"Reversi-Type Virologic Failure" Involved in the Development of NS5A-RAVs in Patients with Genotype 1b HCV Carrying No Signature RAVs at Baseline.
"Reversi-Type Virologic Failure" Involved in the Development of NS5A-RAVs in Patients with Genotype 1b HCV Carrying No Signature RAVs at Baseline.
复制标题
“逆向型病毒学失败”涉及基线时不携带特征性 RAV 的基因型 1b HCV 患者中 NS5A-RAV 的发展。
DOI：
10.1111/hepr.12882
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发表时间：
2017
期刊：
影响因子：
4.2
通讯作者：
Mochida S.
中科院分区：
文献类型：
--
作者：
Uchida Y;Kouyama JI;Naiki K;Sugawara K;Inao M;Imai Y;Nakayama N;Mochida S.
目的非结构蛋白5A(NS5A)-R30Q变异株丙型肝炎病毒非结构蛋白(NS5A)-R30Q变异株患者，尽管NS5A抑制剂的半数有效浓度低于野生型株，但达拉塔韦/阿索奈韦对丙型肝炎病毒非结构蛋白5A(NS5A)-R30Q变异株的疗效仍低于野生型。在这些患者中，对NS5A抑制剂高度耐药的R30Q和Y93H突变株在病毒学失败时出现。方法采用直接测序法对88例经达拉塔韦/阿索奈韦尔治疗后的病毒学失败患者的NS5A耐药相关变异进行分析。结果R30Q和/或R30Q突变株36例，L31M突变株46例，Y93H突变株65例，R30Q和Y93H突变株23例。在其中8例患者的基线血清标本中检测到R30Q突变株；环探针实时聚合酶链式反应显示4例患者的Y93H突变株占总菌株的比例小于1%，4例患者的Y93H突变株占总株的比例在1%~98%之间。系统进化树分析表明，R30Q和Y93H变异株均来源于两种变异的次要毒株，即使在比例小于1%的患者中也是如此。结论在1b型丙型肝炎病毒R30Q变异株中，Y93H和R30Q突变的次要毒株与NS5A抑制剂治疗后病毒学失败有关。
AimsThe therapeutic efficacy of daclatasvir/asunaprevir was inferior in patients with non‐structural protein 5A (NS5A)‐R30Q mutant hepatitis C virus strains at baseline, compared with those with wild‐type strains, even though the half maximal effective concentration of NS5A inhibitors was lower in mutant strains than in wild‐type strains. In these patients, R30Q and Y93H mutant strains, which are highly resistant to NS5A inhibitors, emerged at virologic failure. The mechanisms involved in such virologic failure were examined.MethodsThe NS5A resistance‐associated variants were evaluated using direct sequencing in 88 patients with virologic failure after daclatasvir/asunaprevir therapy. In patients with R30Q and Y93H mutant strains at virologic failure, the original strains responsible for the multiple mutations were evaluated using baseline sera samples.ResultsL28 M and/or R30Q, L31 M, and Y93H mutant strains were found in 36, 46, and 65 patients, respectively, and R30Q and Y93H mutants were seen in 23 patients. R30Q mutant strains were detected in baseline sera samples available from eight of these patients; cycling‐probe real‐time polymerase chain reaction showed that the Y93H mutant strain to total strain ratio was less than 1% in four patients and ranged from 1% to 98% in four patients. A phylogenetic tree analysis undertaken after deep sequencing revealed that the R30Q and Y93H mutant strains originated from minor strains with both mutations at baseline, even in patients with a ratio of less than 1%.ConclusionIn patients with genotype 1b hepatitis C virus strains with R30Q mutation, minor strains with Y93H as well as R30Q mutations contributed to the development of virologic failure after treatment with NS5A inhibitors.