Risk Factors for the Development of Lactic Acidosis and Pancreatitis Among HAART-

描述(由申请人提供)：申请人的长期目标是在非洲范围内独立进行与成人艾滋病毒护理和治疗有关的临床试验，特别是关于HAART的耐受性和毒性。核苷类似物逆转录酶抑制剂(NRTI)是治疗HIV-1感染成人的有效抗逆转录病毒疗法，在资源匮乏的情况下，它们可能仍然是ART方案的关键组成部分。然而，它们抑制人类线粒体聚合酶-伽马的能力与几种长期的线粒体毒性有关；这些毒性包括乳酸酸中毒、胰腺炎、周围神经病和周围脂肪损耗/萎缩。一些研究为某些基因/遗传途径在调节这种毒性中的作用提供了初步证据。博茨瓦纳和南非的初步经验表明，线粒体毒性(特别是乳酸酸中毒)的比率似乎高于其他地方报告的比率。这些线粒体毒性的风险似乎与：(I)性别(主要见于女性)，(Ii)体重(主要见于超重/肥胖者)，以及(Iii)他们所接受的特定NRTI或NRTI组合。与这种明显增加的风险相关的特定流行病学、临床和遗传风险因素尚不清楚，因此我们提出以下具体目标：1.在现有的HAART治疗队列的背景下，我们将确定与博茨瓦纳接受HAART治疗的成年人中线粒体毒性发展相关的临床因素和实验室价值。2.评估来自队列参与者的现有样本，并利用病例对照方法，我们将使用专注于特定基因集的较新的RNA基因表达谱技术识别可能与线粒体毒性相关的基因亚集。3.根据AIMS 1和AIMS 2中获得的信息，我们将识别线粒体、药物代谢和其他单核苷酸多态(SNP)变异，这些变异可能改变参与线粒体功能的相关基因的表达，并与线粒体毒性的发展相关。

DESCRIPTION (provided by applicant): The applicant's long-term goals are to independently conduct clinical trials related to adult HIV care and treatment in the African context, particularly with respect to HAART tolerability and toxicity. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are effective antiretroviral therapies for the treatment of HIV-1 infected adults and they will likely remain a critical component of ART regimens in resource-poor settings. However, their ability to inhibit human mitochondrial polymerase-gamma has been associated with several long-term mitochondrial toxicities; these include lactic acidosis, pancreatitis, peripheral neuropathy, and peripheral fat wasting/atrophy. Some studies provide preliminary evidence for the role of certain genes/genetic pathways in mediating this toxicity. Preliminary experience in Botswana and South Africa has shown that rates of mitochondrial toxicity (and specifically lactic acidosis) appear to be higher than that which has been reported elsewhere. The risk for these mitochondrial toxicities appears to be related to: (i) gender (seen predominantly in females), (ii) body weight (seen primarily in those who are overweight/obese), and (iii) the specific NRTI or combination of NRTIs they are receiving. The specific epidemiologic, clinical, and genetic risk factors associated with this apparent increased risk are unknown, we therefore propose the following Specific Aims: 1. Within the context of an existing HAART-treated cohort, we will determine the clinical factors and laboratory values associated with the development of mitochondrial toxicity among HAART-treated adults in Botswana. 2. Evaluating existing specimens from cohort participants, and utilizing case-control methodology, we will identify subsets of genes that may be associated with mitochondrial toxicity using newer RNA gene expression profiling techniques focusing on specific gene sets. 3. Based on information obtained in Aims 1 and 2; we will identify mitochondrial, drug metabolism, and other single nucleotide polymorphism (SNP) variants that may alter the expression of relevant genes involved in mitochondrial function and be associated with the development of mitochondrial toxicity.