Safety, pharmacokinetics, and resistance to bedaquiline in XDR TB and HIV

描述(申请人提供)：广泛耐药结核病(广泛耐药结核病)已成为一种重大的全球流行病，并对艾滋病毒感染者构成特别威胁。由于几乎没有有效的治疗药物，广泛耐药结核病的死亡率极高。贝达奎林是40年来第一种获得FDA批准的结核病新药，在耐多药结核病患者的早期临床试验中显示出相当大的前景。然而，该药物在接受抗逆转录病毒治疗(ART)的广泛耐药结核病患者或艾滋病毒合并感染患者中尚未得到很好的研究。因此，这种潜在的变革性药物的安全性、耐药机制以及与常见抗逆转录病毒药物的潜在药物相互作用仍不清楚。南非是世界上艾滋病毒和结核病负担最重的国家之一，包括耐药结核病和艾滋病毒混合感染的疫情迅速扩大。2013年，美国国家卫生部制定了一项治疗计划，将贝达奎兰与优化的背景方案相结合，为患有广泛耐药前和广泛耐药结核病的患者提供贝达奎林。南非广泛耐药结核病和艾滋病毒的碰撞为研究贝达奎兰提供了一个独特的机会，这些患者可以从中受益，但在很大程度上被排除在临床试验之外。在目标1中，我们提出了一项针对广泛耐药前和广泛耐药结核病参与者的前瞻性队列研究，以确定贝达奎林与其他延长QT间期的药物一起服用时对QT间期的影响。我们推测贝达奎林与氯法齐明或氟喹诺酮类药物联合应用将导致QT间期增加，并可能导致危险的QT延长，需要停用其中一种或多种药物。在目标2中，我们将使用全基因组测序来鉴定贝达奎兰耐药的遗传机制。在产生耐药性的参与者中，我们将对结核分枝杆菌分离株进行全基因组测序，以确定单核苷酸多态(SNPs)。在目标3中，我们将研究贝达奎兰与ART的药物相互作用。根据对健康志愿者的小剂量单剂量研究，建议贝达奎林与奈韦拉平或基于洛皮那韦/利托那韦的方案一起服用。我们将对接受贝达奎林治疗的参与者进行密集和稀疏的药代动力学抽样，无论是否使用抗逆转录病毒治疗。这项研究的每个目标都将回答关于贝达奎兰的一个基本问题，这将直接告知其在南非和全球的使用情况。我们的研究将从世界上最大的接受贝达奎兰治疗的患者的非试验队列中进行。美国国立卫生研究院和联邦结核病工作组已经为艾滋病毒和耐药结核病之间的相互作用确定了具体的优先研究领域。这项申请将集中在南非的两个这样的贝达奎兰区域--新的耐药性标记和与抗逆转录病毒药物的药理相互作用--南非是耐药结核病和艾滋病毒集中流行的中心。

DESCRIPTION (provided by applicant): Extensively drug-resistant tuberculosis (XDR TB) has emerged as a significant global epidemic and poses a particular threat to HIV-infected persons. With few effective drugs available for treatment, XDR TB carries an extremely high mortality. Bedaquiline is the first new TB drug to receive FDA approval in 40 years and has shown considerable promise in early clinical trials of patients with MDR TB. The drug has not, however, been well-studied in patients with XDR TB or in those with HIV co-infection who are receiving antiretroviral therapy (ART). As a result, much remains unknown about the safety of this potentially transformative drug, the mechanisms of resistance, and the potential drug-drug interactions with common antiretroviral drugs. South Africa has among the highest burden of HIV and TB in the world, including a rapidly expanding epidemic of drug-resistant TB and HIV co-infection. In 2013, the National Department of Health created a treatment program to make bedaquiline available to patients with pre-XDR and XDR TB in combination with an optimized background regimen. The collision of XDR TB and HIV in South Africa offers a unique opportunity to study bedaquiline in patients who could benefit substantially from it, yet who have been largely excluded from the clinical trials. In Aim 1, we propose a prospective cohort study of pre-XDR and XDR TB participants to determine the effect of bedaquiline on the QT-interval when given with other QT-prolonging TB medications. We hypothesize that the co-administration of bedaquiline with clofazimine or fluoroquinolones will lead to additive increases in the QT interval and may lead to dangerous QT prolongation requiring discontinuation of one or more of these medications. In Aim 2, we will use whole genome sequencing to identify the genetic mechanisms of resistance to bedaquiline. Among participants who develop resistance, we will conduct whole genome sequencing of M. tuberculosis isolates to identify single nucleotide polymorphisms (SNPs). In Aim 3, we will examine drug-drug interactions of bedaquiline with ART. Bedaquiline is recommended to be given with either nevirapine or lopinavir/ritonavir-based regimens, based on small, single-dose studies in healthy volunteers. We will conduct intensive and sparse pharmacokinetic sampling on participants receiving bedaquiline, with or without ART. Each aim of this study will answer a fundamental question about bedaquiline that will directly inform its use in South Africa and globally. Our study will draw from the largest non-trial cohort of patients receiving bedaquiline anywhere in the world. The NIH and the Federal TB Task Force have identified specific priority research areas for the interaction between HIV and drug-resistant TB. This application will focus on two such areas for bedaquiline-new markers of resistance and pharmacologic interactions with ART-in South Africa, the epicenter of the convergent epidemics of drug-resistant TB and HIV.