Methods for Long-Term Follow-Up of HIV-Infected Patients

HIV 感染者的长期随访方法

• 批准号: 6947623
• 负责人: VICTOR GERARD DEGRUTTOLA
• 金额: $ 32.8万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947623
• 关键词: HIV infections; antiAIDS agent; antiviral agents; clinical research; data collection methodology /evaluation; drug classification; drug interactions; drug resistance; genotype; human data; indinavir; longitudinal human study; method development; nelfinavir; pharmacogenetics; statistics /biometry; virus genetics; virus load

DESCRIPTION (provided by applicant): The goal of this grant application is development of methods for understanding the consequences of antiretroviral treatment for the development of antiviral resistance. The development of resistance results from the acquisition of mutations over time-a process that both reflects and contributes to amount of replicating virus and perhaps also the fitness of virus. We intend to model these process jointly to study the complex co-evolution of viral genotype and such longitudinal measures as viral load or fitness, and CD4 count. Specifically our aims are: 1) Inclusion of time-varying covariates in hidden Markov models of viral genetic progression to examine the impact of viral diversity, viral load, and other factors on pathways to antiviral resistance. 2) Joint modeling of genetic pathways to resistance (using hidden Markov models) and time to virological failure, in settings where the genetic state is know with error. 3) Semiparametric methods for relating viral genotype to phenotype and to investigate the impact of specific mutations in the presence of others. 4) U-statistic approaches for two group comparisons of repeated measures of viral load, when times of measurement are arbitrary. 5) Assessing surrogacy of high-dimensional longitudinal markers subject to measurement error and missingness. Aim 1) investigates how factors like viral load, treatment, adherence history or other time-varying factors influence the pathways to resistance taken by the virus. Aim 2) investigates the influence of genetic pathway on the time course of longitudinal measures, like viral load or fitness. Aim 3) extends the methods developed in the last grant period to relate genotype to any response variable. The new methods are semi parametric; they should be more robust to nonnormality of errors and more powerful than the previous methods. Aim 4) arose from consideration of the problems raised in an AIEDRP concept sheet to investigate the impact of primary resistance mutations on the virological response to treatment. Aim 5) investigates the degree to which information on short-term response of viral load and on acquisition of resistance mutations can serve as surrogates for longer term clinical outcomes.

描述（由申请人提供）：本授予申请的目标是开发理解抗逆转录病毒治疗对抗病毒抗性发展的后果的方法。抗药性的发展是由于突变逐渐逐步的过程 - 反映并有助于复制病毒的数量以及病毒的适应性。我们打算共同对这些过程进行建模，以研究病毒基因型的复杂共同进化以及病毒载荷或适应性等纵向测量以及CD4计数。具体来说，我们的目的是：1）将随时间变化的协变量包括在病毒遗传进展的隐藏的马尔可夫模型中，以检查病毒多样性，病毒载量和其他因素对抗病毒抗性途径的影响。 2）在遗传状态误认为遗传状态的情况下，遗传途径的遗传途径（使用隐藏的马尔可夫模型）和病毒学故障的时间。 3）将病毒基因型与表型联系起来的半参数方法，并研究其他人存在特定突变的影响。 4）当测量时间是任意的时，用于重复测量病毒载荷的两组比较的U统计方法。 5）评估受测量误差和缺失的高维纵向标记的替代性。 目标1）研究病毒载量，治疗，依从性史或其他随时间变化的因素如何影响病毒采取的抵抗力的途径。目标2）研究遗传途径对纵向测量的时间过程的影响，例如病毒载荷或适应性。 AIM 3）扩展了在最后一个赠款期间开发的方法将基因型与任何响应变量联系起来。新方法是半参数；与以前的方法相比，它们应该对错误的不正常和更强大的功能更强大。目标4）源于在AIEDRP概念表中提出的问题，以研究原发性抗性突变对病毒学反应对治疗的影响。目标5）研究病毒载荷短期反应和抗药性突变的短期反应的信息可以作为长期临床结果的替代物。