Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection
Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection
复制标题
DOI：
10.1073/pnas.1610197114
复制
发表时间：
2017-02-21
影响因子：
11.1
通讯作者：
Watashi, Koichi
中科院分区：
文献类型：
--
作者：
Koizumi, Yoshiki;Ohashi, Hirofumi;Watashi, Koichi
随着直接作用抗病毒药物(DAA)的引入，丙型肝炎病毒(丙型肝炎病毒)的治疗得到了显著改善。为了更好地管理和控制这种世界性传染病，需要以科学证据为基础的“最佳”多种药物治疗。然而，目前还没有一种方法可以系统地量化和比较药物组合的抗病毒效果和耐药性。基于细胞培养系统中实验的抗丙型肝炎病毒谱，我们量化了瞬时抑制潜力(IIP)，这是病毒复制事件减少的对数，对于单药和多药组合。通过计算来自不同类别的15种抗丙型肝炎病毒药物[替拉维韦、丹诺维韦、阿索那普韦、西美普韦、索索布韦(SOF)、VX-222、达沙布韦、恩斯布韦、替戈布韦、达拉他韦、来地巴韦、干扰素-α、干扰素-lambda 1、环孢素A和SCY-635]的IIP，我们发现核苷聚合酶抑制剂SOF具有最大的抑制病毒复制事件的潜力。我们还比较了一组药物组合的内在抗病毒活性。我们的定量分析清楚地表明，与双DAA治疗相比，三重DAA治疗具有优势，三重DAA治疗显示出更强的抗病毒活性，并且在临床相关药物浓度下出现耐药性的可能性显著降低。我们的框架提供了在昂贵的临床试验之前设计多药策略时要考虑的定量信息。
With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-alpha, IFN-lambda 1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.