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Statistical Methods for Long-Term HIV Dynamic Modeling and Design

长期 HIV 动态建模和设计的统计方法

基本信息

批准号：
7842639
负责人：
YANGXIN HUANG
金额：
$ 7.27万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842639
关键词：
AIDS/HIV problem Accounting Acquired Immunodeficiency Syndrome Address Adherence Agreement Anti-Retroviral Agents Antiviral Agents Antiviral Response Blood CD4 Positive T Lymphocytes Cell Count Cell model Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Data Development Disease Progression Dose Drug Combinations Drug Kinetics Drug resistance Effectiveness Epidemic Equation Evaluation Frequencies Goals HIV HIV therapy Highly Active Antiretroviral Therapy Immunologic Markers Immunologics Individual Lead Longitudinal Studies Measurement Mediating Methodology Methods Modeling Monitor Outcome Outcome Measure Pathogenesis Patients Pharmaceutical Preparations Pharmacodynamics Phase Plasma Play Predisposition Protocols documentation Public Health Quantitative Evaluations RNA Research Resistance Risk Role Selection for Treatments Solutions Statistical Methods Statistical Models Study models System T-Lymphocyte Testing Time Tissues Treatment Factor Treatment Protocols Variant Viral Viral Load result Virus antiretroviral therapy base clinical practice design drug efficacy effective therapy flexibility innovation mathematical model meetings model design public health relevance response simulation tool treatment duration treatment effect treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The study of viral dynamics is one of the most important developments in recent HIV/AIDS research for understanding HIV pathogenesis and antiretroviral (ARV) therapies. However, most studies focused on short-term viral dynamics, and the models therein may not be applicable to long-term dynamics. Physiologically-based mathematical models and statistical methods play a critical role in AIDS research. Establishing the relationship of virologic responses (VR) to antiretroviral (ARV) therapy during long-term treatment is critical to the development of effective treatments. This is a challenging task because a practical model must incorporate multiple treatment factors including, but not limited to, drug concentration, drug adherence, drug susceptibility. Viral dynamics may be modeled through differential equations, but there has been only limited development in statistical methodologies for estimating and evaluating such differential equation models. The goals of this project are to develop viral dynamic models via systems of differential equations with time-varying coefficients but without a closed-form solution, and to apply them for characterizing long-term viral dynamics. Aim 1 of this proposal is to (a) study models for long-term HIV/T-cell dynamics and virologic/immunologic responses under ARV therapies, incorporating time-varying drug efficacy, pharmacokinetics, drug adherence and drug resistance; (b) develop flexible methods for fitting Bayesian nonlinear mixed-effects models which incorporate between-patient variations in dynamics; the basic principle of these methodologies were well established, but the applications of methods are nonetheless innovative within the context of a system of nonlinear differential equations of time-varying coefficient, but without a closed-form solution. Aim 2 is to apply the models and methods developed to AIDS clinical trials and to evaluate the models through simulations. It will focus on (a) validating the models and methods; (b) exploring pharmacodynamic relationships between VR and drug concentrations characterized by pharmacokinetic parameters in conjunction with other confounding factors such as drug adherence and resistance, and identifying clinical factors that are critical determinants of VR; (c) evaluating protocol designs used in AIDS clinical trials for their effectiveness in generating desired responses, therefore guiding the selection of ARV therapies with respect to level of dosing, number of subjects, timing and frequency of outcome monitoring. The proposed research will cast new lights on HIV dynamics in terms of the roles of clinical factors in mediating the long-term effectiveness of ARV therapies, hence a better understanding of HIV pathogenesis and long-term virologic responses, and will potentially lead to significant progress in understanding quantitative evaluation of clinical trial designs in response to existing therapies. Although this proposal will concentrate on HIV dynamics, the basic concept of longitudinal dynamic systems and the proposed methodologies in this project are generally applicable to dynamic systems in other fields such as PK/PD studies, biomedicine and public health as long as they meet the relevant technical specification-a set of differential equations. PUBLIC HEALTH RELEVANCE: The AIDS epidemic remains a grave public health threat world-wide. HIV dynamic studies have contributed significantly to the understanding of HIV pathogenesis and antiviral treatment strategies for AIDS patients. The overall goal of this project is to develop long-term HIV dynamic models and associated statistical methods for identifying clinical factors that are critical determinants of virological responses and for providing quantitative guidance to select and design antiretroviral treatments with respect to level of dosing, number of subjects, timing and frequency of outcome monitoring.

描述（由申请人提供）：病毒动力学研究是最近HIV/AIDS研究中最重要的进展之一，用于了解HIV发病机制和抗逆转录病毒（ARV）治疗。然而，大多数研究集中在短期的病毒动力学，其中的模型可能不适用于长期的动态。基于生理学的数学模型和统计方法在艾滋病研究中发挥着关键作用。建立长期治疗期间病毒学应答（VR）与抗逆转录病毒（ARV）治疗的关系对于开发有效的治疗方法至关重要。这是一项具有挑战性的任务，因为实际模型必须包含多个治疗因素，包括但不限于药物浓度、药物依从性、药物敏感性。病毒动力学可以通过微分方程建模，但在用于估计和评估这种微分方程模型的统计方法学方面只有有限的发展。该项目的目标是通过具有时变系数但没有封闭形式解的微分方程系统开发病毒动态模型，并将其应用于表征长期病毒动态。本建议的目标1是（a）研究抗逆转录病毒疗法下长期艾滋病毒/T细胞动态和病毒学/免疫学反应的模型，包括随时间变化的药物效力、药物动力学、药物依从性和抗药性;（B）开发灵活的方法，用于拟合贝叶斯非线性混合效应模型，其中包括患者之间动态的变化;这些方法的基本原理已经很好地确立，但是这些方法的应用在时变系数的非线性微分方程系统的范围内仍然是创新的，但是没有封闭形式的解。目的2是将所建立的模型和方法应用于艾滋病临床试验，并通过仿真对模型进行评价。其重点是（a）验证模型和方法;（B）探索VR与药物浓度之间的药效学关系，其特征是药代动力学参数以及其他混杂因素，如药物依从性和耐药性，并确定作为VR关键决定因素的临床因素;（c）评估艾滋病临床试验中使用的方案设计在产生所需反应方面的有效性，因此，在剂量水平、受试者人数、时间和结果监测频率方面指导抗逆转录病毒治疗的选择。拟议的研究将在临床因素在介导抗逆转录病毒疗法的长期有效性方面的作用方面对艾滋病毒动力学产生新的影响，从而更好地了解艾滋病毒发病机制和长期病毒学反应，并可能导致在了解现有疗法的临床试验设计的定量评估方面取得重大进展。虽然本提案将集中于HIV动力学，但本项目中纵向动力系统的基本概念和提出的方法通常适用于其他领域的动力学系统，如PK/PD研究，生物医学和公共卫生，只要它们满足相关的技术规范-一组微分方程。公共卫生相关性：艾滋病流行仍然是全球范围内严重的公共卫生威胁。HIV动态研究对了解HIV的发病机制和艾滋病患者的抗病毒治疗策略有重要意义。该项目的总体目标是开发长期的艾滋病毒动态模型和相关的统计方法，以确定作为病毒学应答关键决定因素的临床因素，并为选择和设计抗逆转录病毒治疗提供定量指导，包括剂量水平、受试者人数、时间和结果监测频率。