Effect of Low Dose Methotrexate on Arterial Inflammation in HIV

描述(申请人提供)：接受抗逆转录病毒治疗(ART)的艾滋病毒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。小剂量甲氨蝶呤(LDMTX)似乎可以降低类风湿性关节炎患者的心血管疾病风险，与艾滋病毒携带者一样，类风湿关节炎患者的炎症水平也会增加。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。这项“家长研究”是一项随机、双盲、安慰剂对照试验，将评估使用LDMTX治疗24周是否安全，ii)减少循环炎症生物标志物和免疫细胞激活水平，iii)改善臂动脉反应性。然而，作为母公司研究的一部分，生物标记物和内皮功能测试都不会报告动脉粥样硬化性炎症(LDMTX治疗HIV的理想病理生物学目标)。因此，对动脉炎症的直接评估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，其总体目标是确定使用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成像可以非侵入性和重复性地测量动脉粥样硬化性炎症，这是一种经过充分验证的定量技术，可以灵敏地检测动脉粥样硬化性炎症的变化，并已被几个多中心试验用于测量抗炎治疗后动脉炎症的变化。我们的中心假设是，持续的免疫激活会导致慢性动脉炎症，这导致了在HIV中观察到的心血管风险。这项完全整合的辅助研究将在参加父母试验的患者子集中进行：(I)评估LDMTX对动脉炎症的影响，(Ii)评估导致艾滋病毒患者动脉炎症的机制，以及iii)探索LDMTX对动脉壁起作用的机制。因此，拟议的研究将提供独特和高度互补的信息，大大增加从家长研究中获得的知识和机械性见解。这项辅助研究有两个具体目的：1)通过FDG-PET/CT成像评估LDMTX抗炎治疗对病毒抑制HIV感染者动脉炎症的影响；2)评估LDMTX治疗对HIV患者动脉炎症影响的细胞和生化基础。我们预计LDMTX治疗将改善动脉炎症，这项机械性、概念性验证研究将证明炎症和免疫激活在HIV相关心血管疾病中的重要性。因此，这将形成事件驱动试验的基础，以评估抗炎策略是否降低了接受治疗的艾滋病毒感染患者的心血管疾病风险。因此，这项研究有可能改变治疗艾滋病毒感染者动脉粥样硬化的方法，也有可能在其他人群中使用。

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.