Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3•4A protease inhibitors in treatment-naive subjects
Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3•4A protease inhibitors in treatment-naive subjects
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DOI：
10.1086/591141
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发表时间：
2008-09-15
影响因子：
6.4
通讯作者：
Kieffer, Tara L.
中科院分区：
文献类型：
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作者：
Bartels, Doug J.;Zhou, Yi;Kieffer, Tara L.
背景。尚未报道对丙型肝炎病毒（HCV）蛋白酶抑制剂产生耐药性的自然发生变异在初治患者中的患病率和临床意义。我们在此报告此类变异的流行情况及其对临床反应的影响。方法。在 570 名未接受治疗的受试者中进行了 NS3 中心点 4A 蛋白酶的群体序列分析。结果。大多数受试者（98%）携带野生型病毒。其余受试者具有显着比例（接近 100%）的以下变异：V36M，0.9%； R155K，0.7%； V170A，0.2%；和R109K，0.2%。 V36M、R109K 和 V170A 替换赋予复制子细胞中对蛋白酶抑制剂的低水平耐药性（类似于 7 倍）。 R155K 取代赋予特拉匹韦 (TVR) 和博普瑞韦低水平耐药性，并赋予 BILN 2061 和 ITMN-191 高水平耐药性（类似于 70 倍）。五名携带 V36M 或 R109K 变异的受试者接受 8 -24 周的 TVR 和聚乙二醇干扰素治疗 - 类似于 2a (P)，联合或不联合利巴韦林 (R)。其中 4 例获得了持续的病毒反应，1 例失访。在携带 R155K 变异的受试者中，TVR/PR 比单独的 PR 提供了更强的抗病毒活性；然而，抗病毒反应低于在野生型病毒受试者中观察到的反应。结论。在未接受过 HCV 治疗的患者中，高水平的天然存在的蛋白酶抑制剂抗性变体并不常见（每种<1%）。 TVR/PR 有效抑制 V36M 和 R109K 变体，并对 R155K 变体贡献部分抗病毒活性。随着新的 HCV 药物在临床试验中进行评估，监测基线变异对敏感性的影响非常重要。
Background. The prevalence and clinical implications of naturally occurring variants that are resistant to hepatitis C virus (HCV) protease inhibitors in treatment-naive patients has not been reported. We report here the prevalence of such variants and their effect on clinical response.Methods. Population sequence analysis of the NS3 center dot 4A protease was conducted in 570 treatment-naive subjects.Results. Most subjects (98%) had wild-type virus. The remaining subjects had the following variants present in significant proportions (similar to 100%): V36M, 0.9%; R155K, 0.7%; V170A, 0.2%; and R109K, 0.2%. The V36M, R109K, and V170A substitutions confer low-level resistance (similar to 7-fold) to protease inhibitors in replicon cells. The R155K substitution confers low-level resistance to telaprevir (TVR) and boceprevir and confers high-level resistance (similar to 70fold) to BILN 2061 and ITMN-191. Five subjects with the V36M or R109K variant were treated with 8 -24 weeks of TVR and peginterferon-similar to 2a (P) with or without ribavirin (R). Four achieved a sustained viral response, and 1 was lost to follow-up. In subjects with the R155K variant, TVR/ PR provided greater antiviral activity than PR alone; however, the antiviral response was lower than that observed in subjects with wild-type virus.Conclusion. High levels of naturally occurring protease inhibitor -resistant variants were uncommon (< 1% each) in HCV treatment -naive patients. TVR/ PR efficiently inhibited V36M and R109K variants and contributed partial antiviral activity against the R155K variant. As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity.