NS5A Sequence Heterogeneity and Mechanisms of Daclatasvir Resistance in Hepatitis C Virus Genotype 4 Infection
NS5A Sequence Heterogeneity and Mechanisms of Daclatasvir Resistance in Hepatitis C Virus Genotype 4 Infection
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丙型肝炎病毒基因型 4 感染中 NS5A 序列异质性及达卡他韦耐药机制
DOI：
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发表时间：
2015
影响因子：
6.4
通讯作者：
F. Mcphee
中科院分区：
文献类型：
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作者：
N. Zhou;D. Hernandez;Joseph M. Ueland;Xiaoyan Yang;Fei Yu;K. Sims;P. Yin;F. Mcphee
背景：丙型肝炎病毒( )达拉塔韦是一种NS5A抑制剂，被批准用于治疗丙型肝炎病毒(GTS)1-4引起的感染。为了支持丙型肝炎病毒4型感染，我们检测了不同基因型4感染人群中丙型肝炎病毒4亚型的患病率、与达拉塔韦耐药相关的残基(28、30、31或93位)的NS5A多态，以及它们对达拉塔韦体外和临床活性的影响。方法： 我们对186例临床试验患者的4型NS5A基因序列和来自欧洲丙型肝炎病毒数据库的43个序列进行了系统发育分析，并利用4NS5A杂交型2a复制子对NS5A基因多态和患者来源的NS5A序列进行了易感性分析。结果： 临床试验患者中有14个4型亚型；最常见的是4a型(55%)和4d型(27%)。代表不同系统发育簇的10个患者来源的NS5A序列的达拉塔韦50%有效浓度为≤0.080 nM。大多数基线序列在与达拉沙韦耐药相关的残基上存在≥1NS5A多态；然而，只有3名患者(1.6%)在体外存在≥1000倍达拉司韦耐药的多态。在46名参加达拉塔韦试验的患者中，所有20名基线耐药基因多态性的患者都实现了持续的病毒学应答。结论： 循环基因4亚型在遗传上是不同的。在治疗前，导致体外高水平达拉塔韦耐药的基因多态并不常见，临床数据表明，基因4亚型和基线基因多态对含有达拉他韦的方案的疗效影响很小。
Background. Daclatasvir is an NS5A inhibitor approved for treatment of infection due to hepatitis C virus (HCV) genotypes (GTs) 1–4. To support daclatasvir use in HCV genotype 4 infection, we examined a diverse genotype 4–infected population for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with daclatasvir resistance (positions 28, 30, 31, or 93), and their effects on daclatasvir activity in vitro and clinically. Methods. We performed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 sequences from the European HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons. Results. The clinical trial patients represented 14 genotype 4 subtypes; most prevalent were genotype 4a (55%) and genotype 4d (27%). Daclatasvir 50% effective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic clusters were ≤0.080 nM. Most baseline sequences had ≥1 NS5A polymorphism at residues associated with daclatasvir resistance; however, only 3 patients (1.6%) had polymorphisms conferring ≥1000-fold daclatasvir resistance in vitro. Among 46 patients enrolled in daclatasvir trials, all 20 with baseline resistance polymorphisms achieved a sustained virologic response. Conclusions. Circulating genotype 4 subtypes are genetically diverse. Polymorphisms conferring high-level daclatasvir resistance in vitro are uncommon before therapy, and clinical data suggest that genotype 4 subtype and baseline polymorphisms have minimal impact on responses to daclatasvir-containing regimens.
影响因子：
25.7
作者：
Lok, Anna S.;Gardiner, David F.;Pasquinelli, Claudio
通讯作者：
Pasquinelli, Claudio