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首页> 外文期刊>Infection and Drug Resistance >Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse
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Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse

机译：丙型肝炎病毒对grazoprevir的耐​​药性表征揭示了治疗突破后突变的复杂模式，在复发时未观察到

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Purpose: A detailed analysis of hepatitis C virus (HCV) resistance-associated substitutions (RASs) is required to understand why people fail direct-acting antiviral therapies. This study was conducted to assess RASs in an analysis of 2 trials evaluating the second-generation NS3/4A protease inhibitor grazoprevir (GZR) in combination with peginterferon/ribavirin. Patients and methods: From a total of 113 participants with HCV genotype 1 infection, RASs were evaluated in 25 patients who relapsed and 6 patients with on-treatment virologic breakthrough using consensus Sanger and clonal sequence analysis of NS3/NS4a genes, with in vitro testing of replicon mutants. Next-generation sequencing (NGS) was used in a subset of participants to assess minority variants and the evolution of the whole viral genome. Results: Baseline RASs did not predict treatment failure. Relapse was most commonly associated with RASs at D168, although additional RASs (Y56, R155 and A156) were also detected, particularly in participants with on-treatment breakthrough. Treatment-emergent RASs usually reverted to wild-type (WT), suggesting these mutations were associated with a negative fitness cost (confirmed using in vitro assays). NGS was the most sensitive assay for the detection of minor variants. Significant viral sequence divergence (up to 5.9% codons) was observed across whole genomes in association with the acquisition and reversion of RASs. Conclusion: Relapse with GZR and peginterferon/ribavirin is commonly associated with single RASs in NS3 that generally revert to WT, while breakthrough follows more complex patterns of viral resistance. NGS suggests that large diverse pools of viral quasispecies that emerge with RASs facilitate rapid viral evolution.
机译：目的：需要详细分析丙型肝炎病毒（HCV）耐药性相关替代（RASs），以了解人们为何无法通过直接作用抗病毒疗法。这项研究是在对2项评估第二代NS3 / 4A蛋白酶抑制剂grazoprevir（GZR）与聚乙二醇干扰素/利巴韦林联用的试验的分析中评估RAS的。患者和方法：从总共113名HCV基因1型感染的参与者中，使用共有的Sanger和NS3 / NS4a基因的克隆序列分析并通过体外测试，评估了25例复发患者和6例治疗中病毒学突破的RASs复制子突变体。在参与者的子集中使用了下一代测序（NGS）来评估少数变异和整个病毒基因组的进化。结果：基线RAS不能预测治疗失败。复发最常与D168时的RAS相关，尽管也检测到了其他RAS（Y56，R155和A156），尤其是在治疗突破的参与者中。出现治疗的RAS通常会恢复为野生型（WT），这表明这些突变与负的适应性费用相关（已使用体外测定法确认）。 NGS是检测微小变异的最灵敏的检测方法。在整个基因组中观察到与RAS的获取和逆转相关的重要病毒序列差异（最高5.9％密码子）。结论：GZR和聚乙二醇干扰素/利巴韦林的复发通常与NS3中的单一RAS相关，后者通常恢复为WT，而突破则遵循更复杂的病毒抗性模式。 NGS建议，与RAS一起出现的大量多样的病毒准种库可促进病毒的快速进化。

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