Screening for atherosclerotic vascular disease in HIV-infected children

 描述(申请人提供)：在南非，贫困家庭中感染艾滋病毒的儿童通常负责父母照顾年幼的兄弟姐妹(通常没有感染)，因此他们经历的任何疾病事件都会产生深远的后果。与成人一样，尽管有足够的病毒抑制，但艾滋病毒相关慢性炎症导致的动脉粥样硬化是接受抗逆转录病毒治疗(ART)的儿童日益关注的问题。有效的生活方式、饮食和治疗干预措施是可用的，但除非在动脉粥样硬化的发病机制早期建立，否则疗效有限。无症状动脉粥样硬化风险增加的诊断需要在初级卫生诊所层面进行有效的全国性监测。这个纵向队列 对照研究旨在量化接受抗逆转录病毒治疗的艾滋病毒感染儿童的过度动脉粥样硬化风险，并生成和验证一种低技术筛查算法，以使用简单的输入变量来识别受影响的无症状个体，这些变量可以在初级保健随访期间常规收集。目的1通过ART研究病毒抑制的围产期感染儿童动脉粥样硬化性血管疾病(AVD)风险的大小和纵向演变。动脉-股动脉脉搏波速度(PWV)是一种测量动脉弹性的指标，可预测无症状成人发生的心血管事件，是亚临床动脉粥样硬化的可靠金标准标记物。我们将比较携带和不携带HIV的儿童在5年内PWV Z分数的纵向变化。这个主要队列中的PWV将根据收缩压、空腹血脂、血糖、体重指数、饮食和吸烟暴露进行调整。AIM 2将生成一种低技术、低成本、可扩展的诊断筛查算法，以在资源有限的情况下检测无症状的AVD风险增加(定义为异常升高的PWV)。我们将以PWV为金标准，比较各种预测成人心血管事件的候选筛查试验。将使用在主要队列中收集的衡量标准来开发算法。这些措施将在另外75名青春期前艾滋病毒感染儿童的验证队列中重复，这些儿童将在方案环境下接受国家一线抗逆转录病毒疗法，这些儿童将在第3年招募，并纵向跟踪到第5年，以验证该算法的敏感性和特异性。目的3将研究循环生物标记物是否与病毒抑制的儿童的PWV异常有关，并有助于识别增加的AVD风险。预期结果：一种简单的监测工具将能够利用广泛可用的设备和容易获得的技能，在全国范围内监测接受抗逆转录病毒治疗的艾滋病毒感染儿童中AVD风险的增加，从而实现由护士驱动、低成本、高效率的监测，从而促进在发病早期进行治疗干预。最终，早期干预将大大减轻这一高危人群成年后的整体AVD负担，保持他们照顾家庭成员和年幼兄弟姐妹需求的能力。

 DESCRIPTION (provided by applicant): In South Africa, HIV-infected children in poorer families are often responsible for the parental care of younger (often uninfected) siblings and so any disease events they experience have far-reaching consequences. As in adults, atherosclerosis due to HIV-related chronic inflammation despite adequate viral suppression is a growing concern for children on antiretroviral therapy (ART). Effective lifestyle, diet and therapeutic interventions are available but efficacy is limited unless instituted early in pathogenesis of atherosclerosis. Diagnosis of asymptomatic increased atherosclerosis risk requires effective nationwide surveillance at primary health clinic level. This longitudinal cohort control study intends to quantify excess atherosclerosis risk in HIV-infected children on ART and to generate and validate a low tech screening algorithm to identify affected asymptomatic individuals using simple input variables that can be routinely collected during primary healthcare follow-up. AIM 1 will investigate the magnitude and longitudinal evolution of atherosclerotic vascular disease (AVD) risk in virally-suppressed perinatally-infected children on ART. Aorto-femoral pulse wave velocity (PWV), a measure of arterial elasticity, predicts incident cardiovascular events in asymptomatic adults and is a reliable gold- standard marker of subclinical atherosclerosis. We will compare longitudinal change in PWV Z-score over 5 years in children with and without HIV. PWV in this Primary Cohort will be adjusted for systolic blood pressure, fasting lipids, glucose, BMI, diet and tobacco smoke exposure. AIM 2 will generate a low tech, low cost, scalable diagnostic screening algorithm to detect asymptomatic increased AVD risk (defined as abnormally raised PWV) in a resource limited setting. We will compare various candidate screening tests that are predictive of incident cardiovascular events in adults, with PWV as a gold standard. Measures collected in the Primary Cohort will be used to develop the algorithm. Measures will be repeated in a Validation Cohort of 75 additional pre-pubertal HIV-infected children receiving the national first- line ART regimen in a programmatic setting, who will be recruited in year 3 and followed longitudinally until year 5 to validate the sensitivit and specificity of the algorithm. AIM 3 will investigate whether the circulating biomarkers most strongly predictive of vascular disease in adults correlate with abnormal PWV in virally-suppressed children and are useful for identifying increased AVD risk. Expected outcomes: A simple surveillance tool will enable nurse-driven, low-cost, high-efficacy country-wide surveillance for increased AVD risk in HIV-infected children on ART using widely-available equipment and easily-obtainable skills, facilitating therapeutic intervention early in pathogenesis Ultimately, early intervention will substantially reduce overall AVD burden in adulthood in this high-risk population, preserving their ability to care for the needs of family members and younger siblings.