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

 描述(申请人提供)：虽然抗逆转录病毒疗法(ART)可以延长生命，但并不能完全恢复健康。由于仍然存在争议的原因，艾滋病毒感染者在治疗方面做得很好，与未感染艾滋病毒的人相比，他们的寿命较短，而且患上包括心血管疾病在内的许多“非艾滋病”疾病的风险也高于预期。感染艾滋病毒的人患心肌梗死的风险是普通人的两倍，心脏病猝死率也更高。虽然这些临床观察的潜在机制可能是多因素的，但在接受艾滋病毒治疗的背景下，慢性炎症成为疾病过程的关键因素。IL-1？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？的单抗canakinumab抑制IL-1？可显著减少炎症标志物，并已在CANTOS研究中对10000名未感染艾滋病毒的人进行研究，没有任何重大的安全性问题。为了确定长期接受抗逆转录病毒治疗的HIV感染过程中IL-1？抑制对全身炎症的影响，我们建议进行一项单中心病程导向研究，评估Canakinumab对全身炎症、T细胞激活和血管炎症的影响。Canakinumab是一种抑制IL-1？的人类单抗。鉴于炎症在病毒持续存在中的推定作用，我们还将衡量Canakinumab对艾滋病毒储备库大小的影响。在这项研究中，我们将重点放在安全性上，只招募HIV感染的成年人接受长期有效的抗逆转录病毒疗法，CD4T细胞计数=400细胞/mm3，并进行一项分两个阶段的里程碑驱动研究，其中第一阶段(第一阶段)将招募一小批仔细监测的个人(N=10)。一旦确定了安全性，我们将进入第二阶段，将100名受试者随机分为Canakinumab和安慰剂两组。在整个试验过程中，安全数据将由一个独立的安全监测委员会仔细监测。我们提出了以下目标：目标1：确定在有效治疗和抑制HIV感染的成人中使用Canakinumab抑制IL1-？的安全性、耐受性和药代动力学。我们将在10名将全部接受单剂canakinumab的患者中进行初步试点研究；如果该药物安全且耐受性良好(正如预期的那样)，我们将另外招募100名患者参加AIMS 1-3项下的随机、安慰剂对照试验；目标2：证明在接受治疗和抑制HIV感染的患者中，IL-1ü抑制减少炎症标志物和单核细胞激活，并改善血管炎症和内皮功能障碍；目标3：确定IL-1ü抑制是否减少T细胞激活和减少血液中HIV贮存库的大小。这一申请结合了(1)一支专注和成功的多学科团队，在研究艾滋病毒免疫调节药物方面有很强的合作和专门知识记录，(2)从现有的艾滋病毒感染者队列中快速招募受试者的能力，(3)高级研究人员进行创新的免疫学分析和艾滋病毒持久性测量的合作(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)