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

描述(由申请人提供)：这个项目建议NIAID的内壁调查员Colleen Hadigan博士和MGH的医学教授Steven Grincoon博士合作，评估一种新的策略，以减少大量患有NAFLD和NASH的HIV患者的肝脏脂肪，并改善肝脏组织学。肝病是HIV患者最重要的慢性共病之一，在抗逆转录病毒治疗的时代，肝病的死亡率仅次于艾滋病相关的死亡率。越来越多的HIV感染患者(30-40%)被认为患有非酒精性脂肪性肝病(NAFLD)，其特征是甘油三酯在肝细胞中积聚，可能进展为肝脏炎症和严重的肝细胞损伤。到目前为止，治疗HIV中NAFLD的疗法研究很少。对艾滋病毒的新疗法的研究尤其紧迫，在这种情况下，NAFLD的贡献者可能与普通人群不同。目前的应用将探索使用生长激素释放激素(GHRH)类似物Tesamorelin治疗HIV中的NAFLD的新策略，该策略将解决导致HIV中肝脏脂肪的两个潜在关键因素，即内脏脂肪增加和肝脏新生脂肪生成增加。在内脏肥胖症增加的HIV感染者中，生长激素通常会减少。替他莫瑞林可以增加内源性生长激素的分泌，是FDA批准的一种治疗方法，用于减少这一人群的内脏脂肪。我们目前的应用建立在强大的初步数据基础上，表明在选择用于内脏肥胖的队列中，替他莫瑞林减少了40%的肝脏脂肪，同时减少了内脏脂肪。在拟议的研究中，我们将评估替他莫瑞林在NAFLD患者和转氨酶升高患者中降低肝脏脂肪的有效性，后者表明炎症和/或肝细胞损伤。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，替他莫瑞林将减少肝脏脂肪，还可以减少肝脏炎症和潜在的肝细胞损伤。此外，为了阐明NAFLD的代谢相关因素，我们将评估替他莫瑞林对肝脏新生脂肪生成的影响，以及降低肝脏脂肪对肝脏和全身胰岛素敏感性的影响。在这份U01赠款申请中，我们将利用 NIAID的HIV相关肝病专家，包括Colleen Hadigan博士、Caryn Morse博士和David Kleiner博士，他们在NAFLD的临床队列中具有良好的特征，在肝脏组织学方面具有丰富的专业知识，以及MGH的Grspiroon博士和他的团队，他们致力于开发一种成功的策略来降低HIV患者的增值税。这项应用建立在两组的初步数据基础上，这些数据证明了非酒精性脂肪肝与艾滋病毒中的肝脏炎症之间的联系，以及在这一人群中，替他莫瑞林对降低肝脏脂肪的强大和新颖的效果。这项拟议的研究将深入了解艾滋病毒患者这一过程的机制，并可能建议首次成功治疗艾滋病毒患者的肝脏脂肪变性和炎症。

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.