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:
  • 金额:
    $ 58.47万
  • 依托单位:
  • 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

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65岁以下的成年人的第六大死亡原因 美国。尽管诊断和疗法方面取得了进步,但肝硬化的死亡率并未改变 在过去的40年中,显着占有重要地位,并且仍然是重大的公共卫生负担。我们和其他人使用过 建模和数据库评估表明,酒精相关的肝病(ALD)和非酒精脂肪 肝病(NAFLD)是美国肝硬化的两个主要原因。治疗潜在的病因 肝硬化可能有助于纤维化消退,但是肝硬化是否可逆。是否纤维化 一旦建立了肝硬化的诊断,进步就会进展,如果这种进展与代偿性有关 或肝细胞癌(HCC)也不知道。肝硬化的各种并发症,肌肉减少症 由于收缩功能受损而导致的身体脆弱,进行了频繁,进行性和不利影响临床 结果。尽管具有很高的临床意义,但仍未进行发展的前瞻性研究,进展 以及肝硬化中肌肉减少症和脆弱的预测因子。尤其是人类免疫感染的合并症 缺乏症病毒(HIV)使肝硬化患者处于纤维化,代偿作用和 肌肉减少症/脆弱综合症。肠道微生物组及其代谢产物(Xenometabolites)发挥机械作用 在肝损伤和肝硬化并发症中的作用,包括HCC和肌肉减少症,但有限 人类患者的前瞻性研究。大多数关于进展,长期并发症,共同影响的研究 肝硬化的病态和结果是横截面,有少数受试者,并且不翻译 对肝硬化发展或其并发症到临床实践的机械理解的进步。 因此,在特征性肝硬化方面的前瞻性研究对于建立有效的管理至关重要 策略并改善结果。对他汀类药物在管理中的使用越来越兴趣 由于抗炎和抗纤维化作用而引起的肝硬化可能会阻止代偿性和HCC的代偿作用。这 克利夫兰诊所卫生系统是最大的临床计划之一,大量患者 由于我们的专业知识 在创新的患者护理方法中,包括电视节目和数字健康的应用 集成电子病历。为了响应RFA PAR DK-20-003,我们建议成为 肝硬化网络建立急性肝硬化患者的纵向队列,主要是酒精相关的 非酒精性脂肪肝疾病,包括HIV感染在内。我们将开发一个井数据库 表征患者和来自这些患者的生物措施,以提高我们对 肝硬化的进展,并发症的发展并确定新型的生物标志物和疗法以改善 临床结果。我们还将在井中使用辛伐他汀/安慰剂进行前瞻性随机临床试验 将肝硬化患者表征为网络的一部分,以确定临床反应和安全性。

项目成果

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Srinivasan Dasarathy其他文献

Srinivasan Dasarathy的其他文献

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{{ truncateString('Srinivasan Dasarathy', 18)}}的其他基金

Mechanistic basis of exercise responses in liver disease
肝病运动反应的机制基础
  • 批准号:
    10749608
  • 财政年份:
    2023
  • 资助金额:
    $ 58.47万
  • 项目类别:
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:
    10310628
  • 财政年份:
    2021
  • 资助金额:
    $ 58.47万
  • 项目类别:
Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis
改善酒精性肝炎组织损伤的新机制治疗
  • 批准号:
    10676094
  • 财政年份:
    2020
  • 资助金额:
    $ 58.47万
  • 项目类别:
Modeling the Disease Burden and Cost-Effectiveness of Screening and Treatment for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes Patients
模拟 2 型糖尿病患者非酒精性脂肪肝筛查和治疗的疾病负担和成本效益
  • 批准号:
    10474392
  • 财政年份:
    2020
  • 资助金额:
    $ 58.47万
  • 项目类别:
Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis
改善酒精性肝炎组织损伤的新机制治疗
  • 批准号:
    10456629
  • 财政年份:
    2020
  • 资助金额:
    $ 58.47万
  • 项目类别:
Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis
改善酒精性肝炎组织损伤的新机制治疗
  • 批准号:
    10268997
  • 财政年份:
    2020
  • 资助金额:
    $ 58.47万
  • 项目类别:
Modeling the Disease Burden and Cost-Effectiveness of Screening and Treatment for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes Patients
模拟 2 型糖尿病患者非酒精性脂肪肝筛查和治疗的疾病负担和成本效益
  • 批准号:
    10267165
  • 财政年份:
    2020
  • 资助金额:
    $ 58.47万
  • 项目类别:
Sarcopenia in cirrhosis is mediated by a hyperammonemic stress response
肝硬化中的肌肉减少症是由高氨血症应激反应介导的
  • 批准号:
    9976523
  • 财政年份:
    2018
  • 资助金额:
    $ 58.47万
  • 项目类别:
Alcoholic Hepatitis Clinical and Translational Network - Late Phase Clinical Trials and Observational Studies (Collaborative U01)
酒精性肝炎临床和转化网络 - 后期临床试验和观察研究(合作 U01)
  • 批准号:
    9764890
  • 财政年份:
    2018
  • 资助金额:
    $ 58.47万
  • 项目类别:
ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES6/9
酒精性肝炎临床和转化网络:后期临床试验和观察研究6/9
  • 批准号:
    10876683
  • 财政年份:
    2018
  • 资助金额:
    $ 58.47万
  • 项目类别:

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A rigorous test of dual process model predictions for problematic alcohol involvement
对有问题的酒精参与的双过程模型预测的严格测试
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  • 财政年份:
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