Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication
Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication
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DOI：
10.1128/aac.02239-12
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发表时间：
2013-03-01
影响因子：
4.9
通讯作者：
McPhee, Fiona
中科院分区：
文献类型：
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作者：
Friborg, Jacques;Levine, Steven;McPhee, Fiona
聚乙二醇化形式的人 lambda 1 干扰素（IFN-lambda 1；本文中也称为 lambda）的临床功效已在慢性感染代表基因型 1 至 4 的丙型肝炎病毒（HCV）的患者中得到证实。在这些概念验证研究中，与聚乙二醇化形式的 α 干扰素（本文中称为 alfa）相比，lambda 显示出改进的安全性。在本报告所述的研究中，对 III 型 IFN 对不同 HCV 复制子的体外抗病毒活性进行的评估表明，未聚乙二醇化重组形式的 IFN-lambda 1 (rIFN-lambda 1) 发挥了最强的作用，而 rIFN-lambda 3 表现出比 rIFN-lambda 2 更大的活性。更重要的是，在已知降低研究敏感性的复制子细胞系中未观察到对 rIFN-lambda 1 的交叉耐药性。针对 HCV 必需非结构蛋白 NS3、NS5A 或 NS5B 的直接作用抗病毒 (wDAA) 药物。当与 rIFN-α、NS3 蛋白酶抑制剂 (NS3 PI) asunaprevir (ASV)、NS5A 复制复合物抑制剂 (NS5A RCI) daclatasvir (DCV) 或 NS5B 聚合酶位点 I 抑制剂 (NS5B I) BMS-791325 联合使用时，rIFN-lambda 1 显示出相加和协同效应的混合。在三药组合研究中，将 lambda 与 ASV 和 DCV 一起使用也能产生叠加的协同效应。与这些观察结果一致，证明在代表野生型和 NS3 蛋白酶抑制剂抗性序列的基因型 1a 细胞系中，使用 rIFN-lambda 1 与一种或两种 DAA 组合的方案优于不含 IFN 的方案，以清除 HCV RNA。总体而言，这些数据支持 lambda 的进一步临床开发，作为慢性丙肝病毒感染患者与 DAA 替代联合治疗的一部分。
The clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-lambda 1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-ofconcept studies, lambda showed an improved safety profile compared to the pegylated form of alfa interferon (referred to herein as alfa). In the study described in this report, an assessment of the in vitro antiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-lambda 1 (rIFN-lambda 1) exerted the most robust effect, while rIFN-lambda 3 exhibited greater activity than rIFN-lambda 2. More importantly, cross-resistance to rIFN-lambda 1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (wDAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-alpha, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-lambda 1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-lambda 1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.