Exercice testing and training for HAART toxicity

描述（由申请人提供）：众所周知，用于HIV感染的高效抗逆转录病毒治疗（HAART）的一些药物对人类线粒体有潜在的不良影响，例如发生危及生命的乳酸酸中毒的报道。虽然这种情况很少见，但在HAART患者中发现轻度乳酸血症表明，较低程度的线粒体毒性比临床认识到的更为常见。事实上，药物诱导的氧化代谢缺陷被认为是HAART的多种毒性的原因。随着线粒体损伤的机制和对特定临床毒性的贡献得到更好的定义，氧化功能障碍的客观测量将变得越来越重要。因此，需要在临床人群中广泛适用的量化氧化功能的方法，用于旨在减少或逆转药物诱导的线粒体毒性的临床试验。虽然线粒体的形态学和生化评估涉及侵入性程序和高度专业化的技术，但从呼吸气体中测定的摄氧量（VO2）和二氧化碳输出率（VCO2）是氧化代谢的非侵入性测量。运动可以作为一种刺激压力，以可控的方式增加骨骼肌的代谢率，由此产生的VO2和VCO2的变化用于评估肌肉的氧化能力，以及氧化和非氧化过程对所施加工作的能量需求的相对贡献。因此，运动试验是在全身水平上评估线粒体功能和全身线粒体毒性的一种合乎逻辑的方法。此外，由于运动训练本身代表了与HAART相关的一些毒性的潜在干预，因此在这种情况下，有必要更好地了解运动训练的急性运动反应和慢性适应。该提议的假设是，haart相关的线粒体毒性可以通过反映运动应激过程中氧化代谢的呼吸气体交换测量来检测和量化。为了验证这一点，有两个具体的目的：1)证明运动测试在HIV感染患者的横截面中识别氧化功能异常的能力，并确定最能区分患有和不患有haart相关线粒体功能障碍的患者的测试变量。2)通过对运动训练干预前后患者的纵向评估，验证运动试验在监测HAART患者氧化功能变化方面的效用，并反映对治疗干预的重要细胞反应。

DESCRIPTION (provided by applicant): It is well recognized that some drugs used in highly active antiretroviral therapy (HAART) of HIV infection have potentially adverse effects on human mitochondria, as exemplified by reports of the occurrence of life-threatening lactic acidosis. Although this entity is rare, the finding of mild lactic acidemia among patients on HAART suggests that lesser degrees of mitochondrial toxicity are more common than clinically recognized. Indeed, drug-induced defects in oxidative metabolism have been postulated to contribute to diverse toxicities of HAART. As the mechanisms and contribution of mitochondrial impairment to specific clinical toxicities become better defined, objective measures of oxidative dysfunction will be increasingly important. Thus, broadly applicable means of quantifying oxidative function in clinical populations are needed for use in clinical trials directed at reducing or reversing drug-induced mitochondrial toxicity. While morphologic and biochemical assessments of mitochondria involve invasive procedures and highly specialized techniques, rates of oxygen uptake (VO2) and carbon dioxide output (VCO2) determined from respired gases are non-invasive measures of oxidative metabolism. Exercise can be used as a provocative stress to increase the metabolic rate of skeletal muscle in a controlled manner, and the resulting changes in VO2 and VCO2 used to assess muscle oxidative capacity, as well as the relative contributions of oxidative and non-oxidative processes to the energy requirements of the imposed work. Exercise testing is therefore a logical approach to assessing mitochondria function, and systemic mitochondrial toxicity, on a systemic level. In addition, because exercise training itself represents a potential intervention for some toxicities associated with HAART, there is a pragmatic need to better understand both acute exercise responses and chronic adaptations to exercise training in this setting. The hypothesis of this proposal is that HAART-associated mitochondrial toxicity may be detected and quantified by measures of respiratory gas exchange reflecting oxidative metabolism during an exercise stress. To test this there are two specific aims: 1) To demonstrate the ability of exercise testing to identify abnormalities in oxidative function in a cross-section of HIV infected patients, and identify test variables that best discriminate between patients with and without HAARTassociated mitochondrial dysfunction. 2) To validate the utility of exercise testing for monitoring changes in oxidative function in patients receiving HAART and to reflect important cellular responses to treatment interventions, using longitudinal assessments of patients before and after an exercise training intervention.