HIV and Global Drug Therapies: Peripheral Neuropathy Complications and Mechanisms

HIV 和全球药物治疗：周围神经病变并发症和机制

基本信息

批准号：
8133664
负责人：
Cecilia M. Shikuma
金额：
$ 3.42万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133664
关键词：
8-Oxo-2&apos -Deoxyguanosine AIDS clinical trial group AIDS neuropathy Acquired Immunodeficiency Syndrome Address Affect Biopsy Specimen Blood Bone Marrow CCL2 gene CD14 gene Cells Chronic Clinical Clinical Trials Collaborations Combined Modality Therapy Comorbidity Complex Complication DNA Deterioration Developing Countries Development Disease Progression Distal Energy-Generating Resources Enzymes Far East Fatty acid glycerol esters Frequencies Funding Genetic Polymorphism Genomics Grant HIV Hawaii Highly Active Antiretroviral Therapy Incidence Individual Inflammation Inflammatory Inflammatory Response Investigation Lamivudine Lead Leg Limb structure Link Lipoatrophy Measurement Mediating Mediator of activation protein Mitochondria Mitochondrial DNA Modality Monitor National Institute of Allergy and Infectious Disease Nerve Nerve Fibers Nerve Tissue Neurologic Neurology Neurons Neuropathy Nevirapine Nucleosides Oxidative Phosphorylation Oxidative Stress Pain Participant Pathogenesis Pathologic Patients Pattern Peripheral Blood Mononuclear Cell Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacotherapy Plasma Policies Population Predisposition Prevalence Preventive Proteins Public Health Publishing Punch Biopsy RNA-Directed DNA Polymerase Randomized Randomized Clinical Trials Regimen Relative (related person)Research Residual state Reverse Transcriptase Inhibitors Risk Role Schedule Single Nucleotide Polymorphism Skin Specimen Staging Stavudine Tenofovir Testing Thailand Therapeutic Thigh structure Time Toxic effect United States National Institutes of Health Variant Zidovudine antiretroviral therapy arm base clinically relevant cost cytokine density design emtricitabine enzyme activity experience genome sequencing macrophage mitochondrial genome monocyte programs prospective public health relevance sensory neuropathy subcutaneous tripolyphosphate truvada

项目摘要

DESCRIPTION (provided by applicant): Rates of HIV-associated sensory neuropathies (HIV-SN) remain high despite the introduction of highly active antiretroviral therapy (HAART). While both HIV and its inflammatory responses as well as toxic effects of antiretroviral therapy are believed to be important etiologic factors, how these two factors affect the pathogenic mechanisms underlying HIV-SN in individuals initiating HAART; how the pathogenesis and interactions may be altered by stavudine (d4T), a neuropathic anitretroviral (ARV) medication; and whether irreparable damage to the nerves can occur with even short-term use of d4T is not well defined. The issue of d4T-induced neuropathy is of particular concern in developing countries where d4T is heavily used. Our program, through our collaborative coordinating center SEARCH (South East Asia Research Collaboration with Hawaii), intends to launch a 150 n, 72 week, clinical trial (SEARCH 003) to assess the relative toxicities of short-term d4T + lamivudine [3TC] (24 week) followed by zidovudine [ZDV] + 3TC (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in ARV-naive subjects in Bangkok, Thailand. Within the framework of this trial, we propose to evaluate the impact of HAART on serial (baseline, week 24 and week 72) measurements of epidermal nerve fiber density (ENFD), a likely pathologic correlate of HIV-SN. We will assess whether improvement in ENFD typically occurs with the expected HAART-induced improvement in immuno-virologic parameters, how this is altered by the use of d4T, and whether low baseline or differential changes in ENFD predict the development of HIV-SN in individuals initiated on HAART. To assess the pathogenesis involved in its development, we will assess the relationship of neuropathy/ENFD to fat and PBMC mitochondrial (mt) /mt-specific oxidative stress parameters (mtDNA, oxidative phosphorylation Complex I and IV, mt-specific 8-oxodeoxyguanine) and to intracellular levels of d4T triphosphates. We will also assess its relationship to levels of HIV DNA within the CD14+ sub-fraction of PBMCs which we hypothesize represent HIV-infected M/M7s responsible for the inflammation surrounding peripheral nerves. Finally, we will assess how individual mitochondrial genomic variations influence the development of HIV-SN. This research will help to increase our understanding of how HIV-SN develops and potentially lead to effective preventive/ therapeutic modalities. PUBLIC HEALTH RELEVANCE This proposal will study whether low baseline peripheral nerve fiber density (the nerves responsible for pain in the extremities) will predict the development of neuropathy (pain in the extremities) and whether HIV-infected subjects on antiretroviral therapy will have different effects on their nerve fiber densities. We will also study the role of mitochondria (a source of energy for the cell) and HIV in the development of neuropathy.

描述（由申请人提供）：尽管引入了高度活跃的抗逆转录病毒疗法（HAART），但与HIV相关的感觉神经病（HIV-SN）的发生率仍然很高。虽然艾滋病毒及其炎症反应以及抗逆转录病毒疗法的毒性作用都被认为是重要的病因学因素，但这两个因素如何影响启动HAART的个体中HIV-SN的致病机制； stavudine（D4T）如何改变发病机理和相互作用，神经性抗体病毒（ARV）药物；而且，即使短期使用D4T，也无法很好地定义对神经无法弥补的损害。在大量使用D4T的发展中国家，D4T引起的神经病的问题特别关注。我们的计划通过我们的协作协调中心搜索（东南亚与夏威夷的研究合作），打算启动150 N，72周的临床试验（搜索003），以评估短期D4T + lamivudine [3TC]（24周）的相对毒性，然后是Zidovine [ZDV] [ZDV] + 3TC（N = 50），相比之下。 Tenofovir（TDF） + Emtricitabine（FTC）（n = 50），全部在泰国曼谷的ARV-NEIVE受试者中给予Nevirapine（NVP）。在该试验的框架内，我们建议评估HAART对表皮神经纤维密度（ENFD）的测量（基线，基线，第24周和第72周）的影响，这是HIV-SN的病理相关性。我们将评估ENFD的改善是否通常是随着预期的HAART引起的免疫学参数的改善，如何通过使用D4T的使用来改变这一点，以及ENFD的低基线或差异变化是否预测了HAART发起的个体中HIV-SN的发展。为了评估其发育中涉及的发病机理，我们将评估神经病变 /ENFD与脂肪和PBMC线粒体（MT） /MT特异性氧化应激参数（MTDNA，氧化磷酸化复合物I和IV，MT特异性8-氧氧化鸟嘌呤）和静脉内纤维素层的关系。我们还将评估其与PBMC的CD14+亚曲率中的HIV DNA水平的关系，我们假设这代表了负责周围周围神经炎症的HIV感染的M/M7。最后，我们将评估单个线粒体基因组变异如何影响HIV-SN的发展。这项研究将有助于提高我们对HIV-SN如何发展的理解，并可能导致有效的预防/治疗方式。公共卫生相关性本提案将研究低基线周围神经纤维密度（导致肢体疼痛的神经）是否会预测神经病的发展（四肢疼痛），以及对抗逆转录病毒疗法的HIV感染受试者是否对其神经纤维密度产生不同的影响。我们还将研究线粒体（细胞的能量来源）和HIV在神经病发展中的作用。