Effect of Low Dose Methotrexate on Arterial Inflammation in HIV

描述（由申请人提供）：接受抗逆转录病毒治疗（ART）的hiv感染者患心血管疾病（CVD）的风险增加，可能是由于慢性炎症增加。低剂量甲氨蝶呤（LDMTX）似乎可以降低类风湿关节炎患者的心血管疾病风险，类风湿关节炎患者与艾滋病毒感染者一样，炎症水平升高。NHLBI最近为一项针对艾滋病毒过度炎症的临床试验提供了资金。该“母体研究”是一项随机、双盲、安慰剂对照试验，将评估LDMTX治疗24周是否安全，ii)降低循环炎症生物标志物和免疫细胞激活水平，iii)改善肱动脉反应性。然而，作为母体研究的一部分，生物标志物和内皮功能测试都没有报告动脉粥样硬化性炎症（LDMTX治疗HIV所需的病理生物学靶点）。因此，直接评估动脉炎症将大大提高试验的科学价值。我们建议进行一项时间敏感的辅助成像研究，其总体目标是确定用LDMTX治疗病毒学抑制的hiv感染者是否会减少动脉壁内的炎症。FDG-PET/CT成像可以无创、可重复地测量动脉粥样硬化炎症，这是一种经过验证的定量技术，可以灵敏地检测动脉粥样硬化炎症的变化，并已在多个多中心试验中用于测量动脉炎症对抗炎治疗的反应。我们的中心假设是，持续的免疫激活导致慢性动脉炎症，这有助于在HIV中观察到的心血管疾病风险。这项完全整合的辅助研究将在一组参加母试验的患者中进行：(i)评估LDMTX对动脉炎症的影响，（ii）评估艾滋病毒引起动脉炎症的机制，以及（iii）探索LDMTX对动脉壁作用的机制。因此，建议的研究将提供独特和高度补充的信息，这将大大增加从父母研究中获得的知识和机制见解。这项辅助研究有两个特定目的：1)通过FDG-PET/CT成像评估，确定LDMTX抗炎治疗对病毒抑制的hiv感染者动脉炎症的影响。2)探讨LDMTX治疗HIV动脉炎症的细胞和生化基础。我们期望LDMTX治疗将改善动脉炎症，并且这一机制，概念验证研究将证明炎症和免疫激活在hiv相关CVD中的重要性。因此，这将形成事件驱动试验的基础，以评估抗炎策略是否能降低接受治疗的HIV感染个体的心血管疾病风险。因此，该研究有可能改变治疗hiv感染者动脉粥样硬化方法的范式，也有可能在其他人群中进行。

DESCRIPTION (provided by applicant): HIV-infected individuals on antiretroviral therapy (ART) are at increased risk for cardiovascular disease (CVD), likely due to chronically increased inflammation. Low-dose methotrexate (LDMTX) appears to reduce CVD risk in people with rheumatoid arthritis, who like those with HIV, have increased levels of inflammation. The NHLBI recently provided funding for a clinical trial targeting the excess inflammation in HIV. That "Parent Study" is a randomized, double-blind, placebo-controlled trial that will assess whether 24-week treatment with LDMTX: i) is safe, ii) reduces circulating inflammatory biomarkers and levels of immune cell activation and iii) improves brachial artery reactivity. However, neither the biomarkers nor endothelial function tests measured as part of the parent study will report on atherosclerotic inflammation, (the desired pathobiological target of LDMTX therapy in HIV). As such, the direct evaluation of arterial inflammation would substantially enhance the scientific value of the trial. We propose to conduct a time sensitive ancillary imaging study whose overall goal is to determine if treating virologically suppressed, HIV-infected individuals with LDMTX will reduce inflammation within the arterial wall. Atherosclerotic inflammation can be non-invasively and reproducibly measured with FDG-PET/CT imaging, a well-validated quantitative technique that can sensitively detect changes in atherosclerotic inflammation and which has been employed in several multi-center trials to measure changes in arterial inflammation in response to anti-inflammatory treatments. Our central hypothesis is that persistent immune activation results in chronic arterial inflammation, which contributes to the CVD risk observed in HIV. This fully integrated ancillary study would, in a subset of patients enrolled in the parent trial: (i) assess the impact of LDMTX on arterial inflammation, (ii) evaluate mechanisms responsible for arterial inflammation in HIV and iii) explore mechanisms responsible for actions of LDMTX on the artery wall. Accordingly, the proposed study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from Parent Study. The ancillary study has two specific aims1) To determine the impact of anti-inflammatory treatment with LDMTX on arterial inflammation, as assessed by FDG-PET/CT imaging, in virally suppressed HIV-infected individuals., and 2) To evaluate the cellular and biochemical basis of the effect of LDMTX therapy on arterial inflammation in HIV. We expect that LDMTX therapy will improve arterial inflammation and that this mechanistic, proof-of-concept study will demonstrate the importance of inflammation and immune activation in HIV-associated CVD. This would thus form the basis for event-driven trials to evaluate whether anti-inflammatory strategies reduce CVD risk in individuals with treated HIV infection. Accordingly, the study has the potential to shift the paradigm in the approach to treating atherosclerosis in HIV-infected individuals, and potentially in other populations as well.