Global HIV Drug Therapies and Mitochondrial Complications and Mechanisms

描述（由申请人提供）：由于线粒体（mt）功能障碍引起的脂肪萎缩和其他毒性是核苷类逆转录酶抑制剂（NRTIs）的常见并发症。因为高甘油三酯血症和胰岛素抵抗也经常与脂肪萎缩有关；使用d4T或ZDV也可能增加接受这些药物治疗的患者的心血管风险。尽管这些nrti具有毒性，但它们是发展中国家广泛使用的抗逆转录病毒（ARV）方案的组成部分。即使在美国，ZDV和拉米夫定（3TC）继续被卫生和人类服务部列为首选的初始抗逆转录病毒治疗方案之一。因此，了解这些mt毒性发展的致病机制对于找到适当的方法来监测和预防或减少这些药物的并发症是很重要的。夏威夷大学与泰国红十字会艾滋病研究中心合作，打算在泰国曼谷开展一项纵向72周的前瞻性随机临床试验，评估短期使用d4T（24周）后使用ZDV （n=50）与连续使用ZDV + 3TC （n=50）或替诺福韦(TDF) +恩曲他滨（FTC） （n=50）的相对毒性，这些患者均与奈韦拉平（NVP）一起给予HIV+ na - ve患者。临床试验将主要由泰国公共卫生部资助，因为该试验对其国家抗逆转录病毒药物治疗政策非常重要。

DESCRIPTION (provided by applicant): Lipoatrophy and other toxicities due to mitochondrial (mt) dysfunction are common complications seen with the nucleoside reverse transcriptase inhibitors (NRTIs). As hypertriglyceridemia and insulin resistance are also frequently observed in association with lipoatrophy; the use of d4T or ZDV may also increase cardiovascular risk in patients treated with these medications. Despite their toxicities, these NRTIs are widely used components of antiretroviral (ARV) regimens used in developing countries. Even in the United States, ZDV together with lamivudine (3TC) continue to be listed as one of the preferred initial ARV regimens by the Department of Health and Human Services. Therefore, understanding the pathogenic mechanisms underlying the development of these mt toxicities are important to finding appropriate ways to monitor and prevent or minimize the complications of these medications. The University of Hawaii in collaboration with the Thai Red Cross AIDS Research Centre intends to launch a longitudinal 72 week prospective, randomized clinical trial in Bangkok, Thailand assessing the relative toxicities of short-term d4T (24 week) use followed by ZDV (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in 150 HIV+ na¿ve patients. The clinical trial will be predominantly funded by the Thai Ministry of Public Health as this trial is important to its national ARV treatment policies. We hypothesize that the mt toxicities of these medications are driven primarily by alterations in mitochondrial oxidative phosphorylation (OXPHOS) protein/enzyme activity levels, which in turn increase mitochondrial reactive oxygen stress and adipocytes and pre-adipocyte apoptosis, and that these forces are heavily dependent on the intracellular concentration of these drugs. We further hypothesize that levels of OXPHOS proteins/enzyme activities in fat, peripheral blood mononuclear cells (PBMCs) or buccal cells (cheek swabs) will correlate with a decrease in limb fat content as assessed by dual energy x-ray absorptiometry (DEXA). Should these hypotheses be verified, there would be significant human health relevance in the understanding of the pathogenesis of HIV fat loss. Additionally, PBMCs' or buccal cells' OXPHOS protein/enzyme activities may serve as tools to monitor subjects preemptively for the risk of mitochondrial induced limb fat loss. We intend to evaluate adipose tissue, PBMCs, and buccal cells at baseline, wk 24, and wk 72 for mitochondrial OXPHOS protein/enzyme activity using a novel immunological assay and by immunohistochemistry, mtDNA copies/ cells, mitochondrial specific oxidative damage (8-oxo-deoxyguanine), and apoptosis. Additionally, PBMCs intracellular concentrations of ZDV, d4T, 3TC, FTC, and TDF triphosphates will be assessed for exposure-response relationships with mitochondrial toxicity.