Effect of IL-1B inhibition on inflammation and cardiovascular risk in HIV

 描述（由申请人提供）：虽然抗逆转录病毒疗法（ART）延长生命，但不能完全恢复健康。由于仍然存在争议的原因，治疗效果良好的艾滋病毒感染者与未感染者相比寿命缩短，并且患上包括心血管疾病在内的一些“非艾滋病”疾病的风险也高于预期。艾滋病毒感染者心肌梗死的风险增加2倍，心脏性猝死的发生率也更高。虽然这些临床观察结果的潜在机制可能是多因素的，但在治疗HIV的背景下，慢性炎症是疾病过程的关键因素。IL-1 β是一种由单核细胞、巨噬细胞和树突状细胞产生的促炎细胞因子;使用IL-1 β的单克隆抗体卡那单抗抑制IL-1 β可显着减少炎症标志物，并且已在CANTOS研究中对> 10000名无艾滋病毒的个体进行了研究，没有任何重大的安全问题。为了确定长期抗逆转录病毒治疗HIV感染期间IL-1 β抑制对全身炎症的影响，我们建议进行一项单中心发病机制导向研究，评估canakinumab（一种抑制IL-1 β的人单克隆抗体）对全身炎症、T细胞活化和血管炎症的影响。鉴于炎症在促进病毒持久性方面的假定作用，我们还将测量canakinumab对HIV储库大小的影响。我们将通过仅招募接受长期有效ART且CD 4 T细胞计数≥ 400个细胞/mm 3的HIV感染成人，并通过进行两阶段里程碑驱动研究（第一阶段（第I阶段）将招募一小群仔细监测的个体（N=10）），重点关注本研究的安全性。一旦确定安全性，我们将进入第II阶段，并将100例受试者随机分配至canakinumab组与安慰剂组。在整个试验期间，将由独立的安全性监查委员会仔细监查安全性数据。我们提出以下目标：目标1：确定在有效治疗和抑制的HIV感染成人中使用canakinumab抑制IL 1-β的安全性、耐受性和药代动力学。我们将在10名接受单剂量卡那单抗的个体中进行初步试验研究;如果药物安全且耐受性良好，（正如预期的那样），我们将在一项随机、安慰剂对照试验中招募100名额外的个体，目标1-3;目标2：为了证明IL-1 β抑制降低炎症标志物和单核细胞活化，并改善治疗和抑制HIV感染个体的血管炎症和内皮功能障碍;目的3：确定IL-1 β抑制是否减少T细胞活化和减少血液中HIV储库的大小。该应用程序结合了（1）一个专门和成功的多学科团队，在研究HIV免疫调节药物方面具有良好的合作记录和专业知识，（2）能够从现有的HIV感染受试者队列中快速招募受试者，（3）高级研究人员的合作，进行创新的免疫学检测和HIV持久性测量（摘要结束）

 DESCRIPTION (provided by applicant): Although antiretroviral therapy (ART) prolongs life, it does not fully restore health. For reasons that remain controversial, HIV-infected individuals doing well on therapy have a shortened lifespan as compared to their uninfected counterparts and also have a higher than expected risk of a number of "non-AIDS" conditions including cardiovascular disease. HIV-infected individuals have a 2-fold higher risk of myocardial infarction and higher rates of sudden cardiac death. While the underlying mechanism for these clinical observations is likely multifactorial, chronic inflammation in the setting of treated HIV as emerged as a key contributor to the disease process. IL-1ß is a pro-inflammatory cytokine produced by monocytes, macrophages and dendritic cells; IL-1ß inhibition using canakinumab, a monoclonal antibody to IL-1ß, dramatically reduces inflammatory markers, and has been studied in > 10000 individuals without HIV in the CANTOS study without any significant safety issues. In order to determine the impact of IL-1ß inhibition on systemic inflammation during long-term antiretroviral-treated HIV infection, we propose to perform a single center pathogenesis-oriented study assessing the impact of canakinumab-a human monoclonal antibody which inhibits IL-1ß-on systemic inflammation, T cell activation, and vascular inflammation. Given the putative role that inflammation has in contributing to viral persistence, we will also measure the impact of canakinumab on the size of the HIV reservoir. We will focus on safety in this study by only enrolling HIV-infected adults on long-term effective ART with CD4 T-cell counts =400 cells/mm3 and by performing a two-stage milestone driven study in which the first stage (Stage I) will enroll a small cohort of carefully monitored individuals (N=10). Onc safety is established, we will move to Stage II and randomize 100 subjects to canakinumab vs. placebo. Safety data will be carefully monitored by an independent safety monitoring committee throughout the trial. We propose the following aims: Aim 1: To determine the safety, tolerability, and pharmacokinetics of IL1-ß inhibition using canakinumab in effectively treated and suppressed HIV-infected adults. We will perform an initial pilot study in ten individuals who will all receive a single dose of canakinumab; if the drug is safe and well tolerated (as expected), we will enroll 100 additional individuals in a randomized, placebo controlled trial under Aims 1-3; Aim 2: To demonstrate that IL-1ß inhibition decreases inflammatory markers and monocyte activation, and improves vascular inflammation and endothelial dysfunction among treated and suppressed HIV-infected individuals; Aim 3: To determine whether IL-1ß inhibition reduces T cell activation and decreases the size of the HIV reservoir in blood. This application combines (1) a dedicated and successful multidisciplinary team with a strong record of collaboration and expertise in studying immune-modulating drugs in HIV, (2) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects, (3) the collaboration of senior investigators performing innovative immunology assays and measurements of HIV persistence (End of Abstract)