Metabolic Consequences of Thymidine Sparing Regimens

描述（由申请方提供）：脂肪萎缩是抗逆转录病毒（ARV）治疗的一种非常常见的并发症，与生活质量下降、抑制AVR治疗依从性以及可能增加冠状动脉疾病风险相关。我们的研究小组已经表明，脂肪萎缩患者的皮下脂肪组织存在线粒体DNA（mtDNA）缺失、细胞凋亡和全身氧化应激增加。已知胸苷类似物核苷逆转录酶抑制剂（NRTI）的使用与脂肪萎缩和线粒体毒性的高发生率相关。实验室研究表明，非胸苷类似物NRTI诱导mtDNA耗竭的风险较低;这使我们假设胸苷类似物保留方案对线粒体的影响极小或无影响，因此对脂肪细胞凋亡和脂肪含量的影响极小或无影响。由于目前尚无针对脂肪萎缩的治疗方法，因此通过使用“对脂肪细胞友好”的NRTI来预防这种并发症可能会防止大量发病。从机制上讲，我们认为主要由线粒体在氧化磷酸化过程中产生的活性氧（ROS）可能会损伤线粒体DNA和线粒体蛋白，因此可能导致脂肪萎缩的发病机制。 我们的长期目标是了解使用胸苷类似物保留抗逆转录病毒治疗方案的代谢后果。这将在一项为期2年的纵向研究中进行评估，该研究包括50名受试者，这些受试者作为成人艾滋病临床试验组试验#5202的一部分开始他们的第一个ARV方案，其中他们将被随机分配接受替诺福韦/FTC或阿巴卡韦/3 TC（与阿扎那韦/利托那韦或依法韦仑联合）。另一组25例患者将作为对照组;这些既往未接受过治疗的患者将入组一项设计相似的试验，在该试验中，他们将接受含胸苷类似物的ARV方案（ZDV或d4 T +3 TC），并将进行类似的评价。 皮下脂肪活检将获得所有75名患者治疗前，和治疗后两年。我们将评估线粒体DNA，线粒体功能，脂肪细胞凋亡和脂质和线粒体氧化损伤标志物。此外，我们将使用作为母ACTG研究一部分获得的临床/成像数据评价代谢参数。

DESCRIPTION (provided by applicant): Lipoatrophy is a highly prevalent complication of antiretroviral (ARV) therapy, associated with decreased quality of life, disincentive for adherence to AVR therapy, as well as possibly an increased risk of coronary artery disease. Our group has shown that subcutaneous adipose tissue from lipoatrophic patients have mitochondrial DNA (mtDNA) depletion, apoptosis, and increased oxidative stress systemically. It is known that the use of thymidine-analogue nucleoside reverse transcriptase inhibitors (NRTI) agents is associated with a high incidence of lipoatrophy and mitochondrial toxicity. Laboratory investigations have shown that non-thymidine analogue NRTIs carry a lower risk for inducing mtDNA depletion; this leads us to hypothesize that thymidine analogue sparing regimens will result in minimal or no effect on mitochondria and consequently minimal or no effect on fat apoptosis and fat content. Since there is no treatment for established lipoatrophy, prevention of this complication by the use of "mitochondrion-friendly" NRTIs may prevent substantial morbidity. Mechanistically, we believe that reactive oxygen species (ROS) produced principally by the mitochondria during oxidative phosphorylation, could damage mtDNA and mitochondrial proteins and as such could contribute to the pathogenesis of lipoatrophy. Our long-range goal is to understand the metabolic consequences of treatment using thymidine analogue sparing ARV regimens. This will be assessed in a 2 year longitudinal study of 50 subjects who are starting their first ARV regimen as part of the Adult AIDS Clinical Trials Group trial # 5202, in which they will be randomized to receive tenofovir/FTC or abacavir /3TC (in combination with either atazanavir/ritonavir or efavirenz). Another group of 25 patients will serve as the control group; these previously treatment-naive patients will enroll in a similarly designed trial in which they will receive thymidine analogue containing ARV regimens (ZDV or d4T + 3TC) and will have similar evaluations performed. Subcutaneous fat biopsies will be obtained from all 75 patients prior to, and after two years of therapy. We will assess mtDNA, mitochondrial function, fat apoptosis and lipid and mitochondrial oxidative damage markers. In addition, we will evaluate metabolic parameters using the clinical/imaging data obtained as part of the parent ACTG study.