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

IL-1B 抑制对 HIV 炎症和心血管风险的影响

基本信息

批准号：
9247797
负责人：
Priscilla Y. Hsue
金额：
$ 127.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247797
关键词：
Adaptive Immune System Adult Anti-Retroviral Agents Arterial Fatty Streak Atherosclerosis Binding Biological Assay Blood CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cell Count Cells Chronic Clinical Collaborations Coronary heart disease Cytomegalovirus Data Dendritic Cells Disease Disease model Dose Double-Blind Method Drug Kinetics Enrollment FDA approved Familial amyloid nephropathy with urticaria and deafness Fibrinogen Frequencies Future General Population HIV HIV Infections Health Immune Immunology Individual Infection Inflammation Inflammatory Information Management Interleukin-1 beta Interleukin-6 Interruption Intervention Studies Life Longevity Measurement Measures Mediating Modeling Modernization Monitor Monoclonal Antibodies Morbidity - disease rate Myocardial Infarction Organ Outcome PET/CT scan Pathogenesis Pathway interactions Periodicity Pharmaceutical Preparations Phase Pilot Projects Placebo Control Placebos Population Process Production Randomized Randomized Controlled Trials Recruitment Activity Research Personnel Risk Role Safety Signal Pathway Syndrome System T memory cell T-Cell Activation T-Lymphocyte Testing Tissues Vascular Diseases Vasodilation Viral antiretroviral therapy base brachial artery cardiovascular risk factor chemokine cohort cytokine effective therapy endothelial dysfunction fluorodeoxyglucose positron emission tomography high risk human monoclonal antibodies immune activation improved in vivo inflammatory marker innovation latent infection macrophage microbial monocyte mortality multidisciplinary randomized placebo controlled trial receptor sudden cardiac death vascular inflammation

项目摘要

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)

描述（由申请人提供）：尽管抗逆转录病毒疗法（ART）可以延长寿命，但它并不能完全恢复健康。由于仍存在争议的原因，治疗良好的艾滋病毒感染者的寿命比未感染的婴儿要短，而且也有可能会出现这种情况。一些“非艾滋病”疾病（包括心血管疾病）的风险高于预期，感染艾滋病毒的人患心肌梗塞的风险高出两倍，心脏病突发的发生率也更高。虽然这些临床观察的潜在机制可能是多因素的，但 HIV 中的慢性炎症是疾病过程的关键因素，IL-1β 是一种由经过处理的单核细胞、巨噬细胞和树突状细胞产生的促炎细胞因子。使用 Canakinumab（一种 IL-1ß 单克隆抗体）抑制 IL-1ß 可显着降低炎症标志物，并且已在 CANTOS 研究中对超过 10000 名没有 HIV 的个体进行了研究，但没有任何显着的安全性为了确定长期抗逆转录病毒治疗的 HIV 感染过程中 IL-1ß 抑制对全身炎症的影响，我们建议进行一项以发病机制为导向的单中心研究，评估卡那奴单抗（一种抑制 IL 的人单克隆抗体）的影响。 -1ß-对全身炎症、T 细胞激活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，我们还将测量卡那奴单抗对 HIV 病毒库大小的影响。本研究的安全性，仅招募 HIV 感染成年人接受长期有效的 ART，CD4 T 细胞计数 = 400 个细胞/mm3，并进行两阶段里程碑驱动的研究，其中第一阶段（第一阶段）将招募一旦确定了安全性，我们将进入第二阶段，并随机将 100 名受试者分为卡那单抗组和安慰剂组，安全性数据将由独立的安全性监测委员会在整个试验过程中进行仔细监测。我们提出以下目标：目标 1：确定在有效治疗和抑制的 HIV 感染成人中使用卡那单抗抑制 IL1-β 的安全性、耐受性和药代动力学。我们将对 10 名接受治疗的个体进行初步试点研究。单剂量卡那奴单抗；如果该药物安全且耐受性良好（如预期），我们将在目标 1-3 下另外招募 100 名受试者进行随机安慰剂对照试验：证明IL-1ß 抑制可减少炎症标志物和单核细胞活化，并改善受抑制治疗的 HIV 感染者的血管炎症和内皮功能障碍；目标 3：确定 IL-1ß 抑制是否会减少 T 细胞活化并减小 HIV 储存库的大小；该应用程序结合了（1）一个专注且成功的多学科团队，在研究艾滋病毒免疫调节药物方面拥有良好的合作记录和专业知识，（2）从现有队列中快速招募受试者的能力。 HIV 感染者，(3) 高级研究人员的合作，进行创新的免疫学测定和 HIV 持久性测量（摘要结束）