Prospective evaluation of outcomes in cirrhosis of different etiologies: impact of HIV infection and simvastatin therapy

不同病因肝硬化结局的前瞻性评估：HIV 感染和辛伐他汀治疗的影响

• 批准号: 10700112
• 负责人: Srinivasan Dasarathy
• 金额: $ 58.47万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700112
• 关键词: Affect; Age; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Ammonia; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Antioxidants; Architecture; Ascites; Biological Markers; Cause of Death; Cessation of life; Child; Cirrhosis; Clinic; Clinical; Clinical Trials; Cohort Studies; Complication; Computerized Medical Record; Cross-Sectional Studies; Data; Databases; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Disease Progression; Encephalopathies; Enrollment; Ethnic Origin; Etiology; Evaluation; Event; Fibrosis; Functional disorder; Gender; HIV; HIV Infections; Health system; Hemorrhage; Hepatic; High Prevalence; Hospitals; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Icterus; Immune; Impairment; Infection; Injury; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Lobular; Long-Term Care; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Measures; Modeling; Muscle; Muscular Atrophy; Myopathy; Organ; Outcome; Pathogenesis; Patient Care; Patients; Pattern; Pilot Projects; Placebos; Plasma; Play; Portal Pressure; Prevalence; Primary carcinoma of the liver cells; Productivity; Prospective Studies; Prospective, cohort study; Proteomics; Public Health; Publishing; Quality of life; Randomized; Randomized, Controlled Trials; Reporting; Risk; Risk Factors; Role; Safety; Severities; Severity of illness; Simvastatin; Syndrome; System; Telemedicine; Testing; United States; United States National Institutes of Health; Virus; Virus Diseases; adverse outcome; biobank; chronic liver disease; clinical center; clinical practice; clinically significant; comorbidity; cost; digital health; end stage liver disease; follow-up; frailty; gut microbiome; health management; high risk; human data; improved; improved outcome; innovation; interest; liver inflammation; liver injury; liver transplantation; metabolomics; microbial; mortality; new technology; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel marker; novel therapeutics; participant enrollment; patient population; pharmacologic; predict clinical outcome; prevent; primary outcome; profiles in patients; programs; progression marker; progression risk; prospective; randomized placebo controlled trial; randomized, clinical trials; research clinical testing; response; sarcopenia; televisit; therapeutic target; trimethylamine; young adult

Chronic liver disease, primarily cirrhosis, remains the 6th leading cause of death in adults younger than 65y in the United States. Despite advances in diagnostics and therapies, mortality in cirrhosis has not changed significantly over the last 40y and remains a major significant public health burden. We and others have used modeling and database evaluations to show that alcohol related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the 2 major causes of cirrhosis in the United States. Treating the underlying etiology of cirrhosis may help fibrosis regress but whether cirrhosis is reversible is not yet established. Whether fibrosis progresses once a diagnosis of cirrhosis is established and if such a progression is related to decompensation or hepatocellular carcinoma (HCC) are also not known. Of the various complications of cirrhosis, sarcopenia and physical frailty due to impaired contractile function are frequent, progressive and adversely impact clinical outcomes. Despite the high clinical significance, there are no prospective studies on development, progression and predictors of sarcopenia and frailty in cirrhosis. Co-morbidities especially infection with human immune- deficiency virus (HIV) places patients with cirrhosis at high risk of progression of fibrosis, decompensation, and sarcopenia/frailty syndrome. The gut microbiome and their metabolites (xenometabolites) play a mechanistic role in hepatic injury and complications of cirrhosis including HCC and sarcopenia but there are very limited prospective studies in human patients. Most studies on the progression, long term complications, impact of co- morbidities and outcomes in cirrhosis are cross-sectional, have small number of subjects, and do not translate advances in mechanistic understanding of development of cirrhosis or its complications into clinical practice. Therefore, prospective studies in well characterized cirrhosis are critical to develop effective management strategies and improve outcomes. There is increasing interest in the use of statins in the management of cirrhosis due to anti-inflammatory and antifibrotic effects that may prevent decompensation and HCC. The Cleveland Clinic Health System is one of the largest clinical programs with a large population of patients with cirrhosis who are referred for long-term management including liver transplantation, because of our expertise in innovative approaches to patient care including televisits and applications of digital health incorporated into integrated electronic medical records. In response to the RFA PAR DK-20-003, we propose to be a part of a Liver Cirrhosis Network to establish a longitudinal cohort of patients with cirrhosis, primarily alcohol related and non-alcoholic fatty liver disease with co-morbidities including HIV infection. We will develop a database of well characterized patients and a biorepository from these patients to advance our mechanistic understanding of progression of cirrhosis, development of complications and identify novel biomarkers and therapies to improve clinical outcomes. We will also conduct a prospective randomized clinical trial using simvastatin/placebo in well characterized patients with cirrhosis as part of the network to determine clinical responses and safety.

慢性肝病（主要是肝硬化）仍然是 65 岁以下成年人的第六大死因 美国。尽管诊断和治疗取得了进步，但肝硬化的死亡率并未改变 过去 40 年来的显着变化，仍然是一个重大的公共卫生负担。我们和其他人已经使用过 模型和数据库评估表明酒精相关性肝病（ALD）和非酒精性脂肪肝 肝病（NAFLD）是美国肝硬化的两大主要原因。治疗根本病因 肝硬化的治疗可能有助于纤维化消退，但肝硬化是否可逆尚未确定。是否纤维化 一旦确诊肝硬化，并且这种进展与失代偿有关，就会出现进展 或肝细胞癌（HCC）也是未知的。肝硬化、肌少症的各种并发症 由于收缩功能受损而导致的身体虚弱是频繁的、进行性的并对临床产生不利影响 结果。尽管具有很高的临床意义，但尚无关于发育、进展的前瞻性研究 以及肌少症和肝硬化虚弱的预测因子。合并症，尤其是与人体免疫相关的感染 缺乏病毒（HIV）使肝硬化患者处于纤维化、失代偿和进展的高风险中 肌肉减少症/虚弱综合症。肠道微生物组及其代谢物（异代谢物）发挥着机制 在肝损伤和肝硬化并发症（包括 HCC 和肌少症）中的作用，但作用非常有限 对人类患者的前瞻性研究。大多数研究都是关于疾病进展、长期并发症、合并症的影响 肝硬化的发病率和结果是横向的，受试者数量较少，并且不能转化 对肝硬化或其并发症发展的机制理解在临床实践中的进展。 因此，对明确特征的肝硬化进行前瞻性研究对于制定有效的治疗方法至关重要 战略并改善结果。人们对使用他汀类药物进行治疗越来越感兴趣 由于抗炎和抗纤维化作用而导致的肝硬化可能会预防失代偿和肝癌。这 克利夫兰诊所医疗系统是最大的临床项目之一，拥有大量患有以下疾病的患者 由于我们的专业知识，肝硬化患者被转诊接受长期治疗，包括肝移植 患者护理的创新方法，包括将电视访问和数字医疗应用纳入 集成电子病历。为了响应 RFA PAR DK-20-003，我们建议成为 肝硬化网络旨在建立肝硬化患者的纵向队列，主要是与酒精相关和 伴有艾滋病毒感染等并发症的非酒精性脂肪肝。我们将开发一个数据库 描述了患者的特征以及这些患者的生物储存库，以增进我们对 肝硬化的进展、并发症的发展并确定新的生物标志物和疗法以改善 临床结果。我们还将使用辛伐他汀/安慰剂进行前瞻性随机临床试验 将肝硬化患者作为网络的一部分进行表征，以确定临床反应和安全性。