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

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
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-23 至 2026-07-31
关键词:
AffectAgeAlcohol consumptionAlcoholic Liver DiseasesAlcoholsAmmoniaAngiogenesis InhibitorsAnti-Inflammatory AgentsAntioxidantsArchitectureAscitesBiological MarkersCause of DeathCessation of lifeChildCirrhosisClinicClinicalClinical TrialsCohort StudiesComplicationComputerized Medical RecordCross-Sectional StudiesDataDatabasesDevelopmentDiagnosisDiagnosticDiseaseDisease OutcomeDisease ProgressionEncephalopathiesEnrollmentEthnic OriginEtiologyEvaluationEventFibrosisFunctional disorderGenderHIVHIV InfectionsHealth systemHemorrhageHepaticHigh PrevalenceHospitalsHumanHydroxymethylglutaryl-CoA Reductase InhibitorsIcterusImmuneImpairmentInfectionInjuryLiverLiver CirrhosisLiver FibrosisLiver diseasesLobularLong-Term CareLongitudinal StudiesLongitudinal cohortLongitudinal cohort studyMeasuresModelingMuscleMuscular AtrophyMyopathyOrganOutcomePathogenesisPatient CarePatientsPatternPilot ProjectsPlacebosPlasmaPlayPortal PressurePrevalencePrimary carcinoma of the liver cellsProductivityProspective StudiesProspective, cohort studyProteomicsPublic HealthPublishingQuality of lifeRandomizedRandomized, Controlled TrialsReportingRiskRisk FactorsRoleSafetySeveritiesSeverity of illnessSimvastatinSyndromeSystemTelemedicineTestingUnited StatesUnited States National Institutes of HealthVirusVirus Diseasesadverse outcomebiobankchronic liver diseaseclinical centerclinical practiceclinically significantcomorbiditycostdigital healthend stage liver diseasefollow-upfrailtygut microbiomehealth managementhigh riskhuman dataimprovedimproved outcomeinnovationinterestliver inflammationliver injuryliver transplantationmetabolomicsmicrobialmortalitynew technologynew therapeutic targetnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel markernovel therapeuticsparticipant enrollmentpatient populationpharmacologicpredict clinical outcomepreventprimary outcomeprofiles in patientsprogramsprogression markerprogression riskprospectiverandomized placebo controlled trialrandomized, clinical trialsresearch clinical testingresponsesarcopeniatelevisittherapeutic targettrimethylamineyoung adult

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中文摘要
翻译
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
英文摘要
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.
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