Disseminated Tuberculosis in HIV Infection

HIV 感染中的播散性结核病

• 批准号: 7627845
• 负责人: Charles Fordham von Reyn
• 金额: $ 30万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627845
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Adult; Animal Model; Area; Bacteremia; CD4 Lymphocyte Count; Cause of Death; Cellular Immunity; Cessation of life; Childhood; Clinical; Complication; Consensus; Cross-Sectional Studies; Data; Developed Countries; Developing Countries; Diagnostic; Dose; Enrollment; Genus Mycobacterium; Goals; HIV; HIV Infections; HIV Seropositivity; Heating; Human Resources; Human immunodeficiency virus test; Hypersensitivity skin testing; Immune response; Immunity; Immunization; Immunologics; In Vitro; Infection; Laboratories; Lung; Mycobacterium bovis; Mycobacterium tuberculosis; Numbers; Organism; Pathogenesis; Patients; Persons; Placebo Control; Prevention strategy; Process; Prospective Studies; Pulmonary Tuberculosis; Randomized; Rate; Relative (related person); Reporting; Research Personnel; Risk; Risk Factors; Safety; Secondary Immunization; Series; Site; Standards of Weights and Measures; Surrogate Markers; Syndrome; Tanzania; Training; Tuberculosis; Vaccines; base; booster vaccine; cohort; design; efficacy trial; follow-up; immunogenic; in vitro Assay; mortality; mycobacterial; novel vaccines; prevent; programs; response; vaccine efficacy; vaccine-induced immunity

This is a competitive renewal to complete our ongoing study of disseminated tuberculosis (dTB) in HIV infection. Tuberculosis is the most common cause of death from HIV infection in the developing world and dTB represents a substantial proportion of these deaths. Our hypotheses are (1) that most cases of dTB occur in advanced AIDS and represent reactivation or re-infection in persons with waning cellular immunity to mycobacteria, and (2) that if BCG-primed subjects are boosted with an inactivated mycobacterial vaccine in earlyiHIV infection, their subsequent risk of both dTB and pulmonary tuberculosis (pTB) will be reduced by 50%. Heat-inactivated M. vaccae (MV) is a vaccine that protects against tuberculosis in an animal model, is safe and immunogenic in subjects with HIV infection and CD4 counts>200, and boosts mycobacterial immune responses primed by BCG. Our specific aims are: (1) To define risk factors for HIV-associated dTB and to assess the relative contributions of primary infection, re-infection, and reactivation in its pathogenesis, and (2) To assess the safety and efficacy of a prime-boost immunization strategy for the prevention of HIV- associated dTB and pTB. Patient enrollment was delayed one year by the regulatory review process (initial monthly enrollment limits were reduced from 100 to 33) and the need to identify a new study site. We established laboratories and clinical facilities in Dar es Salaam, Tanzania, trained study personnel and developed referral relationships with 22 HIV testing centers. In 3 years we have screened 3228 subjects, enrolled 1303 (57%) of the targeted 2274 BCG-positive subjects, and administered 4695 doses of vaccine. GCP study standards have been met, and multiple reviews by the DSMB based on pre-approved safety criteria have all been satisfactory. We have documented the highest reported rate of previously undiagnosed active tuberculosis in ambulatory patients with HIV (15%), identified a new syndrome of subclinical tuberculosis and shown that 85% of subjects have detectable baseline immune responses to mycobacteria and are primed for booster immunization. A three year renewal is requested to complete enrollment and follow-up. Vaccine efficacy against dTB and pTB will be determined, and in vitro immunologic responses will be used to identify surrogate markers of efficacy. This study has important implications for the reduction of mortality from HIV-associated tuberculosis and for design of new vaccine trials against tuberculosis.

这是完成我们正在进行的HIV传播结核病（DTB）的竞争性更新 感染。结核病是发展中国家艾滋病毒感染的最常见死亡原因， DTB代表了这些死亡的很大一部分。我们的假设是（1）大多数DTB病例 发生在高级辅助物中，表示细胞免疫力衰竭的人的重新激活或重新感染 对分枝杆菌，（2）如果BCG引发的受试者被灭活的分枝杆菌疫苗增强 在早期感染中，其随后的DTB和肺结核（PTB）的风险将通过 50％。热灭活的疫苗（MV）是一种预防动物模型中结核病的疫苗， HIV感染和CD4计数> 200的受试者的安全和免疫原性，并增强分枝杆菌 BCG启动的免疫反应。我们的具体目的是：（1）定义与HIV相关的DTB的危险因素 并评估原发性感染，再感染和重新激活的相对贡献， （2）评估预防HIV的促进免疫策略的安全性和功效 相关的DTB和PTB。通过监管审查过程将患者入学率推迟了一年（初始 每月入学率从100降低到33），并且需要确定一个新的研究地点。我们 坦桑尼亚达累斯萨拉姆建立的实验室和临床设施，训练有素的学习人员和 与22个艾滋病毒测试中心建立了推荐关系。在三年内，我们筛选了3228名受试者， 靶向2274名BCG阳性受试者中有1303（57％），并给予4695剂疫苗。 GCP研究标准已经满足，DSMB的多次评论基于预先批准的安全 标准都令人满意。我们已经记录了报告的先前未诊断的最高率 艾滋病毒室内患者的活性结核（15％），确定了一种新的亚临床综合征 结核病，表明85％的受试者对分枝杆菌具有可检测的基线免疫反应 并用于增强免疫。要求三年的续约完成注册和 后续。将确定针对DTB和PTB的疫苗功效，并将体外免疫反应 用于识别功效的替代标记。这项研究对减少 与HIV相关的结核病以及针对结核病的新疫苗试验设计的死亡率。