HAART Associated Cardiotoxicity in HIV-Infected Children

HIV 感染儿童的 HAART 相关心脏毒性

• 批准号: 6923698
• 负责人: STEVEN EDWARD LIPSHULTZ
• 金额: $ 39.93万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923698
• 关键词: AIDS; AIDS therapy; adolescence (12-20); antiviral agents; biomarker; cardiogenesis; cardiotoxin; cardiovascular disorder; cardiovascular disorder epidemiology; cardiovascular disorder risk; chemical structure function; child (0-11); clinical research; combination chemotherapy; disease /disorder etiology; drug adverse effect; echocardiography; gene mutation; heart ventricle; human data; human genetic material tag; human tissue; longitudinal human study; mitochondrial disease /disorder; patient oriented research

DESCRIPTION (Provided by Applicant): HIV-infected children are often given highly active anti-retroviral therapy (HAART) to reduce HIV-associated disease. The long-term effects and toxicities associated with this chronic therapy in children are not known, but severe cardiotoxicity has been suggested in animal models. This study will use the NIH-sponsored WITS and P2C2 HIV-infected pediatric cohorts to determine how left ventricular (LV) function (particularly fractional shortening and contractility) and structure (particularly wall thickness and mass), are affected by cumulative intensity of HAART exposure. The P2C2 HIV-infected pediatric cohort received non-HAART therapies in various intensities. Yet, this cohort has exhibited persistent and significant depression of LV contractility compared to uninfected children after 5 years of follow-up. These same echocardiographic measures have proven to be independently predictive of mortality. Most of the children in the WITS HIV-infected pediatric cohort have been exposed to HAART at varying times and at varying regimen intensities. By assessing LV structure and function with the same echocardiographic protocol in the WITS cohort as was used previously in the P2C2 cohort, we will be able to determine the incremental effects of HAART and non-HAART therapies on LV structure and function. In addition, the hypothesis that HAART results in impaired mitochondrial function resulting in cardiomyopathy will be assessed by comparison of the parameters of LV structure and function that define cardiomyopathy to the frequency of mitochondrial DNA mutations in cells from these same patients. This will be done through a nested-case-control study of mitochondrial mutations to assess the relationship between HAART, mitochondrial compromise and LV structure and function. Treatment intensity for both HAART and non-HAART regimens will be captured through a cumulative score based on an existing 8-point ordinal scale. Intensity will be measured at 3 points in time: in utero; during the first year of life; and after the first year of life. Analysis of the longitudinal echocardiographic and mitochondrial data will provide valuable information about dose intensity and the comparative impact of HAART versus less aggressive drug regimens, and about the impact of therapy during different stages of child development. Similar longitudinal data on viral load and duration of HIV will enable us to control for the effects of HIV infection on cardiovascular toxicity. The findings will help determine the need for cardiovascular follow-up, prevention and therapeutic trials.

描述（由申请人提供）：HIV感染儿童通常接受高效抗逆转录病毒治疗（HAART）以减少HIV相关疾病。这种慢性疗法在儿童中的长期影响和毒性尚不清楚，但在动物模型中已提出严重的心脏毒性。本研究将使用NIH申办的WITS和P2 C2 HIV感染儿童队列，以确定HAART暴露的累积强度如何影响左心室（LV）功能（特别是缩短分数和收缩性）和结构（特别是壁厚度和质量）。P2 C2 HIV感染儿童队列接受了不同强度的非HAART治疗。然而，在5年随访后，与未感染儿童相比，该队列显示出持续和显著的LV收缩性抑制。这些相同的超声心动图测量已被证明是死亡率的独立预测。WITS HIV感染儿科队列中的大多数儿童在不同的时间和不同的方案强度下暴露于HAART。通过在WITS队列中使用与先前在P2 C2队列中使用的相同超声心动图方案评估LV结构和功能，我们将能够确定HAART和非HAART治疗对LV结构和功能的增量效应。此外，HAART导致线粒体功能受损从而导致心肌病的假设将通过比较定义心肌病的LV结构和功能参数与来自这些相同患者的细胞中线粒体DNA突变频率来评估。这将通过线粒体突变的巢式病例对照研究来完成，以评估HAART、线粒体受损与LV结构和功能之间的关系。HAART和非HAART方案的治疗强度将通过基于现有8分顺序量表的累积评分来获取。将在3个时间点测量强度：子宫内;出生后第一年;出生后第一年。纵向超声心动图和线粒体数据的分析将提供有价值的信息，剂量强度和HAART与侵略性较小的药物方案的比较影响，以及在儿童发育的不同阶段治疗的影响。关于病毒载量和HIV持续时间的类似纵向数据将使我们能够控制HIV感染对心血管毒性的影响。这些发现将有助于确定心血管随访、预防和治疗试验的需求。