Global Immunological Response to Effective Antiretroviral Therapy (GiREAT:CD4)

描述(由申请人提供)：最初显示，随着有效的抗逆转录病毒疗法(ART)的开始，CD4细胞计数急剧增加。这一最初的增长之后是一个减弱的增长速度。然而，关于CD4水平如何对ART做出反应，仍有许多问题。通过检查自治疗开始以来的时间中值的CD4细胞计数、线性混合模型或广义线性模型来分析对抗逆转录病毒治疗的CD4反应。这些方法在研究样本中提供了一般的CD4反应模式。然而，在发起抗逆转录病毒治疗的人群中，个体反应中的其他模式、更复杂的模式很可能存在。我们假设，个体的反应模式可能聚集在几种不同的反应模式类型中，如有效应答者(在正常的CD4水平时，CD4迅速增加)，无效应答者(CD4缓慢增加，平台低于正常水平)，无应答者(CD4稳定或非常缓慢地增加)，间歇性应答者(有反应但随后减少的个体)，以及其他潜在的反应模式。此外，在开始有效治疗后，CD4水平是处于正常水平还是低于正常水平的问题仍未得到回答。这些知识上的差距阻碍了对成功免疫反应的定义的制定，因为目前的艾滋病毒指南只给出了广泛的指导。这些指南指出，治疗的目标是恢复和保护免疫功能，但没有概述实现可获得的CD4计数的具体目标。因此，全球免疫应对有效抗逆转录病毒疗法的目标是：1)确定抗逆转录病毒治疗的典型CD4应答模式，并确定这些模式的潜在预测因子，包括一个基于网络的工具，用于预测未来的CD4应答；2)开发类似于儿童生长发育图表的CD4应答图表，作为提供者的工具，并确定CD4增加的衰减率和CD4平台水平；3)确定CD4应答模式和个人应答与所有原因和特定原因死亡率的关联。将在全球7个地区检查这些CD4对抗逆转录病毒治疗反应的差异，以确定是否存在地区差异的反应。GiREAT：CD4将被嵌套在国际艾滋病流行病学数据库(IeDEA)中，IeDEA是由国家过敏和传染病研究所建立的七个地区中心组成的国际研究联盟。GIREAT：CD4采用了一种创新的新方法来研究CD4水平如何响应ART启动的问题。这将通过使用新的分析方法以及开发新的统计方法来实现。通过GiREAT收集的信息：CD4将定义对抗逆转录病毒治疗的成功免疫反应，从而改善艾滋病毒感染者的临床护理。

DESCRIPTION (provided by applicant): CD4 cell counts have been shown to initially increase sharply in response to the initiation of effective antiretroviral therapy (ART). This initial increse is then followed by an attenuated rate of increase. However, many questions remain regarding how CD4 levels respond to ART. CD4 response to ART has been analyzed by examining the median CD4 cell count over time since the initiation of treatment, linear mixed models, or generalized linear models. These approaches provide the general CD4 response pattern in the study sample. Yet other patterns, more complex patterns in individual response are likely to be present within a population initiating ART. We hypothesize that an individual's response pattern may cluster within several distinct response pattern types such as effective responders (quickly increase in CD4 which plateaus at normal CD4 levels), ineffective responders (slowly increase in CD4 and plateaus below normal), non-responders (CD4 is stable or very slowly increases), intermittent responders (individuals who respond but then decrease), as well as other potential response patterns. Additionally, the question of whether CD4 levels after the initiation of effective treatment plateau at normal or below normal levels remains unanswered. These gaps in knowledge hinder the development of a definition of successful immune response as current HIV guidelines only give broad guidance. These guidelines state that the goal of treatment is to restore and preserve immunologic function but do not outline a specific objective in terms of achieving an obtainable CD4 count. Therefore the goal of the Global immunological Response to Effective Antiretroviral Therapy: CD4 (GiREAT:CD4) is to 1) identify typical CD4 patterns of response to ART and identify potential predictors of these patterns including a web-based tool for predicting future CD4 response; 2) Develop CD4 response charts which are analogous to children's growth charts as a tool for providers and identify the rate of attenuation of CD4 increase and the level of CD4 plateau; and 3) determine the association of CD4 response patterns and individual's response with all-cause and cause-specific mortality. These differences in CD4 response to ART will be examined across 7 global regions to determine if regional differences in response are present. GiREAT:CD4 will be nested within the International epidemiologic Database to Evaluate AIDS (IeDEA) an international research consortium of seven regional centers established by the National Institute of Allergy and Infectious Disease. GiREAT:CD4 takes an innovative fresh approach to examining the question of how CD4 levels respond to the initiation of ART. This will be achieved using novel analytical methods as well as through the development of new statistical methods. The information gleaned through GiREAT:CD4 will define a successful immune response to ART and thereby improve clinical care of HIV infected individuals.