Exercice testing and training for HAART toxicity

描述(由申请人提供)：众所周知，艾滋病毒感染的高效抗逆转录病毒疗法(HAART)中使用的一些药物对人类线粒体有潜在的不良影响，如发生危及生命的乳酸酸中毒的报道。尽管这种情况很少见，但在接受HAART的患者中发现轻度乳酸酸血症表明，较轻程度的线粒体毒性比临床认识的更常见。事实上，药物引起的氧化代谢缺陷被认为是导致HAART不同毒性的原因。随着线粒体损伤对特定临床毒性的机制和贡献得到更好的确定，氧化功能障碍的客观测量将变得越来越重要。因此，在临床试验中需要广泛适用的量化临床人群氧化功能的方法，以减少或逆转药物诱导的线粒体毒性。虽然线粒体的形态和生化评估涉及侵入性程序和高度专业化的技术，但根据呼吸气体测定的氧摄取率(VO2)和二氧化碳输出量(VCO2)是氧化代谢的非侵入性测量。运动可以作为一种刺激应激，以控制的方式提高骨骼肌的代谢率，以及由此产生的用于评估肌肉氧化能力的VO2和VCO2的变化，以及氧化和非氧化过程对施加的工作的能量需求的相对贡献。因此，运动试验是在系统水平上评估线粒体功能和全身线粒体毒性的合乎逻辑的方法。此外，由于运动训练本身代表着对与HAART相关的某些毒性的潜在干预，因此有必要在这种情况下更好地了解急性运动反应和对运动训练的慢性适应。这一建议的假设是，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的测量来检测和量化。为了测试这一点，有两个具体的目标：1)证明运动测试在横断面HIV感染患者中识别氧化功能异常的能力，并确定最能区分HAART相关线粒体功能障碍患者和非HAART相关线粒体功能障碍患者的测试变量。2)利用对运动训练干预前后患者的纵向评估，验证运动测试在监测接受HAART治疗的患者的氧化功能变化方面的有效性，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.