Evaluation of HIV-related Complications

HIV相关并发症的评估

基本信息

批准号：
7593078
负责人：
JOSEPH A KOVACS
金额：
$ 6.54万
依托单位：
CLINICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7593078
关键词：
Acquired Immunodeficiency Syndrome Adipose tissue Affect Algorithms Anti-Retroviral Agents Biological Assay Biological Markers Biopsy Biopsy Specimen Brain Cardiomyopathies Cells Central Nervous System Lymphoma Cerebrum Clinical Development Diagnosis Encephalitis Enrollment Enzymes Evaluation Fatigue Fibrosis Gene Proteins Goals Gold Guidelines HIV Hepatitis B Hepatitis B Virus Hepatitis C virus Hepatotoxicity Histopathology Human Herpesvirus 4 Infection Invasive Lactic Acidosis Lead Lesion Lipodystrophy Liver Liver Fibrosis Liver diseases Lymphocyte Malignant Neoplasms Measurement Measures Methods Microscopic Mitochondria Mitochondrial DNA Morbidity - disease rate Muscle Myopathy Natural History Nature Nucleosides Numbers Opportunistic Infections Pancreatitis Participant Pathogenesis Patients Peripheral Blood Mononuclear Cell Peripheral Nervous System Diseases Persons Pharmaceutical Preparations Pilot Projects Ploidies Polymerase Chain Reaction Positron-Emission Tomography Prevalence Procedures Protease Inhibitor Protocols documentation Quality of life Questionnaires Rate Recording of previous events Reference Standards Reverse Transcriptase Inhibitors Score Series Severities Skeletal Muscle Standards of Weights and Measures Syndrome System Testing Time Toxic effect Transaminases Treatment Protocols Virus Diseases antiretroviral therapy clinically relevant cohort design diagnosis evaluation improved liver biopsy mitochondrial dysfunction mortality nucleoside analog viral detection

项目摘要

Epstein Barr Virus (EBV)-associated primary central nervous system lymphoma (PCNSL) remains a major problem among AIDS patients. The clinical presentation is often clinically indistinguishable from toxoplasmic encephalitis. The method of choice for establishing the definitive diagnosis is brain biopsy. This procedure can be associated with a significant morbidity and mortality, and therefore less invasive means of diagnosing cerebral mass lesions have been studied. We have undertaken a study to evaluate an algorithm for the workup of HIV infected patients with focal brain lesions so as to expedite the diagnosis and subsequent treatment of PCNSL, using the combination of EBV detection in the CSF and FDG-PET scanning. Up to one hundred twenty HIV-infected patients with a history of at least one focal brain lesion will be screened for enrollment. All patients will be treated empirically for toxoplasmic encephalitis until an alternative diagnosis is confirmed. Those patients with a positive EBV-PCR in the CSF or a positive FDG-PET scan will undergo immediate brain biopsy. All enrolled patients will be treated concurrently with antiretroviral therapy. Patients identified to have PCNSL will be referred to an NCI Treatment of PCNSL Protocol for further treatment. Both HIV infection and antiretroviral nucleoside analogues (nucleoside reverse transcriptase inhibitors or NRTIs) are known to affect mitochondrial DNA content and mitochondrial function. A number of important clinical syndromes observed in HIV-infected persons relate to mitochondrial dysfunction including lactic acidosis, myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, and possibly lipodystrophy 1, 2. Fatigue, one of the most prevalent complaints among persons with HIV infection, may also be the result of mitochondrial toxicity, though this has not been clearly established. Availability of minimally invasive tests to assess mitochondrial toxicity would greatly facilitate understanding of the contribution of mitochondrial dysfunction to clinical syndromes. Muscle and liver biopsies are currently considered to be the reference standards for the evaluation and diagnosis of mitochondrial toxicity in muscle and liver, but these invasive tests are impractical for routine and repeated evaluations. The recent development of a real-time polymerase chain reaction (PCR) assay to accurately quantify the mtDNA copy numbers per cell in peripheral blood mononuclear cells (PBMCs) may allow non-invasive assessment of mitochondrial toxicity. We have undertaken a pilot study seekings to examine the relationship between fatigue and other clinical parameters and markers of mitochondrial dysfunction. The goals of this study are threefold: 1) to investigate the relationship between subjective fatigue ratings and mitochondrial dysfunction through measurements of mtDNA depletion in skeletal muscle 2) to determine whether there is a relationship between evidence of mitochondrial dysfunction in muscle and evidence of mitochondrial dysfunction in lymphocytes or adipose tissue suggesting that examination of lymphocytes or adipose tissue may be adequate for the accurate diagnosis of mitochondrial dysfunction and 3) to identify genes and proteins as potential biomarkers for fatigue and mitochondrial toxicity. Three groups of participants will be enrolled: HIV positive patients on NRTI-containing and protease-inhibitor sparing regimens (n=30), HIV patients currently taking no antiretroviral medications (n=30) and healthy controls (n=15). HIV patients on NRTIs will be stratified according to their fatigue level (0-3, 4-7 or 8-10). Participants will complete a battery of questionnaires regarding fatigue and undergo muscle and adipose tissue biopsy. At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeficiency virus (HIV) should be stopped in the setting of elevated liver enzymes. In large part, this is due to a limited understanding of the natural history of ARV-related hepatotoxicity. We have undertaken a pilot study to estimate the prevalence of hepatic fibrosis in a cohort of sixty HIV-infected patients who have chronically elevated transaminases while on ARV therapy in the absence of Hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens will be evaluated for fibrosis by microscopic examination, the current gold standard for assessing the nature and severity of liver disease. Fibrosis, as well as other histopathology, will be measured using a validated scoring system. This study should provide clinically relevant information on the significance of elevated transaminases in HIV-infected patients without co-infection with HCV or HBV.

爱泼斯坦Barr病毒（EBV）相关的原发性中枢神经系统淋巴瘤（PCNSL）仍然是艾滋病患者的主要问题。临床表现通常在临床上与弓形虫性脑炎没有区别。确定确定诊断的首选方法是脑活检。该程序可能与显着的发病率和死亡率有关，因此已经研究了诊断脑肿瘤病变的侵入性方法。 我们已经进行了一项研究，以使用CSF和FDG-PET扫描中的EBV检测结合使用EBV检测的组合，以评估患有HIV感染的HIV感染局灶性脑损伤患者的算法。多达一百二十名感染了至少一个局灶性脑部病变病史的HIV感染患者将被筛查以进行入学。所有患者将接受弓形虫性脑炎的经验治疗，直到确认替代性诊断。那些在CSF或FDG-PET阳性扫描阳性的EBV-PCR阳性的患者将立即进行脑活检。所有入学的患者将同时接受抗逆转录病毒疗法的治疗。确定患有PCNSL的患者将转介给PCNSL方案的NCI治疗以进行进一步治疗。 已知HIV感染和抗逆转录病毒核苷类似物（核苷逆转录酶抑制剂或NRTIS）都会影响线粒体DNA含量和线粒体功能。在HIV感染者中观察到的许多重要的临床综合征与线粒体功能障碍有关，包括乳酸性酸中毒，肌病，心肌病，胰腺炎，胰腺炎，周围神经病中的许多重要的临床综合症，以及可能与脂肪症的人1，2。毒性，尽管尚未清楚地确定。 可用于评估线粒体毒性的微创测试的可用性将极大地理解线粒体功能障碍对临床综合征的贡献。目前，肌肉和肝活检被认为是评估和诊断肌肉和肝脏中线粒体毒性的参考标准，但是对于常规和重复评估，这些侵入性测试是不切实际的。实时聚合酶链反应（PCR）测定的最新发展，以准确量化外周血单核细胞（PBMC）中每个细胞的mtDNA拷贝数（PBMC）可能允许对线粒体毒性进行非侵入性评估。我们已经进行了一项试点研究，以检查疲劳与其他临床参数与线粒体功能障碍的标记之间的关系。这项研究的目标是三个方面：1）研究通过测量骨骼肌中的mtDNA耗竭的测量值和线粒体功能障碍之间的关系2）确定线粒体功能障碍的证据与线粒体功能障碍的证据之间是否存在线粒体的症状或象征性症状的证据。淋巴细胞或脂肪组织可能足以准确诊断线粒体功能障碍，3）鉴定基因和蛋白质是疲劳和线粒体毒性的潜在生物标志物。将招募三组参与者：含NRTI的和蛋白酶抑制剂的保留方案（n = 30）的HIV阳性患者，目前未服用抗逆转录病毒药物的HIV患者（n = 30）和健康对照组（n = 15）。 NRTIS的HIV患者将根据其疲劳水平进行分层（0-3、4-7或8-10）。参与者将完成一系列有关疲劳和肌肉和脂肪组织活检的问卷。 目前，尚无关于何时在肝酶升高的情况下停止抗逆转录病毒（ARV）治疗人类免疫缺陷病毒（HIV）的准则。在很大程度上，这是由于对与ARV相关的肝毒性的自然史有限的理解。我们已经进行了一项初步研究，以估计一组60例HIV感染的患者的肝纤维化患病率，这些患者在没有肝炎（HBV）或C（HCV）共感染的情况下进行了ARV治疗时长期升高的转氨酶。将通过微观检查评估肝活检标本的纤维化，这是当前评估肝病的性质和严重程度的金标准。将使用经过验证的评分系统测量纤维化以及其他组织病理学。这项研究应提供临床上相关的信息，内容涉及艾滋病毒感染患者升高的意义，而无需与HCV或HBV共同感染。