failure, with indications of changes of diversity and association of mutations.
达卡他韦（DCV）是一种已获批的NS5A抑制剂，具有强大的抗丙型肝炎病毒（HCV）活性且覆盖多种基因型。已报道了感染基因1型（GT1）患者的DCV耐药相关变异（RAV），但由于移民导致欧洲国家GT4流行率增加，引发了对该基因型的关注。
通过超深度测序评估初治HCV基因4型感染患者的NS5A变异性，并对接受聚乙二醇干扰素/利巴韦林 + DCV治疗出现病毒学失败的患者进行耐药相关变异动态变化的病例研究。
评估5例初治GT4患者（GT4a [n = 1]，GT4d [n = 3]，GT4o [n = 1]）是否纳入COMMAND - 4研究并接受聚乙二醇干扰素/利巴韦林±DCV治疗。
患者1接受聚乙二醇干扰素/利巴韦林治疗；患者2 - 4接受聚乙二醇干扰素/利巴韦林 + DCV治疗；患者5筛查未通过。患者1复发；患者2在第4周出现突破；患者3和4实现了持续病毒学应答。基线时未检测到与DCV耐药相关的替代突变。就患者1和2的病毒血症时间点而言，治疗前NS5A多样性程度与病毒载量无显著相关性（r = -0.568；p = 0.035）。在患者2中，突破后在NS5A氨基酸位置28、31和93观察到多个与DCV耐药相关的替代突变。这些替代突变在同一单倍型上频繁出现（L28S + M31I在第4、8和9周分别为55.52%、82.50%和99.36%；L28S + M31I + Y93H在第4、8和9周分别为11.77%、5.01%和<0.6%）。
这是首次描述感染GT4d患者中DCV耐药的报告，支持了最近描述的RAV（L28S）可能发挥的作用，并呈现了治疗失败期间HCV准种的动态变化，包括多样性变化和突变关联的迹象。
