Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin
Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin
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DOI：
10.1128/jcm.03633-14
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发表时间：
2015-07-01
影响因子：
9.4
通讯作者：
Morand, Patrice
中科院分区：
文献类型：
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作者：
Larrat, Sylvie;Vallet, Sophie;Morand, Patrice
治疗前存在的蛋白酶抑制剂（PI）耐药相关变异（RAVs）并不能预测首次治疗患者的三联治疗结果。然而，它们可能会影响效果较差的聚乙二醇化干扰素(pegIFN)-利巴韦林（RBV）骨干患者的预后。使用丙型肝炎病毒（HCV）群体序列分析，我们回顾性调查了IFN-RBV不良应答（即先前无效应答或在pegIFN-RBV导入阶段病毒载量下降< 1 log IU/ml的患者）的多中心队列中基线非结构性3 (NS3) RAVs的流行情况。研究了这些RAVs的存在对三联治疗结果的影响。在282例患者中，基线RAVs的患病率（95%置信区间）从5.7%（3.3%至9.0%）到22.0%（17.3%至27.3%）不等，具体取决于所使用的算法。在使特拉匹韦或博昔韦50%抑制浓度（IC50）发生3倍变化的突变中，T54S是最常见的突变（3.9%），其次是A156T、R155K（0.7%）、V36M和V55A（0.35%）。基因型1a患者的突变发生率（7.5 ~ 23.6%）高于基因型1b患者（3.3 ~ 19.8%）（P = 0.03）。没有其他社会人口学或病毒临床特征与RAVs的高患病率显著相关。未观察到基线RAVs对病毒载量的明显影响。在这个对IFN-RBV反应较差的队列中，没有发现与三联治疗的持续病毒学反应有关，无论用于检测突变的算法如何。基于交叉研究比较，基线RAVs在较差的IFN-RBV应答者中并不比未接受治疗的患者更频繁，即使在这些难以治疗的患者中，该研究也表明对治疗结果没有影响，因此反对在治疗前进行耐药性分析。
The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of < 1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a > 3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P = 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.