Second-Phase Hepatitis C Virus RNA Decline During Telaprevir-Based Therapy Increases With Drug Effectiveness: Implications for Treatment Duration
Second-Phase Hepatitis C Virus RNA Decline During Telaprevir-Based Therapy Increases With Drug Effectiveness: Implications for Treatment Duration
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DOI：
10.1002/hep.24272
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发表时间：
2011-06-01
期刊：
影响因子：
13.5
通讯作者：
Perelson, Alan S.
中科院分区：
文献类型：
--
作者：
Guedj, Jeremie;Perelson, Alan S.
在抗病毒治疗期间，丙型肝炎病毒（HCV） RNA衰变的特点是第一阶段快速，随后是较慢的第二阶段。目前对病毒动力学的理解将第一阶段的衰退归因于治疗效果，而第二阶段的衰退归因于受感染细胞的逐渐丧失。在这里，我们分析了44例接受特拉匹韦治疗的患者的数据，特拉匹韦是一种有效的HCV蛋白酶抑制剂。使用一个病毒动力学模型来解释telaprevir的药代动力学，我们发现病毒下降的第二阶段斜率与治疗效果密切相关，并且比以干扰素为基础的治疗快大约四倍。由于目前还不知道telaprevir会增加感染细胞的死亡率，因此我们的研究结果表明，病毒衰退的第二阶段斜率不仅是由感染细胞的死亡驱动的，还可能涉及其他机制，例如细胞内病毒RNA的治疗效果依赖性降解。由于telaprevir的高抗病毒效果导致病毒衰减增强，我们预测，如果使用适当的抗病毒药物组合可以避免耐药，清除HCV所需的治疗时间可能会大大缩短。事实上，我们预测在95%的完全依从的患者中，最后一个病毒颗粒应该在治疗的第7周被清除。如果剩余的受感染肝细胞是感染复发的潜在储存库，95%的完全依从性患者不超过10周的治疗应足以清除感染。然而，如果患者错过剂量，则需要延长治疗时间。(肝脏病学53:1801 2011;1808)
Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second-phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second-phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment-effectiveness-dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011;53:1801-1808)