Triphasic decline of hepatitis C virus RNA during antiviral therapy
Triphasic decline of hepatitis C virus RNA during antiviral therapy
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DOI：
10.1002/hep.21657
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发表时间：
2007-07-01
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：
Dahari, Harel;Ribeiro, Ruy M.;Perelson, Alan S.
当慢性感染丙型肝炎病毒(丙型肝炎病毒)的患者接受聚乙二醇化干扰素(干扰素)-α或干扰素-α加利巴韦林(RBV)抗病毒治疗时，丙型肝炎病毒RNA通常以双相方式下降。然而，据报道，在部分患者中出现了三相下降。三个阶段的下降包括病毒载量快速下降的第一阶段(1-2天)，随后是病毒载量缓慢衰退或保持不变的“肩期”(4-28天)，以及病毒再次衰退的第三阶段。我们表明，通过包括未感染细胞和感染细胞的增殖，病毒动力学模型可以解释三相的丙型肝炎病毒RNA衰变。该模型预测，只有在治疗前大多数肝细胞感染的患者中才会出现三相下降。肩期并不代表感染细胞的固有死亡率，而是当总体疗效接近1时，第三时相斜率接近感染细胞的固有死亡率。结论：三相反应是可以预测的。通过包含肝细胞的稳态增殖，对现有的病毒动力学模型进行了概括。这一普遍模型也可以解释平坦部分应答者的病毒动力学。最后，与单独使用干扰素-α相比，联合使用干扰素-α和RBV治疗的患者的第三相增强可以用RBV对丙型肝炎病毒的突变效应来解释。
When patients chronically infected with hepatitis C virus (HCV) are placed on antiviral therapy with pegylated interferon (IFN)-alpha or IFN-alpha plus ribavirin (RBV), HCV RNA generally declines in a biphasic manner. However, a triphasic decline has been reported in a subset of patients. A triphasic decline consists of a first phase (1-2 days) with rapid virus load decline, followed by a "shoulder phase" (4-28 days) in which virus load decays slowly or remains constant, and a third phase of renewed viral decay. We show that by including the proliferation of both uninfected and infected cells, a viral kinetic model can account for a triphasic HCV RNA decay. The model predicts that a triphasic decline occurs only in patients in which a majority of hepatocytes are infected before therapy. The shoulder phase does not represent the intrinsic death rate of infected cells, but rather the third phase slope is close to the intrinsic death rate of infected cells when overall drug efficacy is close to 1. Conclusion: Triphasic responses can be predicted. from a generalization of existent viral kinetic models through the inclusion of homeostatic proliferation of hepatocytes. This generalized model can also explain the viral kinetics seen in flat partial responders. Finally, the enhanced third phase in patients treated with IFN-alpha in combination with RBV versus patients treated with IFN-alpha alone can be explained by a mutagenic effect of RBV against HCV.