HIV and Asthma in the Post- ART Era

后 ART 时代的艾滋病毒和哮喘

• 批准号: 8915897
• 负责人: John A Bartlett
• 金额: $ 72.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-13 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915897
• 关键词: Adrenal Cortex Hormones; Adrenal gland hypofunction; Adult; Adult asthma; Adverse effects; Affect; Aging; Anti-Retroviral Agents; Area; Asthma; Beclomethasone; Biological Markers; Breathing; Bronchodilator Agents; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Characteristics; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Clinic; Clinical; Code; Communicable Diseases; Conflict (Psychology); Cushing Syndrome; Data; Databases; Development; Diagnosis; Disease; Dose; Elderly; Electronic Health Record; Fibrin fragment D; Fostering; General Population; Glucocorticoids; Goals; Guidelines; HIV; Health; High Prevalence; Hypersensitivity; ICD-9; Immune; Immune system; Immunologic Tests; Inflammation Mediators; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-6; Investigation; Knowledge; Lead; Life; Life Expectancy; Light; Literature; Longitudinal Studies; Lung diseases; Measurement; Measures; Medical; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Placebos; Plasma; Play; Population; Prevalence; Production; Protease Inhibitor; Puberty; Public Health; Pulmonary function tests; Questionnaires; Regulatory T-Lymphocyte; Reporting; Respiratory physiology; Ritonavir; Role; Serum; Severities; Specimen; Symptoms; Techniques; Testing; Time; United States; Universities; Veterans; Viral Load result; Virus Diseases; Woman; Work; antiretroviral therapy; base; biobank; clinical phenotype; cohort; cytokine; effective therapy; immune activation; improved; interleukin-23; meetings; men; methacholine; mortality; patient population; randomized placebo controlled trial; reconstitution; repository; restoration

 DESCRIPTION (provided by applicant): Due to the remarkable progress made in the treatment of HIV infection, the life expectancy of HIV-infected patients in the US has increased dramatically. However, chronic diseases, including lung disease, in this patient population are becoming increasingly common. In HIV-uninfected U.S. adults, asthma is one of the most common respiratory diseases affecting 5-10% of the general population. In patients with HIV infection, the limited data available suggest that asthma prevalence is increased, ranging from 12-25%. However, the diagnosis is often made based upon ICD-9 codes, which are not entirely accurate. If true, this increase may be due, in part, to increases in specific inflammatory mediators such as interleukin-6 (IL-6), a consistently elevated cytokine in numerous HIV disease states. A T-helper 2 (Th2) inflammatory and pro-fibrotic cytokine, interleukin (IL)-6 may drive a Th2 inflammatory phenotype commonly seen in asthma and is persistently elevated despite anti-retroviral therapy (ART). Thus, we hypothesize that HIV-associated asthma in the post-ART era manifests as a Th2 inflammatory phenotype driven, in part, by IL-6, which modulates asthma severity and control. To test this hypothesis, we will first characterize asthma phenotypes and determine asthma prevalence in HIV-infected patients with possible asthma at the Duke and the Durham Veterans' Affairs Infectious Disease Clinics. This will be done through use of electronic health records and through prospectively phenotyping subjects at the Duke Asthma, Allergy and Airway Center using state-of-the-art physiologic techniques, measurements of biomarkers and questionnaires (Aim 1). In Aim 2, we will determine whether IL- 6 plays a major role in the immunological phenotype of asthma before and after initiation of ART initiation by evaluating asthma severity, control and exacerbations in HIV-infected patients with asthma as compared to a cohort of HIV-uninfected patients with asthma in a six-month longitudinal study. To guide this aim's immunological measures, we will leverage the Duke HIV Biorepository and measure several serum cytokines relevant to inflammatory phenotypes in HIV-infected subjects with asthma including IL-4, IL-5, IL-6, IL-13, IL- 17, IL-23 and interferon gamma. There are also challenges in treating asthma in these patients as most inhaled corticosteroids, first lin therapy for asthma, significantly interact with protease inhibitors and the pharmacoenhancer, cobicistat. Therefore, Aim 3 will determine if HFA beclomethasone diproproniate, an inhaled corticosteroid, can be safely and effectively used to treat asthma in HIV-infected patients receiving ART containing protease inhibitors or cobicistat, in a randomized, placebo controlled trial of three months duration. Through these combined aims, this proposal will not only accurately determine the prevalence and severity of asthma in an HIV-infected population, it will also increase our understanding of the inflammatory phenotypes in the setting of HIV infection and asthma and provide a safe option for therapy that can inform guideline-based asthma management in HIV-infected patients. ¿

 描述（由申请人提供）：由于在治疗HIV感染方面取得的显著进展，美国HIV感染患者的预期寿命大幅增加。然而，包括肺部疾病在内的慢性疾病在这一患者群体中变得越来越常见。在未感染HIV的美国成年人中，哮喘是影响5-10%普通人群的最常见的呼吸道疾病之一。在HIV感染患者中，现有的有限数据表明哮喘患病率增加，范围为12- 25%。然而，诊断往往是根据ICD-9编码，这是不完全准确的。如果是真的，这种增加可能部分是由于特定炎症介质的增加，如白细胞介素-6（IL-6），这是一种在许多HIV疾病状态中持续升高的细胞因子。作为一种辅助性T细胞2（Th 2）炎症和促纤维化细胞因子，白细胞介素（IL）-6可能驱动哮喘中常见的Th 2炎症表型，尽管进行了抗逆转录病毒治疗（ART），但其持续升高。因此，我们假设艾滋病毒相关性哮喘在后ART时代表现为Th 2炎症表型，部分由IL-6驱动，IL-6调节哮喘的严重程度和控制。为了验证这一假设，我们将首先描述哮喘表型，并确定在杜克和达勒姆退伍军人事务部传染病诊所可能患有哮喘的HIV感染患者的哮喘患病率。这将通过使用电子健康记录和通过在杜克哮喘、过敏和气道中心使用最先进的生理技术、生物标志物测量和问卷对受试者进行前瞻性表型分型来完成（目标1）。在目标2中，我们将通过在一项为期6个月的纵向研究中，与一组未感染HIV的哮喘患者相比，评估HIV感染的哮喘患者的哮喘严重程度、控制和加重情况，确定IL- 6是否在ART启动前后哮喘的免疫表型中起主要作用。为了指导这一目标的免疫学措施，我们将利用杜克HIV生物储存库并测量与患有哮喘的HIV感染受试者的炎性表型相关的几种血清细胞因子，包括IL-4、IL-5、IL-6、IL-13、IL- 17、IL-23和干扰素γ。在这些患者中治疗哮喘也存在挑战，因为大多数吸入性皮质类固醇（哮喘的首选疗法）与蛋白酶抑制剂和药效增强剂cobicistat显著相互作用。因此，目标3将在一项为期三个月的随机、安慰剂对照试验中确定HFA二丙氯米松（一种吸入性皮质类固醇）是否可以安全有效地用于治疗接受含有蛋白酶抑制剂或cobicistat的ART的艾滋病毒感染患者的哮喘。通过这些综合目标，该提案不仅将准确确定艾滋病毒感染人群中哮喘的患病率和严重程度，还将增加我们对艾滋病毒感染和哮喘背景下炎症表型的理解，并提供一种安全的治疗选择，可以为艾滋病毒感染患者提供基于指南的哮喘管理。¿