Doxycycline for COPD in HIV-Infected Patients

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）正在成为hiv感染患者发病的重要原因，可能是由于多种因素，包括吸烟流行率增加、慢性炎症和免疫激活、氧化应激和呼吸道感染。我们的初步数据表明，一些肺基质金属蛋白酶（MMPs）在hiv感染的吸烟者中上调，这可能通过它们降解细胞外基质和基底膜成分的能力而加速肺气肿。基于这些观察结果，我们假设强力霉素（fda唯一批准的MMPs抑制剂）对MMPs的药理学抑制将有利于改变hiv感染患者COPD的自然史。为了验证这一假设，我们建议在hiv感染患者中进行一项多西环素治疗COPD的随机、安慰剂对照试验。我们的研究团队由一名具有hiv相关COPD专业知识的肺病学家/转化研究员和一名传染病专家/临床试验专家领导，有能力向美国国立卫生研究院资助的艾滋病临床试验小组（ACTG）提出这样一项试验。为此，我们首先建议进行一项试点研究，以达致以下具体目标：确定每日两次强力霉素治疗hiv感染COPD患者6个月的安全性、耐受性和生物学效应；和Aim 2。准备并提交多西环素治疗hiv感染者COPD的II期临床试验申请。为了实现第一个目标，我们将进行一项随机、双盲、安慰剂对照的试点研究，在30名hiv感染的COPD患者中使用强力霉素100 mg，每天两次（2:1：强力霉素：安慰剂）。主要终点将是安全性/耐受性，次要终点将包括FEV1的变化、上皮内膜液和支气管镜获得的细胞中MMP活性的降低以及血液、ELF和BAL细胞颗粒中的强力霉素水平。除了提供多西环素在肺中的生物学效应的新见解外，该试点研究将为II期试验的终点选择提供信息，最终将解决hiv感染患者COPD/肺气肿新干预措施的未满足的医疗需求。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is emerging as an important cause of morbidity in HIV-infected patients, likely due to multiple factors, including an increased prevalence of smoking, chronic inflammation and immune activation, oxidant stress and respiratory infections. Our preliminary data suggest that several lung matrix metalloproteinases (MMPs) are upregulated in HIV-infected smokers, which could contribute to accelerated emphysema by virtue of their ability to degrade extracellular matrix and basement membrane components. Based on these observations, we hypothesize that pharmacologic inhibition of MMPs by doxycycline, the only FDA-approved inhibitor of MMPs, will favorably modify the natural history of COPD in HIV-infected patients. To test this hypothesis, we propose conducting a phase II randomized, placebo-controlled trial of doxycycline for COPD in HIV-infected patients. Our research team, led by a pulmonologist / translational researcher with expertise in HIV-associated COPD and an infectious diseases specialist/clinical trials expert, is well positioned to propose such a trial to the NIH-funded AIDS Clinical Trials Group (ACTG). To achieve this end, we first propose to conduct a pilot study to enable us to address the following Specific aims: Aim 1. To determine the safety, tolerability, and biologic effects of twice daily doxycycline for 6 months in HIV-infected subjects with COPD; and Aim 2. To prepare and submit an application for a phase II clinical trial of doxycycline for COPD in HIV-infected subjects. To address the first aim, we will conduct a randomized, double-blind, placebo-controlled pilot study of doxycycline 100 mg twice daily in 30 HIV-infected subjects with COPD (2:1 doxy:placebo). The primary endpoint will be safety/tolerability and secondary endpoints will include change in FEV1, reduction of MMP activity in epithelial lining fluid and cells obtained by bronchoscopy and doxycycline levels in blood, ELF and BAL cell pellets. In addition to providing novel insights into the biologic effects of doxycycline in the lung, the pilot study will inform selection of endpoints for a phase II trial, which ultimately will address an unmet medical need for novel interventions for COPD/emphysema in HIV-infected patients. PUBLIC HEALTH RELEVANCE: Chronic obstructive lung disease (COPD)/emphysema is an important public health problem in the general population and, in particular, in HIV-infected patients. The proposed work is testing a novel intervention for this disorder that, if successful, has the potential to reduce the progression of COPD/emphysema. The findings from the proposed work will have implications for all persons with COPD/emphysema, regardless of HIV status.