Rates and determinants of decreased bone health among HIV-infected patients

描述(由申请人提供)： 自采用高效抗逆转录病毒疗法(HAART)以来，随着HIV感染者存活率的提高，低骨量和骨质疏松性骨折似乎正在成为影响HIV阳性人群老龄化的重要慢性问题。此外，估计有15%至30%的艾滋病毒感染患者合并感染丙型肝炎(丙型肝炎)，这也与骨质疏松有关。对于给定的骨密度下降，在普通人群中，骨折风险随着年龄的增长而急剧增加。尽管如此，从未对大规模艾滋病毒队列中骨折风险的趋势进行评估，以确定这是否是艾滋病毒感染患者中日益严重的问题，也没有对风险因素进行深入评估，包括抗逆转录病毒疗法(ART)和丙型肝炎病毒联合感染的类型和持续时间。此外，可能导致HIV感染患者骨密度降低和骨质疏松性骨折风险增加的与丙型肝炎病毒感染相关的因素--形成减少或吸收增加--尚未阐明。最后，骨质疏松性骨折对艾滋病相关和非艾滋病相关发病率和死亡率的影响尚不清楚。我们建议结合以下几个方面来帮助弥合这些知识上的差距：1)在退伍军人健康管理局(VHA)临床病例登记(CCR)中对骨质疏松性骨折风险、他们的预测因素和结果进行回顾分析，其中包含自1984年以来跟踪的近60,000名现任和前任患者的数据，为解决这些重要问题提供了一个极好的来源；2)一项横断面研究，比较了在退伍军人事务部北得克萨斯医疗保健系统(VANTHCS)接受护理的HIV/丙型肝炎混合感染、HIV和丙型肝炎单一感染患者之间的骨密度和骨转换标志物(BTM)，其中包括650名当前HIV患者(1/3合并感染丙型肝炎病毒)和近5000名丙型肝炎患者。目前拟议的工作将涉及三个具体目标： 1)确定抗逆转录病毒治疗对HIV感染患者骨健康的影响。使用CCR，骨质疏松性骨折将通过ICD-9代码进行识别。将计算年龄调整的骨质疏松性骨折的标准化发生率(SIRS)，并比较HAART前(1984-1995)和HAART(1996-2009)时代的情况。然后将进行生存分析，预测HIV感染患者骨折的发生，并将不同的ART暴露作为时间依赖变量； 2)探讨HIV感染者合并感染丙型肝炎病毒对骨健康的影响。我们将评估在VANTHCS接受治疗的艾滋病毒/丙型肝炎混合感染患者以及年龄、性别和种族匹配的艾滋病毒单一感染患者和丙型肝炎病毒单一感染患者的骨密度、骨形态发生量、促钙激素和性腺激素以及炎性细胞因子。将进行方差分析以检测三组患者之间的差异。骨质疏松性骨折的年龄调整SIRS将被计算出来，并在HIV/丙型肝炎病毒混合感染和仅感染HIV的患者之间进行比较。我们将进一步比较HAART之前和HAART时代的SIRS； 3)确定骨健康状况下降和骨质疏松性骨折与HIV感染患者的发病率和死亡率的关系。在横断面分析中，我们将评估血脂异常、胰岛素抵抗和高乳酸血症与BMD和BTMS的相关性。此外，我们将使用CCR数据，通过将血脂异常、高血糖和高乳酸血症作为时间依赖协变量纳入Cox生存模型，来探讨它们是否可以预测骨质疏松性骨折的发生。最后，将根据CCR数据构建生存模型，以探索骨质疏松性骨折与全原因死亡率、艾滋病和非艾滋病相关死亡率的关系。

DESCRIPTION (provided by applicant): With the improved survival of HIV-infected patients since the introduction of Highly Active Antiretroviral Therapy (HAART), low bone mass and osteoporotic fractures seem to be emerging as important chronic problems that affect the aging HIV-positive population. Furthermore, an estimated 15 to 30% of HIV-infected patients are co-infected with hepatitis C (HCV), also associated with osteoporosis. For a given decrease in bone mineral density (BMD), the fracture risk increases dramatically with age in the general population. Despite this fact, trends in fracture risk in a large HIV cohort have never been evaluated to determine whether this is a growing problem among HIV-infected patients nor has an in-depth evaluation of risk factors been conducted, including type and duration of antiretroviral therapy (ART) and HCV co-infection. Furthermore, factors associated with HCV infection that might mediate a higher risk of decreased bone density and osteoporotic fractures - either decreased formation or increased resorption - among HIV-infected patients have not been elucidated. Finally, the impact of osteoporotic fractures on AIDS-related and non-AIDS-related morbidity and mortality is not known. We propose to help bridge these gaps in knowledge with a combination of: 1) a retrospective analysis of osteoporotic fracture risk, their predictors and outcomes in the Veterans Health Administration (VHA) Clinical Case Registry (CCR) which contains data on close to 60,000 current and former patients followed since 1984, provides an excellent source for addressing these important questions; and 2) a cross-sectional study comparing BMD and bone turnover markers (BTMs) between HIV/HCV co-infected, HIV and HCV mono-infected patients receiving care at the VA North Texas Health Care System (VANTHCS), with 650 current HIV patients (1/3 co-infected with HCV) and close to 5000 HCV patients. The current proposed work will address three specific aims: 1) To determine the impact of ART on bone health in HIV-infected patients. Using the CCR, osteoporotic fractures will be identified by ICD-9 code. Age-adjusted standardized incidence rates (SIRs) of osteoporotic fractures will be calculated and compared between the pre-HAART (1984-1995) and HAART (1996-2009) eras. Survival analyses will then be performed predicting onset of fractures among HIV-infected patients with various ARTexposure as time-dependent variables; 2) To determine the impact of HCV co-infection on bone health in HIV patients. We will assess BMD, BTMs, calciotropic and gonadal hormones and inflammatory cytokines in HIV/HCV co-infected patients and age-, gender-, and race-matched HIV mono-infected patients and HCV mono-infected patients receiving care at the VANTHCS. The ANOVA analysis will be conducted to detect difference among the three groups of patients. Age-adjusted SIRs of osteoporotic fractures will be computed and compared between HIV/HCV co- infected and HIV-only infected patients. We will further compare the SIRs within the pre-HAART and HAART eras; 3) To determine the association of decreased bone health and osteoporotic fractures with morbidity and mortality of HIV-infected patients. In the cross-sectional analysis, we will evaluate the correlation of dyslipidemia, insulin resistance and hyperlactatemia with BMD and BTMs. Furthermore, we will use the CCR data to explore whether dyslipidemia, hyperglycemia and hyperlactemia predict the onset of osteoporotic fractures by including them into the Cox survival model as time-dependent covariates. Finally, survival models will be constructed from CCR data to explore the association of osteoporotic fractures with all- cause mortality, AIDS and non-AIDS-related mortality.