Oral Wash for Nucleic Acid Diagnosis and Prognosis of TB in HIV-Infected Ugandans

描述(由申请人提供)：这是为加州大学旧金山分校(UCSF)的肺部/重症监护内科医生Lucian Davis博士申请K23奖项。戴维斯博士在以患者为导向的临床研究中确立了自己作为研究员的地位，这些研究针对高负担、资源有限的环境(RLS)中的艾滋病毒相关结核病的新诊断方法。这一K23奖项将为戴维斯博士提供必要的支持，以实现以下目标：(1)成为以患者为导向的临床研究专家，以改进艾滋病毒患者的结核病诊断和预后检测；(2)学会将核酸扩增实验室研究技术应用于临床标本；(3)学会应用先进的生物统计学方法来评估诊断和预后检测；以及(4)学会应用先进的分析方法来评估诊断检测的有效性和成本效益；以及(5)发展独立的临床研究事业。为了实现这些目标，Davis博士组建了一个导师团队，成员包括一名主要导师、加州大学旧金山分校医学教授、国际公认的艾滋病毒相关肺部疾病专家研究员Laurence Huang博士；以及两名共同导师：加州大学旧金山分校医学教授、全球公认的结核病控制权威Philip Hopewell博士，以及加州大学旧金山分校流行病学和生物统计学教授、艾滋病毒及其呼吸道并发症领域的流行病学家Dennis Osmond博士。缺乏对结核病的快速、敏感和负担得起的诊断是全球控制该疾病的主要限制，特别是在艾滋病毒高流行地区。Davis博士的研究将确定广泛使用的结核分枝杆菌DNA检测与一种新的标本--口腔冲洗是否能比目前的标准检测--痰涂片镜检(Aim 1)--更准确地诊断出艾滋病毒感染患者中的结核病；定量扩增抗原85B mRNA--一种与分枝杆菌活力和结核病治疗效果相关的转录本--是否可以预测疾病早期的治疗失败(目标2)；以及在这种高负担的环境下，口腔洗涤加核酸检测是否是诊断结核病成本合算的方法。(目标3)戴维斯博士将利用国际艾滋病毒相关机会性肺炎研究(1R01 HL090335-01)的现有基础设施，招募和跟踪300名感染艾滋病毒的结核病嫌疑人。这项研究将为未来对该地区结核病诊断的常规诊断试验和新型诊断试验进行比较的随机试验奠定基础。公共卫生影响：我们正在研究快速的新测试，即在盐水漱口水上进行DNA指纹测试，是否便宜和准确地诊断艾滋病毒患者肺部的结核病。我们还试图弄清楚，类似的测试是否可以告诉这些患者，一旦他们开始治疗，情况是否会好转。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Lucian Davis, a pulmonary/critical care physician at the University of California, San Francisco (UCSF). Dr. Davis is establishing himself as an investigator in patient-oriented clinical research on novel diagnostics for HIV-associated tuberculosis in high-burden, resource-limited settings (RLS). This K23 award will provide Dr. Davis with the support necessary to accomplish the following goals: (1) to become expert at patient-oriented clinical research into improved diagnostic and prognostic tests for TB in patients with HIV; (2) to learn to apply laboratory research techniques for nucleic acid amplification to clinical specimens; (3) to learn to apply advanced biostatistical methods for evaluating diagnostic and prognostic tests; and (4) to learn to apply advanced analytic methods for evaluating the efficacy and cost effectiveness of diagnostic tests; and (5) to develop an independent clinical research career. To achieve these goals, Dr. Davis has assembled a mentoring team comprised of a primary mentor, Dr. Laurence Huang, Professor of Medicine at UCSF and an internationally recognized expert researcher in HIV-associated pulmonary diseases; and two co-mentors: Dr. Philip Hopewell, Professor of Medicine at UCSF and an internationally recognized authority on global TB control; and Dr. Dennis Osmond, Professor of Epidemiology and Biostatistics at UCSF, and an expert epidemiologist in the field of HIV and its respiratory complications. A lack of rapid, sensitive, affordable diagnostics for TB is a major limitation to global control of the disease, especially in high HIV-prevalence areas. Dr. Davis' research will determine if a widely available DMA test for Mycobacterium tuberculosis paired with a novel specimen, the oral wash, is more accurate for diagnosis of TB in HIV-infected patients than the current standard test, sputum smear microscopy (Aim 1); if quantitative amplification of antigen 85B mRNA, a transcript associated both with mycobacterial viability and with TB treatment effects, can predict treatment failure early in the course of disease (Aim 2); and if the oral wash plus nucleic acid test is cost-effective for diagnosing TB in this high-burden setting. (Aim 3) Dr. Davis will use the existing infrastructure of the International HIV-associated Opportunistic Pneumonias study (1R01 HL090335-01) to enroll and follow 300 HIV-infected TB suspects. This research will form the basis for a future randomized trial comparing conventional and novel diagnostic tests for TB diagnosis in this region. Public Health Impact: We are studying if fast new tests that do DNA fingerprinting on salt water mouthwashes are cheap and accurate for diagnosing tuberculosis in the lungs of patients with HIV. We are also trying to find out if a similar test can tell if these patients are getting better once they start treatment.