Doxycycline for COPD in HIV-Infected Patients

描述(申请人提供)：慢性阻塞性肺疾病(COPD)正在成为艾滋病毒感染患者发病的一个重要原因，可能是由于多种因素，包括吸烟、慢性炎症和免疫激活、氧化应激和呼吸道感染的增加。我们的初步数据表明，几种肺基质金属蛋白酶(MMPs)在HIV感染的吸烟者中表达上调，它们可能通过降解细胞外基质和基底膜成分而导致加速肺气肿。基于这些观察，我们假设，FDA批准的唯一MMPs抑制剂多西环素对MMPs的药理抑制将有利于改变HIV感染患者的COPD自然病史。为了验证这一假设，我们建议在HIV感染患者中进行多西环素治疗COPD的II期随机、安慰剂对照试验。我们的研究团队由一位在HIV相关COPD方面有专长的肺病学家/翻译研究员和一位传染病专家/临床试验专家领导，能够很好地向NIH资助的艾滋病临床试验小组(ACTG)提出这样的试验建议。为了实现这一目标，我们首先提议进行一项先导性研究，以使我们能够解决以下具体目标：目的1.确定每天两次的多西环素治疗慢性阻塞性肺疾病的安全性、耐受性和生物效应；以及目的2.准备并提交多西环素在HIV感染患者中治疗COPD的II期临床试验申请。为了达到第一个目标，我们将对30名患有慢性阻塞性肺疾病(2：1 Doxy：安慰剂)的HIV感染者进行一项随机、双盲、安慰剂对照的试验研究，每天两次服用多西环素100 mg。主要终点将是安全性/耐受性，次要终点将包括FEV1的变化，上皮衬衬液和支气管镜获得的细胞中基质金属蛋白酶活性的降低，以及血液、ELF和BAL细胞球中的多西环素水平。除了对多西环素在肺部的生物效应提供新的见解外，这项试点研究还将为II期试验的终点选择提供信息，该试验最终将解决艾滋病毒感染患者对COPD/肺气肿新干预措施的未得到满足的医疗需求。

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.