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: 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
• 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

 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（由适用提供）：尽管抗逆转录病毒疗法（ART）延长了寿命，但并不能完全恢复健康。由于仍然存在争议的原因，与未感染的艾滋病毒相比，在治疗方面表现良好的艾滋病毒感染者的寿命缩短，并且在包括心血管疾病在内的许多“非AID”疾病的风险高于预期的风险。艾滋病毒感染者的心肌违规风险高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的情况下，作为疾病过程的关键因素而出现了慢性炎症。 IL-1ß是由单核细胞，巨噬细胞和树突状细胞产生的促炎细胞因子。 IL-1ß使用Canakinumab抑制作用，Canakinumab，一种对IL-1ß的单克隆抗体，大大降低了炎症标志物，并且在Cantos研究中没有HIV的> 10000个患者中进行了研究，而没有任何重大安全问题。为了确定IL-1ß抑制对长期抗逆转录病毒治疗的HIV感染期间全身感染的影响，我们建议进行一项以中心发病机理为导向的研究，以评估Canakinumab-A人类单克隆抗体的影响，从而抑制IL-1ß-on-1ß-on-1ß-on-1 honsic-on-1ul-1β细胞细胞活化，t t t t t t t t t t t t t t t t t t t t t t t t t te。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晶状体大小的影响。在这项研究中，我们将专注于安全性，仅在CD4 T细胞计数= 400个细胞/mm3的长期有效艺术中，并通过进行两阶段的里程碑式驱动的研究，其中第一阶段（I阶段I）将招募一小部分精心监测的个体（n = 10）。建立了ONC安全性，我们将转到II阶段，并将100名受试者随机为Canakinumab与安慰剂。在整个审判过程中，独立安全监控委员会将仔细监控安全数据。我们提出以下目的：目标1：确定使用Canakinumab在有效治疗和抑制的HIV感染的成年人中使用Canakinumab对IL1-β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；目标2：证明IL-1ß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-1ß抑制是否会减少T细胞的激活并减少血液中HIV储量的大小。 This application combines (1) a dedicated and successful multidisciplinary team with a strong recording of collaboration and expertise in studying immunomodulation 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 assessments and measurements of HIV persistence (End of Abstract)