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（由适用提供）：尽管抗逆转录病毒疗法可以延长寿命，但它并不能完全恢复健康。由于仍然是中心的原因，与未感染的同类产品相比，在治疗方面表现良好的HIV感染者的寿命缩短，并且在包括心血管疾病在内的许多“非AID”疾病的风险也高于预期的风险。感染HIV的个体的心肌梗塞风险高2倍，心脏猝死率更高。尽管这些临床观察的基本机制可能是多因素的，但在治疗的HIV感染的情况下，慢性感染已成为疾病过程的关键因素。 IL-1是单核细胞，巨噬细胞和树突状细胞产生的促炎细胞因子。 IL-1是使用Canakinumab抑制作用，Canakinumab是与IL-1的单克隆抗体，大大降低了炎症标记，并且在Cantos研究中已在没有HIV的> 8500个个体中进行了研究。 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.鉴于炎症在导致病毒持久性方面的推定作用，我们还将衡量cankinumab对HIV储层大小的影响。我们将进行一项随机的双盲安慰剂对照概念验证临床试验，评估对未检测到的HIV RNA水平的长期抗逆转录病毒治疗患者的安全性和影响。我们提出以下目的：目标1：确定使用Cankinumab在有效治疗和抑制的HIV感染成年人中使用Cankinumab对IL-1抑制的安全性，耐受性和药代动力学。我们将对十个人进行初步的试点研究，他们都会收到一剂cankinumab。如果该药物是安全且耐受性良好的（如预期的那样），我们将在AIMS 1-3的随机，安慰剂对照试验中招募100名个人；目的2：证明IL-1抑制作用会下降炎症标记和单核细胞激活，并改善治疗和抑制的HIV感染者之间的血管感染和内皮功能障碍；目标3：确定IL-1是否抑制T细胞激活并减少血液中HIV储量的大小。该应用程序结合了（1）一个专门的多学科团队，并具有很强的协作记录，（2）能够从现有的HIV感染受试者中快速招募受试者，（3）进行创新免疫学评估和HIV持久性测量的高级研究人员的协作。