HIV/TB in Uganda: Punctuated Antiretroviral Therapy

描述(申请人提供)：结核病(TB)是发展中国家，特别是撒哈拉以南非洲地区人类免疫缺陷病毒1型(HIV)感染的一种常见和严重的并发症。自从艾滋病在非洲流行以来，结核病的发病率急剧上升，使整个非洲的国家结核病控制计划不堪重负。在非洲，到结核病诊所就诊的结核病患者中有一半以上是艾滋病毒感染者，通常在艾滋病毒感染的早期阶段出现。世界卫生组织最近关于艾滋病毒相关性肺结核病的管理指南建议对CD4+T细胞数为200个/微升的患者进行抗逆转录病毒(ARV)治疗，但不建议对存在高CD4+细胞的艾滋病毒感染结核病患者进行抗逆转录病毒(ARV)治疗。在乌干达，超过一半的艾滋病毒感染的活动性结核病患者的CD4+细胞数超过200个/L。即使这些结核病患者处于艾滋病毒感染的早期，也有临床和科学原因需要对他们进行抗逆转录病毒治疗。首先，艾滋病毒相关结核病的死亡率很高，即使患者对有效的抗结核治疗有反应。其次，当CD4+细胞数高于200细胞/微升时，与结核病相关的超额死亡率最为明显。第三，在双重感染的患者中，结核病会导致免疫激活时间延长，这可能会增强病毒复制，加速CD4+细胞的下降。这项拟议的研究将测试在治疗活动性结核病期间给予间断ARV疗法的新方法是否将减缓CD4+细胞和GT；350细胞/微升的结核病患者的艾滋病毒疾病的进展。这项研究还将评估间歇性抗逆转录病毒疗法的可能风险(例如，药物毒性和耐药性)和益处(例如，更快地清除结核分枝杆菌和减少结核病复发)。这项建议的具体目标将在一项针对艾滋病毒感染结核病患者(CD4+大于或等于350个/微升)的开放式随机临床试验中与同期、非随机、观察性对照组中没有活动性结核病(CD4+大于或等于350个/微升)的艾滋病毒感染者进行。我们将比较两年来结核病患者之间的CD4+细胞数量下降的比率，这些患者被随机分成两组，一组是在结核病治疗期间立即接受间歇性ARV治疗6个月，另一组是在CD4+细胞数量降至200个/L以下时开始延迟ARV治疗。我们还将比较结核病患者和同期观察性对照组中CD4+细胞数量下降的比率，这些患者的CD4+细胞数量大于或等于350个/MUL以上，而不是结核病，以量化活动性结核病患者CD4+细胞下降加速的程度，并确定在接受间歇性ARV治疗的患者中，这种下降被抵消的程度。来自乌干达-凯斯西部储备研究合作和加州大学圣地亚哥分校抗病毒单位的研究小组在临床试验、结核病和艾滋病毒发病机制以及抗逆转录病毒治疗方面拥有完成这项研究所需的经验。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a common and serious complication of human immunodeficiency virus-type 1 (HIV) infection in the developing world, especially in sub-Saharan Africa. Since the emergence of the HIV epidemic in Africa, the incidence rates of TB have risen dramatically, overwhelming national TB control programs across Africa. Over one-half of TB patients presenting to TB clinics in Africa are HIV-infected, often presenting in early stages of HIV infection. Recent WHO guidelines on the management of HIV-associated pulmonary TB recommend antiretroviral (ARV) therapy in patients with CD4+ T cells < 200 cells/muL but not for HIV-infected TB patients who present with high CD4+ cells. In Uganda, over half of HIV-infected patients with active TB present with CD4+ counts above 200 cells/?L. There are clinical and scientific reasons for treating these TB patients with ARV therapy even when they present in early stages of HIV infection. First, mortality in HIV-associated TB is high, even when patients respond to effective anti-tuberculous therapy. Second, excess mortality associated with TB is most evident when CD4+ counts are above 200 cell/muL. Third, in dually-infected patients, TB results in prolonged immune activation which may enhance viral replication and accelerate the decline of CD4+ cells. The proposed study will test whether a novel approach of punctuated ARV therapy given during treatment of active TB will slow progression of HIV disease in TB patients with CD4+ cells > 350 cells/muL. The study will also assess the possible risks (e.g., drug toxicities and resistance) and benefits (e.g., more rapid clearance of MTB and reduced TB relapse) of punctuated ARV therapy. The Specific Aims of this proposal will be addressed in an open label, randomized, clinical trial of HIV-infected TB patients (CD4+ greater than or equal too 350 cells/muL) with a concurrent, nonrandomized, observational comparison group of HIV-infected persons without active TB (CD4+ greater than or equal too 350 cells/muL). We will compare rates of CD4+ cell count decline over 2 years between TB patients who are randomized to either immediate, punctuated ARV therapy given for six months during TB treatment or delayed ARV therapy which is started when CD4+ cell counts fall below 200 cells/?L. We will also compare the rates of CD4+ cell count decline among TB patients with a concurrent, observational comparison group of patients with CD4+ counts greater than or equal too 350 cells/muL without TB to quantify the extent to which CD4+ cell decline is accelerated with active TB and to determine the extent to which the decline is neutralized in patients who receive punctuated ARV therapy. The research team from the Uganda-Case Western Reserve Research Collaboration and the Antiviral unit at the University of California, San Diego has the necessary experience in clinical trials, TB and HIV pathogenesis, and antiretroviral therapy to complete the study.