Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM.
Hepatology. 2011 Jun;53(6):1801-8. doi: 10.1002/hep.24272. Epub 2011 May 2.
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.
丙型肝炎病毒 (HCV) 在抗病毒治疗过程中的 RNA 衰减表现为快速的第一阶段，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衰减的幅度归因于治疗效果，而第二阶段衰减归因于感染细胞的逐渐丧失。在这里，我们分析了 44 名接受替拉瑞韦治疗的患者的数据。使用一种考虑替拉瑞韦药代动力学的病毒动力学模型，我们发现病毒下降的第二阶段斜率与治疗效果密切相关，并且比基于干扰素的治疗方法报告的速度快约四倍。由于替拉瑞韦不被认为会增加感染细胞的死亡率，我们的结果表明，病毒下降的第二阶段斜率不仅受到感染细胞死亡的驱动，还可能涉及其他机制，例如与治疗效果相关的细胞内病毒 RNA 降解。由于替拉瑞韦的高抗病毒效果导致病毒衰减增强，我们预测，如果通过适当的抗病毒药物组合避免耐药性，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%的完全依从性患者中，最后一个病毒颗粒将在治疗的第 7 周被清除。如果剩余的感染肝细胞作为感染复发的潜在储库，那么在 95%的完全依从性患者中，只需不到 10 周的治疗即可清除感染。然而，如果患者漏服药物，治疗时间将需要延长。
