Modeling HIV dynamics and antiviral response with consideration of time-varying drug exposures, adherence and phenotypic sensitivity
Modeling HIV dynamics and antiviral response with consideration of time-varying drug exposures, adherence and phenotypic sensitivity
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DOI：
10.1016/s0025-5564(03)00058-0
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发表时间：
2003-08-01
影响因子：
4.3
通讯作者：
Wu, HL
中科院分区：
文献类型：
--
作者：
Huang, YX;Rosenkranz, SL;Wu, HL
由逆转录酶抑制剂药物和蛋白酶抑制剂药物组成的高活性抗逆转录病毒疗法，可以迅速将HIV抑制在检测限以下，是目前治疗HIV感染者最有效的治疗方法。尽管如此，许多患者未能实现病毒抑制，可能是由于现有或正在发展的耐药性、依从性差、药代动力学问题和其他临床因素。在本文中，我们开发了一种病毒动态模型来评估随时间变化的药物暴露和药物敏感性如何影响抗病毒反应。反过来，血浆浓度使用标准药代动力学 (PK) 单室开放模型进行建模，其中一级吸收和消除是固定个体 PK 参数和剂量时间的函数。在 PK 模型中，不完美的依从性被认为是漏服剂量。我们讨论了病毒动态模型的分析特性，并研究了随时间变化的治疗效果如何影响抗病毒反应，特别是病毒载量和 T 细胞计数。研究了实际失效时间（病毒增长率从负值变为正值的时间）和可检测失效时间（病毒载量反弹至检测限以上的时间）之间的关系。我们发现近似线性关系可用于根据可检测的回弹失效时间来估计实际回弹失效时间。此外，还研究了坚持对抗病毒反应的影响。我们特别研究了不同的依从模式如何影响抗病毒反应。结果表明，较长的错过剂量序列会增加治疗失败的机会并加速失败。模拟实验旨在说明抗病毒反应与药代动力学、随时间变化的依从性和耐药性之间的关系。所提出的模型和方法可能在艾滋病临床试验模拟中有用。 (C) 2003 Elsevier Science Inc. 保留所有权利。
Highly active antiretroviral therapies consisting of reverse transcriptase inhibitor drugs and protease inhibitor drugs, which can rapidly suppress HIV below the limit of detection, are currently the most effective treatment for HIV infected patients. In spite of this, many patients fail to achieve viral suppression, probably due to existing or developing drug resistance, poor adherence, pharmacokinetic problems and other clinical factors. In this paper, we develop a viral dynamic model to evaluate how time-varying drug exposure and drug susceptibility affect antiviral response. Plasma concentrations, in turn, are modeled using a standard pharmacokinetic (PK) one-compartment open model with first order absorption and elimination as a function of fixed individual PK parameters and dose times. Imperfect adherence is considered as missed doses in PK models. We discuss the analytic properties of the viral dynamic model and study how time-varying treatment efficacies affect antiviral responses, specifically viral load and T cell counts. The relationship between actual failure time (the time at which the viral growth rate changes from negative to positive) and detectable failure time (the time at which viral load rebounds to above the limit of detection) is investigated. We find that an approximately linear relationship can be used to estimate the actual rebound failure time from the detectable rebound failure time. In addition, the effect of adherence on antiviral response is studied. In particular, we examine how different patterns of adherence affect antiviral response. Results suggest that longer sequences of missed doses increase the chance of treatment failure and accelerate the failure. Simulation experiments are presented to illustrate the relationship between antiviral response and pharmacokinetics, time-varying adherence and drug resistance. The proposed models and methods may be useful in AIDS clinical trial simulations. (C) 2003 Elsevier Science Inc. All rights reserved.