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

• 批准号: 8915892
• 负责人: Priscilla Y. Hsue
• 金额: $ 82.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915892
• 关键词: Adult; Anti-Retroviral Agents; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Blood; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Clinical Trials; 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 system; Immunology; Individual; Infection; Inflammation; Inflammatory; Information Management; Interleukin-1; Interleukin-6; Intervention Studies; Life; Longevity; Macrophage Activation; Measurement; Measures; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Myocardial Infarction; Organ; Outcome; PET/CT scan; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Population; Process; RNA; Randomized; Randomized Controlled Trials; Rare Diseases; 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; 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

DESCRIPTION (provided by applicant): Project Summary Although antiretroviral therapy prolongs life, it does not fully restore health. For reasons that remain controversial, HIV-infecte 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 infection has emerged as a key contributor to the disease process. IL-1� is a pro-inflammatory cytokine produced by monocytes, macrophages and dendritic cells; IL-1� inhibition using canakinumab, a monoclonal antibody to IL-1�, dramatically reduces inflammatory markers, and has been studied in > 8500 individuals without HIV in the CANTOS study. In order to determine the impact of IL-1� 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-1�-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 perform a randomized double-blinded placebo-controlled proof-of-concept clinical trial evaluating the safety and effects of canakinumab administered to long-term antiretroviral treated patients who have undetectable HIV RNA levels. We propose the following aims: Aim 1: To determine the safety, tolerability, and pharmacokinetics of IL-1� inhibition using canakinumab in effectively treated and suppressed HIV infected adults. We will perform an initial pilot study in ten individuals who will all receivea 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-1� 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-1� 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, (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.

描述(申请人提供)：项目摘要虽然抗逆转录病毒疗法可以延长生命，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，但在接受治疗的艾滋病毒感染背景下的慢性炎症已经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；用抗IL-1�的单抗Canakinumab抑制IL-1�可显著减少炎症标志物，在CANTOS研究中已在8,500名未感染艾滋病毒的人中进行了研究。为了确定长期接受抗逆转录病毒治疗的艾滋病病毒感染期间抑制IL-1�对全身炎症的影响，我们建议进行一项面向发病机制的单中心研究，以评估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。我们将进行一项随机、双盲、安慰剂对照的概念验证临床试验，评估长期接受抗逆转录病毒治疗、艾滋病毒RNA水平无法检测到的患者使用Canakinumab的安全性和效果。我们提出了以下目标：目的1：确定在有效治疗和抑制艾滋病病毒感染的成人中，使用Canakinumab抑制IL-1�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：证明抑制IL-1�可减少治疗和抑制的艾滋病毒感染者中的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-1�抑制是否降低T细胞激活和减少血液中艾滋病毒贮存库的大小。这一应用结合了(1)专注和成功的多学科团队以及强大的合作记录，(2)从现有的艾滋病毒感染受试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。