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: 9754980
• 负责人: NAGA P CHALASANI
• 金额: $ 170.31万
• 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/9754980
• 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; HIV-1; 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; 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; food insecurity; genetic risk factor; genetic variant; gut microbiome; improved; interest; liver biopsy; meetings; mortality; 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

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 本申请是NASH临床研究网络（NASH CRN）的一项辅助研究， 进行了几项重要的临床研究，包括里程碑式的临床试验。然而，进行的研究 NASH CRN系统地排除了HIV感染者，因为他们的肝脏疾病被认为是 由于持续的HIV感染、抗逆转录病毒治疗和伴随治疗， 药物和复发性感染。这种对艾滋病毒感染者的排除导致了巨大的知识差距 与脂肪肝相关的疾病最近的横向研究表明， HIV感染的成人中脂肪肝的患病率，重要的是他们晚期纤维化的风险可能是 明显高于一般人群。为了填补联合国系统内的重大知识空白， 在HIV中的NAFLD和NASH领域，我们在R 01申请中提出了以下广泛的具体目标， 对PAR-18-042的响应。具体目标1：在交叉研究中检查肝脂肪变性的患病率。 HIV感染者大队列的横断面研究。这项横断面研究将确定非- 与HIV感染者肝脂肪变性相关的遗传和遗传危险因素。一个强大的生物库 包括血浆、血清、基因组DNA、PBMC、粪便和尿液。所有参与者将 收集（a）肝脏生化;（B）VCTE;和（c）血浆和基因组DNA。具体目标2： 对400名HIV感染者进行前瞻性观察研究， NAFLD。该HIV-NAFLD队列的参与者将与非HIV感染的NAFLD个体进行比较， 正在进行的NASH CRN成人数据库2（DB2）基线临床特征和人口统计学研究， 人体测量、代谢和心血管风险。将对参与者进行年度纵向跟踪 根据模仿DB2协议的调度。具体目标3：仔细表征肝脏 组织学检查证实为NAFLD的HIV感染个体。这一目标的主要目标是：（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）评估肝组织学中的组织学相似性和不同性 HIV感染者和非感染者之间的NAFLD。NASH CRN病理小组委员会将 审查HIV感染者的肝活检。具体目标4：进行一项多中心、随机、 一项在160名HIV感染者中进行的新型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的消退，关键次要终点为（a） NAS改善2分;（B）纤维化改善;（c）转氨酶改善;（d） 心血管风险的改善;和（e）安全性和耐受性。