Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative U01 Grant

Tesamorelin 对 HIV 肝脏脂肪和组织学的影响：U01 合作资助

基本信息

批准号：
9177746
负责人：
STEVEN K. GRINSPOON
金额：
$ 68.53万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177746
关键词：
Acquired Immunodeficiency Syndrome Address Adipose tissue Adult Adverse effects Applications Grants Biopsy Cardiovascular Diseases Central obesity Chronic Cirrhosis Clinical Collaborations Comorbidity Data Development Dyslipidemias Enzymes FDA approved Fasting Fatty Liver Fatty acid glycerol esters Fibrosis General Hospitals General Population Genes Grant HIV HIV Infections Health Hepatic Hepatocellular Damage Hepatocyte High Prevalence Histologic Histology Hormonal Individual Inflammation Inflammatory Injury Insulin Resistance Intervention Investigation Lead Liver Liver Fibrosis Liver diseases Magnetic Resonance Spectroscopy Massachusetts Measures Medicine Metabolic National Institute of Allergy and Infectious Disease Obesity Participant Pathologist Patients Peripheral Phase Phenotype Physiological Physiology Placebos Play Population Process Randomized Controlled Trials Recruitment Activity Research Research Methodology Research Personnel Role Somatotropin Somatotropin-Releasing Hormone Steatohepatitis Testing Therapeutic Transaminases Triglycerides United States National Institutes of Health Visceral Vitamin E Work adiponectin antiretroviral therapy cohort design elastography experience glucose metabolism hepatic gluconeogenesis hormone analog improved indexing insight insulin sensitivity lipid biosynthesis lipid metabolism liver biopsy liver imaging liver inflammation liver injury mortality non-alcoholic fatty liver nonalcoholic steatohepatitis novel novel strategies novel therapeutics open label professor public health relevance stable isotope treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This project proposes a collaboration between Dr. Colleen Hadigan, Intramural Investigator at NIAID, and Dr. Steven Grinspoon, Professor of Medicine at MGH, to assess a novel strategy to reduce liver fat and improve liver histology in the large number of HIV patients with NAFLD and NASH. Liver disease is one of the most significant chronic co-morbid conditions among HIV patients, and, in the era of antiretroviral therapy, mortality from liver disease is second only to AIDS related mortality. An increasing percentage of HIV-infected patients (30-40%) are thought to have non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride accumulation in hepatocytes that may progress to hepatic inflammation and significant hepatocellular injury. To date, therapies to treat NAFLD in HIV have been poorly studied. Investigation of new therapies is particularly urgent in HIV, in which contributors to NAFLD may be distinct from those in the general population. The current application will investigate a novel strategy to treat NAFLD in HIV using tesamorelin, a growth hormone releasing hormone (GHRH) analogue, which will address two potentially critical contributors to liver fat in HIV, namely increased visceral adiposity and increased hepatic de novo lipogenesis. Growth hormone is generally decreased in HIV-infected individuals with increased visceral adiposity. Tesamorelin, which increases endogenous growth hormone secretion, is an FDA approved therapy to reduce visceral fat in this population. Our current application builds on strong preliminary data, showing that tesamorelin reduced liver fat by 40% in association with reductions in visceral fat in a cohort chosen for visceral obesity. In the proposed studies, we will assess the efficacy of tesamorelin to reduce liver fat in patients chosen for NAFLD and increased transaminases, with the latter indicating inflammation and/or hepatocellular damage. We will also investigate effects of GHRH analogue on liver inflammation, hepatocellular damage, and liver fibrosis. We hypothesize that tesamorelin will reduce liver fat and also reduce hepatic inflammation and potentially hepatocellular injury. Further, to elucidate metabolic correlates of NAFLD, we will assess the effects of tesamorelin on hepatic de novo lipogenesis, and the effects of liver fat reduction on hepatic and whole body insulin sensitivity. In this U01 grant application, we will leverage a strong collaboration between experts in HIV-associated liver disease at NIAID, including Drs. Colleen Hadigan and Caryn Morse and David Kleiner, with a well-characterized clinical cohort with NAFLD and significant expertise in liver histology and Dr. Grinspoon and his team at MGH, who have worked to develop a successful strategy to reduce VAT in HIV patients. This application builds on preliminary data from both groups demonstrating the linkage between NAFLD and liver inflammation in HIV and the robust and novel effects of tesamorelin to reduce hepatic fat in this population. The proposed investigation will provide insight into the mechanism of this process in HIV patients and may suggest the first successful treatment for hepatic steatosis and inflammation in HIV patients.

描述（由申请人提供）：该项目提出了NIAID壁内研究者Colleen Hadigan博士与MGH医学教授Steven Grinspoon博士之间的合作，以评估一种新的策略，以减少肝脏脂肪并改善大量HIV患者NAFLD和Nash的HIV患者的肝组织学。肝病是HIV患者中最重要的慢性合并症之一，在抗逆转录病毒疗法的时代，肝病的死亡率仅次于艾滋病相关死亡率。越来越多的HIV感染患者（30-40％）被认为患有非酒精性脂肪肝病（NAFLD），其特征是肝细胞中甘油三酸酯的积累，可能会发展为肝炎炎症和严重的肝细胞损伤。迄今为止，对HIV治疗NAFLD的疗法的研究很差。在艾滋病毒中，对新疗法的调查尤其紧迫，其中NAFLD的贡献者可能与普通人群中的贡献不同。当前的应用将研究一种新的策略，以使用Tesamorelin（一种生长激素释放激素（GHRH）类似物）来治疗HIV中的NAFLD，该策略将针对HIV中肝脏脂肪的两个潜在至关重要的促进者，即增加内脏肥胖性和增加Novo De Novo De Novo脂肪生成。艾滋病毒感染的个体的生长激素通常会降低，内脏肥胖增加。增加内源性生长激素分泌的家属是FDA批准的疗法，可减少该人群的内脏脂肪。我们当前的应用以强大的初步数据为基础，这表明，在选择用于内脏肥胖症的同类中，对内脏脂肪减少了肝脏脂肪，将肝脏脂肪降低了40％。在拟议的研究中，我们将评估对选择用于NAFLD和跨激酶增加的患者减少肝脏脂肪的功效，后者表明炎症和/或肝细胞壁损伤。我们还将研究GHRH类似物对肝脏炎症，肝细胞损伤和肝纤维化的影响。我们假设对氨基甲甲素会减少肝脏脂肪，并减少肝发炎和潜在的肝细胞损伤。此外，为了阐明NAFLD的代谢相关性，我们将评估家属对肝脂肪生成的影响，以及肝脏脂肪降低对肝和全身胰岛素敏感性的影响。在此U01赠款应用程序中，我们将利用 NIAID的HIV相关肝病专家，包括Drs。 Colleen Hadigan和Caryn Morse和David Kleiner，拥有良好的临床队列，具有NAFLD，并在肝组织学方面拥有巨大的专业知识，Grinspoon博士及其MGH的团队，他们努力制定了一项成功的策略，以减少HIV患者的增值税。该应用基于两组的初步数据，证明了HIV中NAFLD和肝脏炎症之间的联系，以及托索洛林对减少该人群中肝脂肪的强大和新作用。拟议的调查将洞悉HIV患者该过程的机制，并可能建议首次成功治疗HIV患者的肝脂肪变性和炎症。