HAART Associated Cardiotoxicity in HIV-Infected Children

描述（由申请人提供）：感染艾滋病毒的儿童经常接受高效抗逆转录病毒治疗（HAART），以减少艾滋病毒相关疾病。这种慢性治疗对儿童的长期影响和毒性尚不清楚，但在动物模型中表明存在严重的心脏毒性。本研究将使用nih赞助的WITS和P2C2 hiv感染儿童队列来确定左心室（LV）功能（特别是分数缩短和收缩性）和结构（特别是壁厚和质量）如何受到HAART暴露累积强度的影响。P2C2 hiv感染儿童队列接受不同强度的非haart治疗。然而，经过5年的随访，与未感染的儿童相比，该队列表现出持续且显著的左室收缩性下降。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。在WITS艾滋病毒感染的儿童队列中，大多数儿童在不同时间和不同方案强度下接受过HAART治疗。通过在WITS队列中使用与先前在P2C2队列中使用的相同超声心动图方案评估左室结构和功能，我们将能够确定HAART和非HAART治疗对左室结构和功能的增量影响。此外，HAART导致线粒体功能受损导致心肌病的假设将通过将定义心肌病的左室结构和功能参数与来自这些患者的细胞中线粒体DNA突变的频率进行比较来评估。这将通过线粒体突变的巢式病例对照研究来评估HAART、线粒体损伤与左室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分序数量表的累积评分来捕获。将在三个时间点测量强度：在子宫内；在生命的第一年；一岁之后。纵向超声心动图和线粒体数据的分析将提供有关剂量强度和HAART与低侵袭性药物方案的比较影响的有价值的信息，以及关于治疗在儿童发育不同阶段的影响。类似的病毒载量和HIV持续时间的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是否需要进行心血管随访、预防和治疗试验。

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.