Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients
Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients
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DOI：
10.1002/hep.21781
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发表时间：
2007-09-01
期刊：
影响因子：
13.5
通讯作者：
Zeuzem, Stefan
中科院分区：
文献类型：
--
作者：
Kieffer, Tara L.;Sarrazin, Christoph;Zeuzem, Stefan
TELAPREVR(VX-950)是一种口服活性的、特定靶向的丙型肝炎病毒(丙型肝炎病毒)抗病毒疗法，已被证明能显著降低I型肝炎患者的血浆丙型肝炎病毒RNA。使用一种高灵敏度的测序分析来检测病毒变异的少数群体(>；=5%)，在体外鉴定出对替拉韦尔具有低水平(V36M/A、T54A或R155K/T)或高水平(A156V/T和36/155)耐药性的突变。我们报告了16名接受TELAPREVR或TELAPREVR+聚乙二醇化干扰素-α-2a(PEG干扰素-α-2a)治疗14天的患者对这些变异的详细动力学分析。在4名单独服用替拉维韦的病毒反弹患者中，在丙型肝炎病毒RNA最初急剧下降的过程中，检测到了R155K/T和A156V/T变异。在反弹阶段，R155K/T和A156V/T变异被V36(M/A)/R155(K/T)双突变所取代。在其余12名单独服用或联合服用泰瑞韦/聚乙二醇化干扰素-α-2a的患者中，部分患者检测到A156V/T变异，但所有患者的病毒水平都在继续下降。结论：这些研究表明，对替拉韦的最初抗病毒反应是由于野生型病毒的急剧减少，野生型病毒发现了先前存在的对替拉韦耐药的变异体。在单独服用telapvir的患者中，病毒反弹可能是因为选择了更适合的变种。然而，替拉维韦和聚乙二醇化干扰素-α-2a的结合抑制了野生型和抗药性变异体。在本研究中，每个在14天服药期后开始使用聚乙二醇化干扰素-α-2a和利巴韦林的患者在24周时都检测不到丙型肝炎病毒RNA水平，这表明耐药变异对聚乙二醇化干扰素-α-2a和利巴韦林敏感。
Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype I patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants ( >= 5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a (PEG-IFN-alpha-2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing telaprevir-resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG-IFN-alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN-alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN-alpha-2a and ribavirin.