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）相关的脂肪营养不良综合征（HALS）的特征是皮下脂肪组织的损失和腹腔内脂肪组织的积累1。该综合征通常还伴有代谢异常，如胰岛素抵抗、血脂异常和糖尿病。HALS的发病机制还不完全清楚;抗逆转录病毒药物的使用、类型和持续时间可能对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）的主要诱发条件。因此，可以预期的是，HALS患者（其特征在于腹腔内脂肪沉积和胰岛素抵抗）将发生肝脂肪变性和脂肪性肝炎。事实上，通过核磁共振光谱法估计的肝脏脂肪百分比，发现在接受HAART治疗的HIV感染患者中，脂肪代谢障碍比接受HAART治疗的HIV感染患者高10倍，并且与胰岛素抵抗相关。因此，HALS的特征在于“肥胖相关”NAFLD/NASH的发病学特征，并且已经在小型研究中显示与肝脂肪变性和脂肪性肝炎相关。然而，HALS是否与可能由NAFLD/NASH介导的肝硬化的发展相关的临床相关问题，就我们所知尚未得到回答。 丙型肝炎病毒（HCV）合并感染发生在多达25%的HIV感染患者中。已知肝脂肪变性是慢性HCV感染的常见和致病特征，其导致向纤维化和肝硬化的进展增加。因此，HALS也可以通过诱导肝脂肪变性促进HCV合并感染患者向肝硬化的进展，但这从未被研究过。 如果像我们假设的那样，HALS与肝硬化的发展有关，并且抗逆转录病毒药物被认为是HALS发病机制的核心，那么研究抗逆转录病毒药物的暴露是否与肝硬化的发展有关以及是否与肝硬化的发展有关也很重要。这种关联是由HALS的发展介导的。 我们假设HALS是HIV感染患者发生肝硬化的一个重要危险因素。这种关联可能具有许多临床意义，因为肝硬化是HIV感染者死亡的第二大原因。我们提出了初步的数据来支持这一假设，并建议进一步研究它与以下具体目标：1。确定HALS与HIV-1感染患者肝硬化发展之间是否存在关联。 2.确定HALS和肝硬化之间的关联是否在合并或不合并病毒性肝炎感染的HIV-1感染患者中存在差异。 3.确定特定的抗逆转录病毒药物或药物组合是否与HIV-1感染患者肝硬化的发展相关。 我们的第二个目的是研究HALS和肝硬化之间是否有其他重要的关联，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）HIV临床病例登记处的数据来实现这些目标，该登记处包含全国各地在VA设施接受护理的所有诊断的HIV感染患者的临床数据（n= 23，463）。这是世界上最大、最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或抗逆转录病毒药物是否有助于HALS的发展，是否是VA设施中所有确诊的HIV感染患者中肝硬化的重要新风险因素。这将产生以下重要影响：1.提高对HIV感染者肝硬化病因的认识; 2.允许更好地分层肝硬化的风险，这种诊断通常很晚才做出，因为几乎没有机会获得有效治疗; 3.为研究最近研究的用于治疗HALS脂肪再分布的药物是否也能减少HALS相关的肝脂肪变性、坏死性炎症和纤维化并最终预防肝硬化的发展提供依据。4.确定与肝硬化密切相关的特定抗逆转录病毒药物，在有大量肝坏死性炎症或纤维化证据的患者中应避免使用，以防止进展为肝硬化。5.最终，帮助减轻肝硬化的负担，肝硬化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.