Modelling how ribavirin improves interferon response rates in hepatitis C virus infection
Modelling how ribavirin improves interferon response rates in hepatitis C virus infection
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DOI：
10.1038/nature03153
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发表时间：
2004-12-16
期刊：
影响因子：
64.8
通讯作者：
Perelson, AS
中科院分区：
文献类型：
--
作者：
Dixit, NM;Layden-Almer, JE;Perelson, AS
目前全世界有近2亿人感染丙型肝炎病毒（HCV）(1)。聚乙二醇化干扰素和利巴韦林联合治疗是HCV感染的最新治疗方法，只有约50%的治疗患者产生长期反应（2-4）。没有有效的替代治疗存在无反应(5)。因此，人们正在继续做出重大努力，以最大限度地提高对联合治疗的反应（6,7）。然而，由于对利巴韦林作用于HCV8的机制了解不足，无法进行合理的治疗优化。单独使用利巴韦林可引起HCV病毒载量的短暂早期下降或不下降（9-12），但与干扰素联合使用可显著提高长期应答率（2-4,13-15）。在这里，我们提出了一个HCV动力学模型，根据越来越多的证据（16-21），我们假设利巴韦林以剂量依赖的方式降低了感染者的HCV传染性。该模型定量预测干扰素单药和联合治疗的长期应答率，拟合治疗患者HCV RNA下降的观察模式，调和利巴韦林对HCV RNA下降影响的矛盾观察，为利巴韦林作用于HCV的机制提供关键见解，并建立合理的治疗优化框架。
Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV)(1). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated(2-4). No effective alternative treatments exist for non-responders(5). Consequently, significant efforts are continuing to maximize response to combination therapy(6,7). However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV8. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load(9-12), but in combination with interferon it significantly improves long-term response rates(2-4,13-15). Here we present a model of HCV dynamics in which, on the basis of growing evidence(16-21), we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.