Metabolic Consequences of Thymidine Sparing Regimens

胸苷保留方案的代谢后果

• 批准号: 7167149
• 负责人: GRACE A MCCOMSEY
• 金额: $ 21.23万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167149
• 关键词: 8-Oxo-2' -Deoxyguanosine; AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adherence; Adipocytes; Adipose tissue; Adult; Adverse event; Affect; Affinity; Anti-Retroviral Agents; Apoptosis; Atazanavir; Biological Assay; Biological Markers; Biopsy; Blinded; Body Composition; Body fat; Characteristics; Chronic Disease; Clinical; Clinical Trials; Complication; Consequences of HIV; Control Groups; Controlled Clinical Trials; Coronary Arteriosclerosis; Cultured Cells; DNA Fragmentation; DNA Nucleotidylexotransferase; DNA biosynthesis; DNA chemical synthesis; DNA-Directed DNA Polymerase; Data; Digoxigenin; Disincentive; Distress; Dual-Energy X-Ray Absorptiometry; Electron Transport; Elevation; End Point; Enrollment; Evaluation; F2-Isoprostanes; Fatty acid glycerol esters; Funding; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Image; Immunohistochemistry; Incidence; Investigation; Label; Laboratories; Laboratory Study; Lamivudine; Lead; Leg; Limb structure; Lipids; Lipoatrophy; Long-Term Effects; Longitudinal Studies; Measurement; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Morbidity - disease rate; Nucleosides; Oxidative Phosphorylation; Oxidative Stress; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Physicians; Ploidies; Polymerase Chain Reaction; Prevention; Quality of life; Randomized; Range; Reactive Oxygen Species; Recommendation; Research Personnel; Resources; Reverse Transcriptase Inhibitors; Risk; Ritonavir; Role; Safety; Scanning; Site; Stavudine; Tenofovir; Testing; Thymidine; Time; Toxic effect; Treatment Protocols; United States National Institutes of Health; Update; Upper arm; Vertebral column; Week; Work; Zidovudine; abacavir; analog; antiretroviral therapy; design; efavirenz; emtricitabine; indexing; mitochondrial dysfunction; nucleoside analog; prevent; prospective; subcutaneous

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.

描述（由申请人提供）：脂肪萎缩是抗逆转录病毒 (ARV) 治疗的一种非常普遍的并发症，与生活质量下降、不利于坚持 AVR 治疗以及可能增加冠状动脉疾病的风险有关。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) 耗尽、细胞凋亡和全身氧化应激增加的情况。众所周知，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有关。实验室研究表明，非胸苷类似物 NRTI 引起 mtDNA 耗竭的风险较低；这使我们推测胸苷类似物保留方案将对线粒体影响最小或没有影响，因此对脂肪细胞凋亡和脂肪含量影响最小或没有影响。由于目前尚无针对已确定的脂肪萎缩症的治疗方法，因此通过使用“线粒体友好型”NRTI 来预防这种并发症可能会大大降低发病率。从机制上讲，我们认为活性氧（ROS）主要由线粒体在氧化磷酸化过程中产生，可能会损害线粒体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疗法的代谢后果。这将在一项为期 2 年的纵向研究中进行评估，该研究纳入了 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 的一部分开始其第一个 ARV 治疗方案，其中他们将被随机分配接受替诺福韦/FTC 或阿巴卡韦/3TC（在与阿扎那韦/利托那韦或依非韦伦联合）。另一组25名患者作为对照组；这些先前未接受过治疗的患者将参加一项类似设计的试验，其中他们将接受含有 ARV 方案（ZDV 或 d4T + 3TC）的胸苷类似物，并将进行类似的评估。 将对所有 75 名患者在治疗前和治疗两年后进行皮下脂肪活检。我们将评估 mtDNA、线粒体功能、脂肪细胞凋亡以及脂质和线粒体氧化损伤标记物。此外，我们将使用作为父 ACTG 研究的一部分获得的临床/影像数据来评估代谢参数。