HIV/TB in Uganda: Punctuated Antiretroviral Therapy

描述（由申请人提供）：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）感染的一种常见且严重的并发症。自从艾滋病毒在非洲流行以来，结核病的发病率急剧上升，使非洲各国的结核病控制计划不堪重负。在非洲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，往往是在艾滋病毒感染的早期阶段出现的。世卫组织最近关于艾滋病毒相关肺结核管理的指南建议对CD4+ T细胞< 200细胞/多升的患者进行抗逆转录病毒（ARV）治疗，但不建议对CD4+细胞水平较高的艾滋病毒感染结核病患者进行治疗。在乌干达，超过一半的艾滋病毒感染的活动性结核病患者CD4+计数高于200细胞/ L。有临床和科学理由对这些结核病患者进行抗逆转录病毒药物治疗，即使他们出现在艾滋病毒感染的早期阶段。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+计数高于200个细胞/毫升时，与结核病相关的超额死亡率最为明显。第三，在双重感染患者中，结核病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抗逆转录病毒治疗的新方法是否会减缓CD4+细胞达到350细胞/ μ l的结核病患者的艾滋病毒疾病进展。该研究还将评估间歇抗逆转录病毒治疗的可能风险（例如，药物毒性和耐药性）和益处（例如，更快地清除MTB和减少结核病复发）。本提案的具体目标将通过一项开放标签、随机、hiv感染结核病患者（CD4+大于或等于350个细胞/muL）的临床试验来解决，同时还有一组非随机、观察性的无活动性结核病hiv感染者（CD4+大于或等于350个细胞/muL）。我们将比较两组结核病患者在2年内CD4+细胞计数下降的比率，这些患者被随机分为两组，一组在结核病治疗期间接受6个月的即时间断抗逆转录病毒治疗，另一组在CD4+细胞计数低于200个细胞/ L时开始接受延迟抗逆转录病毒治疗。我们还将比较结核病患者的CD4+细胞计数下降率与同时存在的观察性对照组中CD4+细胞计数大于或等于350细胞/ μ l的非结核病患者的CD4+细胞计数下降率，以量化活动性结核病加速CD4+细胞下降的程度，并确定接受间断抗逆转录病毒治疗的患者的下降被中和的程度。来自乌干达-凯斯西部保护区研究合作组织和加州大学圣地亚哥分校抗病毒部门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.