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

年，慢性肝病，主要是肝硬变，仍然是65岁以下成年人死亡的第六大原因。 美国。尽管诊断和治疗取得了进步，但肝硬变的死亡率并没有改变。 在过去的40年里显著增加，并且仍然是一个重大的公共卫生负担。我们和其他人已经使用了 建模和数据库评估显示酒精相关性肝病(ALD)和非酒精性脂肪 在美国，肝病(NAFLD)是导致肝硬变的两大原因。治疗潜在的病因 肝硬变可能有助于纤维化消退，但肝硬变是否可逆尚不确定。纤维化是否 一旦确诊为肝硬变，如果进展与失代偿有关，就会进展 或者肝细胞癌(HCC)也是未知的。关于肝硬变、骨质疏松症的各种并发症 由于收缩功能受损而导致的身体虚弱是常见的、进行性的，并对临床造成不利影响 结果。尽管有很高的临床意义，但还没有关于发育、进展的前瞻性研究。 以及预测肝硬变患者骨质疏松症和虚弱的指标。共病，特别是人类免疫感染- 缺乏病毒(HIV)使肝硬变患者处于进展纤维化、失代偿和 骨质疏松症/虚弱综合征肠道微生物组和它们的代谢物(异物代谢物)起着一种机械作用 在肝损伤和包括肝细胞癌和骨质疏松症在内的肝硬变并发症中的作用 人类患者的前瞻性研究。大多数关于COPD的进展、远期并发症、影响的研究 肝硬变的发病率和结果是横断性的，受试者数量很少，不能转化。 肝硬变及其并发症发生的机制研究进展。 因此，对特征良好的肝硬变进行前瞻性研究对于开发有效的治疗方法至关重要。 战略和改善结果。他汀类药物在药物治疗中的应用日益受到关注。 由于抗炎和抗肝纤维化的作用，可以防止失代偿和肝细胞癌。这个 克利夫兰临床卫生系统是最大的临床项目之一，拥有大量的 由于我们的专业知识，被转介进行包括肝移植在内的长期治疗的肝硬变患者 在病人护理的创新方法中，包括电视节目和数字医疗的应用 综合电子病历。为响应RFA标准DK-20-003，我们建议成为 肝硬变网络建立一个纵向队列的肝硬变患者，主要是与酒精和 非酒精性脂肪性肝病与包括艾滋病毒感染在内的共病。我们将开发一个油井数据库 特征化的患者和来自这些患者的生物信息库，以促进我们对 肝硬变的进展、并发症的发展以及寻找新的生物标志物和治疗方法以改进 临床结果。我们还将在Well中使用辛伐他汀/安慰剂进行前瞻性随机临床试验。 将肝硬变患者作为网络的一部分，以确定临床反应和安全性。

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.