Ancillary Studies of NAFLD and NASH in HIV infected Adults

HIV 感染成人 NAFLD 和 NASH 的辅助研究

• 批准号: 10555206
• 负责人: NAGA P CHALASANI
• 金额: $ 154.26万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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/10555206
• 关键词: Address; Adult; Adverse event; Adverse reactions; Age; 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; 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; 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; Obesity; 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; Serum Markers; Site; Sleep; System; Testing; Therapeutic; Transaminases; United States; Urine; Work; antiretroviral therapy; biobank; cardiovascular risk factor; chronic liver disease; clinical center; clinical predictors; 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-genetic; nonalcoholic steatohepatitis; novel; novel therapeutics; pre-clinical; primary endpoint; prognostic; prospective; recurrent infection; research study; response; secondary endpoint; sex; vibration; working group

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.

项目概要 该应用程序是 NASH 临床研究网络 (NASH CRN) 的一项辅助研究，该网络已 进行了多项重要的临床研究，包括具有里程碑意义的临床试验。然而，进行的研究 NASH CRN 系统性地排除了 HIV 感染者，因为他们的肝脏疾病被认为是 由于持续的艾滋病毒感染、抗逆转录病毒治疗以及伴随的治疗，与一般人群不同 药物治疗和反复感染。这种对艾滋病毒感染者的排斥导致了巨大的知识差距 与该人群的脂肪肝疾病有关。最近的横断面研究表明， HIV 感染成人脂肪肝的患病率，重要的是，他们发生晚期纤维化的风险可能是 明显高于一般人群。为了解决困扰人们的关键知识差距 在 HIV 中的 NAFLD 和 NASH 领域，我们在 R01 应用中提出了以下广泛的具体目标： 对 PAR-18-042 的回应。具体目标 1：检查交叉研究中肝脂肪变性的患病率 对大量艾滋病毒感染者进行的局部研究。这项横断面研究将确定非 与艾滋病毒感染者肝脂肪变性相关的遗传和遗传风险因素。强大的生物样本库 将建立由血浆、血清、基因组DNA、PBMC、粪便和尿液组成的样本。所有参与者将 (a) 肝脏生物化学； (b) VCTE； (c) 收集血浆和基因组 DNA。具体目标 2： 对 400 名具有组织学特征的 HIV 感染者进行前瞻性观察研究 非酒精性脂肪性肝病。该 HIV-NAFLD 队列的参与者将与患有 NAFLD 的非 HIV 感染者进行比较 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， 人体测量、代谢和心血管风险。每年将对参与者进行纵向跟踪 根据模仿 DB2 协议的调度。具体目标 3：仔细表征肝脏 对 HIV 感染者进行组织学检查，活检证实为 NAFLD。该目标的主要目标是 (a) 验证 在人群中广泛使用的 NASH CRN 组织学评分系统和欧洲 SAF 评分系统 同时患有 HIV 和 NAFLD 的人，以及 (b) 评估肝脏组织学的组织学相似性和差异性 HIV 感染者和非 NAFLD 感染者之间的差异。 NASH CRN 病理学小组委员会将 检查 HIV 感染者的肝脏活检。具体目标 4：开展多中心、随机、 在 160 名 HIV 感染者中进行了一种新型 PPARα/γ 激动剂的双盲、安慰剂对照临床试验 活检证实 NASH。主要终点将是 NASH 的解决，关键次要终点是 (a) NAS 提高 2 点； (b) 纤维化的改善； (c) 转氨酶的改善； (四) 改善心血管风险； (e) 安全性和耐受性。