Ancillary Studies of NAFLD and NASH in HIV infected Adults

HIV 感染成人 NAFLD 和 NASH 的辅助研究

基本信息

批准号：
10371070
负责人：
NAGA P CHALASANI
金额：
$ 155.9万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-21 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371070
关键词：
Address Adult Adverse event Adverse reactions Agonist Alcohols Ancillary Study Area Beverages Biochemistry Biopsy Body Weight CD4 Positive T Lymphocytes Cell Count Characteristics Clinical Clinical Data Clinical Research Clinical Trials Coffee Controlled Clinical Trials Cross-Sectional Studies Data Data Coordinating Center Databases Diagnostic Diet Disease Double-Blind Method Eligibility Determination Ethnic Origin European Exclusion Fatty Liver Feces Fibrosis Frequencies Funding GTP-Binding Protein alpha Subunits, Gs Gender General Population Genomic DNA HIV HIV Infections High Prevalence Histologic Histology Individual Infection Inflammation Insulin Resistance Knowledge Lipoproteins Liver Liver Fibrosis Liver diseases Lobular Metabolic Mission Morbidity - disease rate Multicenter Studies National Institute of Diabetes and Digestive and Kidney Diseases Observational Study Oral PPAR alpha Participant Pathogenesis Pathology Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Physical activity Placebo Control Placebos Plasma Population Prevalence Protocols documentation Quality of life RNA Race Randomized Randomized Controlled Trials Research Research Infrastructure Resolution Risk Risk Factors Safety Schedule Seminal Serious Adverse Event Serum Markers Site Sleep System Testing Therapeutic Transaminases United States Urine Work antiretroviral therapy base biobank cardiovascular risk factor chronic liver disease clinical center clinical diagnostics cohort design elastography fatty liver disease food insecurity genetic risk factor genetic variant gut microbiome improved interest liver biopsy meetings mortality multi-ethnic non-alcoholic fatty liver non-alcoholic fatty liver disease non-genetic nonalcoholic steatohepatitis novel novel therapeutics obesity genetics pre-clinical primary endpoint prognostic prospective recurrent infection research study response secondary endpoint sex vibration working group

项目摘要

PROJECT SUMMARY This application is an ancillary study to the NASH Clinical Research Network (NASH CRN) which has conducted several important clinical studies including landmark clinical trials. However, the studies conducted by the NASH CRN have systematically excluded individuals with HIV infection as their liver disease is thought to be distinct from general population due to ongoing HIV infection, antiretroviral therapy, and concomitant medications and recurrent infections. This exclusion of HIV infected persons led to a large knowledge gap related to fatty liver disease in this population. Recent cross-sectional studies have shown that there is high prevalence of fatty liver disease in HIV infected adults and importantly their risk for advanced fibrosis may be significantly higher than the general population. In order to address the critical knowledge gaps plaguing the field of NAFLD and NASH in HIV, we are proposing the following broad specific aims in our R01 application in response to the PAR-18-042. Specific Aim 1: To examine the prevalence of hepatic steatosis in a cross- sectional study on large cohort of HIV infected individuals. This cross-sectional study will identify both non- genetic and genetic risk factors associated with hepatic steatosis in HIV infected individuals. A robust biobank consisting of plasma, serum, genomic DNA, PBMC, stool and urine will be established. All participants will have (a) liver biochemistries; (b) VCTE; and (c) plasma and genomic DNA collected. Specific Aim 2: To conduct a prospective observational study of 400 HIV infected individuals with histologically characterized NAFLD. Participants in this HIV-NAFLD cohort will be compared to non-HIV infected individuals with NAFLD in the ongoing NASH CRN adult database 2 (DB2) studies for baseline clinical characteristics and demographic, anthropometric, metabolic and cardiovascular risks. Participants will be followed longitudinally on an annual basis according to a scheduling mimicking the DB2 protocol. Specific Aim 3: To carefully characterize liver histology in HIV infected individuals with biopsy proven NAFLD. Key objectives of this aim are (a) to validate the widely used NASH CRN histological scoring system and European SAF scoring systems in population of persons with both HIV and NAFLD and (b) to assess histological similarities and dissimilarities in liver histology between HIV infected and non-infected individuals with NAFLD. NASH CRN Pathology Subcommittee will review liver biopsies from HIV infected individuals. Specific Aim 4: To conduct a multicenter, randomized, double-blind, placebo-controlled, clinical trial of a novel PPARα/γ agonist in 160 HIV infected individuals with biopsy proven NASH. Primary end point will be resolution of NASH with key secondary endpoints being (a) improvement in NAS by 2 points; (b) improvement in fibrosis; (c) improvement in aminotransferases; (d) improvement in cardiovascular risks; and (e) safety and tolerability.

项目摘要该应用是对NASH临床研究网络（NASH CRN）的辅助研究进行了几项重要的临床研究，包括具有里程碑意义的临床试验。但是，研究进行了纳什CRN被系统地排除了艾滋病毒感染的个体，因为他们的肝病被认为由于持续的艾滋病毒感染，抗逆转录病毒疗法和伴随药物和反复感染。艾滋病毒感染者的这种排除导致了巨大的知识差距与该人群中的脂肪肝病有关。最近的横断面研究表明艾滋病毒感染的成年人的脂肪肝病患病率，重要的是，他们的晚期纤维化风险可能是显着高于一般人群。为了解决困扰的关键知识差距 NAFLD和NASH艾滋病毒领域，我们在我们的R01应用程序中提出以下广泛的特定目标对PAR-18-042的响应。特定目的1：检查横向上肝脂肪变性的患病率关于大型艾滋病毒感染个体的大量研究。这项横断面研究将确定 HIV感染个体中与肝脂肪变性相关的遗传和遗传危险因素。强大的生物库将建立由血浆，血清，基因组DNA，PBMC，粪便和尿液组成的。所有参与者都会有（a）肝生物化学；（b）VCTE; （c）收集的血浆和基因组DNA。具体目标2：对具有组织学表征的400名HIV感染的个体进行前瞻性观察性研究 nafld。该HIV-NAFLD队列的参与者将与非HIV感染的人进行比较正在进行的NASH CRN成人数据库2（DB2）研究基线临床特征和人口统计学，人体测量学，代谢和心血管风险。参与者将在年度上纵向遵循根据模仿DB2协议的计划。特定目标3：仔细描述肝脏艾滋病毒中的组织学感染了活检证明的NAFLD。此目标的关键目标是（a）验证广泛使用的Nash CRN组织学评分系统和欧洲SAF评分系统艾滋病毒和NAFLD和（b）的人评估肝组织学的组织学相似性和差异在患有NAFLD的艾滋病毒感染和未感染的个体之间。纳什CRN病理小组委员会将回顾来自艾滋病毒感染者的肝活检。特定目标4：进行多中心，随机，新型PPARα/γ激动剂的双盲，安慰剂对照，160个HIV感染的个体的临床试验活检证明了纳什。主要终点将是NASH的分辨率，关键次要终点为（a） NAS改善2分；（b）纤维化的改善；（c）改善氨基转移酶；（D）心血管风险的改善；（e）安全性和耐受性。