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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

基本信息

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
项目类别：
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

项目摘要

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，仍然是美国65岁以下成年人死亡的第六大原因