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

• 批准号: 8112457
• 负责人: Cecilia M. Shikuma
• 金额: $ 65.97万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112457
• 关键词: 8-Oxo-2' -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; Health; 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; sensory neuropathy; subcutaneous; tripolyphosphate; truvada

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）：尽管采用了高效抗逆转录病毒疗法（HAART），但 HIV 相关感觉神经病（HIV-SN）的发病率仍然很高。虽然 HIV 及其炎症反应以及抗逆转录病毒治疗的毒性作用被认为是重要的病因因素，但这两个因素如何影响开始 HAART 的个体中 HIV-SN 的致病机制？司他夫定 (d4T)（一种神经病性抗逆转录病毒 (ARV) 药物）如何改变发病机制和相互作用；即使短期使用 d4T 是否也会对神经造成不可挽回的损害尚不清楚。 d4T 引起的神经病变问题在大量使用 d4T 的发展中国家尤其令人关注。我们的计划通过我们的合作协调中心 SEARCH（与夏威夷的东南亚研究合作），打算启动一项 150 n、72 周的临床试验 (SEARCH 003)，以评估短期 d4T + 拉米夫定 [3TC] 的相对毒性（24 周）随后使用齐多夫定 [ZDV] + 3TC (n=50) 与连续 ZDV + 3TC 相比(n=50) 或替诺福韦 (TDF) + 恩曲他滨 (FTC) (n=50)，均与奈韦拉平 (NVP) 一起用于泰国曼谷未接受过抗逆转录病毒治疗的受试者。在本试验的框架内，我们建议评估 HAART 对表皮神经纤维密度 (ENFD) 连续测量（基线、第 24 周和第 72 周）的影响，ENFD 可能是 HIV-SN 的病理相关性。我们将评估 ENFD 的改善是否通常伴随着预期的 HAART 诱导的免疫病毒学参数的改善而发生，使用 d4T 如何改变这种改善，以及 ENFD 的低基线或差异变化是否可以预测个体中 HIV-SN 的发展开始HAART。为了评估其发展中涉及的发病机制，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-氧化脱氧鸟嘌呤）的关系以及 d4T 三磷酸的细胞内水平。我们还将评估其与 PBMC 的 CD14+ 亚组分中 HIV DNA 水平的关系，我们假设该亚组分代表感染 HIV 的 M/M7，导致周围神经周围的炎症。最后，我们将评估个体线粒体基因组变异如何影响 HIV-SN 的发展。这项研究将有助于增加我们对 HIV-SN 如何发展的了解，并有可能导致有效的预防/治疗方式。公共卫生相关性 该提案将研究低基线周围神经纤维密度（负责四肢疼痛的神经）是否可以预测神经病（四肢疼痛）的发展，以及接受抗逆转录病毒治疗的 HIV 感染者是否会对神经病变产生不同的影响。他们的神经纤维密度。我们还将研究线粒体（细胞的能量来源）和艾滋病毒在神经病发展中的作用。