Is HIV-associated lipodystrophy a risk factor for cirrhosis of the liver?

描述(由申请人提供)： HIV-1和高效抗逆转录病毒治疗(HAART)相关性脂肪营养不良综合征(HALS)的特征是皮下脂肪组织丢失和腹内脂肪组织积聚1。该综合征还通常伴有代谢异常，如胰岛素抵抗、血脂异常和糖尿病。HALS的发病机制尚不完全清楚，很可能抗逆转录病毒药物的使用、类型和持续时间对HALS的发展和严重程度很重要。胰岛素抵抗和腹内脂肪增加也是非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)的主要诱因。因此，以腹内脂肪沉积和胰岛素抵抗为特征的HALS患者可能会发生肝脏脂肪变性和脂肪性肝炎。事实上，通过核磁共振波谱估计，HAART合并脂肪营养不良的HIV感染患者的肝脏脂肪百分比比没有脂肪营养不良的HAART治疗的HIV感染患者高10倍，并且与胰岛素抵抗有关。因此，HALS具有“肥胖相关的”NAFLD/NASH的致病特征，并在小型研究中被证明与肝脏脂肪变性和脂肪性肝炎有关。然而，据我们所知，可能由NAFLD/NASH介导的HALS是否与肝硬化的发生有关的临床相关问题尚未得到回答。多达25%的艾滋病毒感染者同时感染丙型肝炎病毒(丙型肝炎病毒)。众所周知，肝脏脂肪变性是慢性丙型肝炎病毒感染的一种常见的致病特征，导致肝纤维化和肝硬变的加重。因此，HALS还可以通过诱导肝脏脂肪变性来促进丙型肝炎病毒感染患者进展为肝硬变，但这一点从未被研究过。如果正如我们假设的那样，HALS与肝硬化的发展有关，并且抗逆转录病毒药物被认为在HALS的发病机制中处于核心地位，那么研究接触抗逆转录病毒药物是否与发展中的肝硬变相关，以及这种联系是否由HALS的发展所介导也是重要的。我们假设HALS是HIV感染患者发展为肝硬变的重要危险因素。这种联系可能具有许多临床意义，因为肝硬变是艾滋病毒感染者的第二大死因。我们提供了支持这一假说的初步数据，并建议进一步检验它，具体目的如下：1.确定HALS是否与HIV-1感染患者的肝硬变发展有关。2.确定合并或不合并病毒性肝炎的HIV-1感染者HALS与肝硬变的相关性是否不同。3.确定特定的抗逆转录病毒药物或药物组合是否与HIV-1感染患者发展为肝硬变有关。我们的第二个目标是调查HALS和肝硬变之间是否有其他重要的影响因素，包括体重指数、种族和糖尿病。我们将通过分析来自国家退伍军人事务部(VA)艾滋病毒临床病例登记的数据来实现这些目标，其中包含全国退伍军人事务部(VA)机构接受护理的所有确诊的艾滋病毒感染患者的临床数据(n=23,463)。这是世界上最大的、全面的艾滋病毒感染者临床数据库之一。 公共卫生相关性： 我们将调查HALS或有助于HALS发展的抗逆转录病毒药物是否是在VA设施中所有被诊断为HIV感染的患者中导致肝硬变的重要的、新的危险因素。这将具有以下重要意义：1.提高我们对艾滋病毒感染患者中肝硬变病因的了解；2.允许更好地对肝硬变的风险进行分层，这一诊断通常在几乎没有有效治疗机会的情况下做出；3.为研究最近研究的治疗HALS中脂肪再分布的药物是否也减少HALS相关的肝脏脂肪变性、坏死性炎症和纤维化，并最终防止肝硬变的发展提供了理论基础。4.确定与肝硬变密切相关的特定抗逆转录病毒药物，对于有明显肝脏坏死性炎症或纤维化的患者应避免服用，以防止进展为肝硬变。5.归根结底，有助于减轻肝硬变的负担，肝硬变是艾滋病毒感染者死亡的第二大原因。

DESCRIPTION (provided by applicant): HIV-1 and highly active antiretroviral treatment (HAART)-Associated Lipodystrophy Syndrome (HALS) is characterized by loss of subcutaneous adipose tissue and accumulation of intra-abdominal adipose tissue1. The syndrome is also commonly accompanied by metabolic abnormalities such as insulin resistance, dyslipidemia, and diabetes mellitus. The pathogenesis of HALS is not entirely understood; it is likely that the use, type and duration of anti-retroviral medications are important in the development and severity of HALS. Insulin resistance and increased intra-abdominal fat are also the major predisposing conditions of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Therefore, it would be expected that patients with HALS, which is characterized by intra-abdominal fat deposition and insulin resistance, would develop hepatic steatosis and steatohepatitis. Indeed, the percentage of liver fat, estimated by nuclear magnetic resonance spectroscopy, was found to be 10 times higher in HIV-infected patients on HAART with lipodystrophy than in HIV-infected patients on HAART without lipodystrophy, and was correlated with insulin resistance. Thus, HALS is characterized by the pathogenetic features of "obesity-related" NAFLD/NASH and has been shown in small studies to be associated with hepatic steatosis and steatohepatitis. However, the clinically relevant question of whether HALS is associated with the development of cirrhosis, likely mediated by NAFLD/NASH, has not been answered to our knowledge. Hepatitis C virus (HCV) co-infection occurs in as many as 25% of HIV-infected patients. Hepatic steatosis is known to be a common and pathogenetic feature of chronic HCV infection causing increased progression to fibrosis and cirrhosis. Therefore, HALS could also promote the progression to cirrhosis in HCV co-infected patients, by inducing hepatic steatosis, but this has never been investigated. If HALS is related to the development of cirrhosis, as we hypothesize, and antiretroviral medications are believed to be central in the pathogenesis of HALS, then it is also be important to investigate whether exposure to antiretroviral medications is associated with the development cirrhosis and whether such an association is mediated by the development of HALS. We hypothesize that HALS is an important risk factor for the development of cirrhosis in HIV-infected patients. This association could have many clinical implications because cirrhosis is the second leading cause of death in HIV-infected persons. We present preliminary data to support this hypothesis and propose to examine it further with the following specific aims: 1. Determine whether there is an association between HALS and the development of cirrhosis among HIV-1-infected patients. 2. Determine whether the association between HALS and cirrhosis is different among HIV-1- infected patients with or without viral hepatitis co-infection. 3. Determine whether specific antiretroviral medications or combinations of medications are associated with the development of cirrhosis in HIV-1-infected patients. Our secondary aim is to investigate whether there are other important modifiers of the association between HALS and cirrhosis, including body mass index, race-ethnicity, and diabetes. We will achieve these aims by analyzing data from the national Veterans Affairs (VA) HIV Clinical Case Registry, which contains clinical data on all diagnosed, HIV-infected patients receiving care in VA facilities throughout the country (n=23,463). This represents one of the largest, comprehensive clinical databases of HIV-infected patients in the world. PUBLIC HEALTH RELEVANCE: We will investigate whether HALS, or antiretroviral medications that can contribute to the development of HALS, are important, novel risk factors for cirrhosis among all diagnosed HIV-infected patients in VA facilities. This will have the following important implications: 1. Improve our understanding of the causes of cirrhosis in HIV-infected patients; 2. Allow better stratification of the risk of cirrhosis, a diagnosis that is often made late when there is little chance of effective treatment; 3. Provide a rationale for investigating whether medications recently studied for the treatment of fat redistribution in HALS also reduce HALS-related hepatic steatosis, necroinflammation and fibrosis and ultimately prevent the development of cirrhosis. 4. Identify specific antiretroviral medications strongly associated with cirrhosis which ought to be avoided in patients with evidence of substantial hepatic necroinflammation or fibrosis, in order to prevent progression to cirrhosis. 5. Ultimately, help reduce the burden of cirrhosis which is the second leading cause of death in HIV-infected persons.