Modulation of TB-HIV drug interaction by host genetic influences

宿主遗传影响对 TB-HIV 药物相互作用的调节

• 批准号: G0901364/1
• 负责人: Saye Khoo
• 金额: $ 19.53万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901364%2F1
• 关键词: Modulation; TB; HIV; drug; interaction

Tuberculosis (TB) and HIV are leading causes of death from infection worldwide, and co-infection is common with each epidemic fuelling the other. Concurrent treatment of both diseases is necessary, yet complex because of drug interactions. Efavirenz (EFV) is the HIV drug of choice when using rifampicin (RIF)-based TB regimens, and likely to remain so for the foreseeable future. EFV exposure is decreased by RIF, but less so than for other HIV drugs. However, people differ considerably in EFV exposure despite standardised dosing: pharmacogenetic variation in their genes (principally cytochrome P450 CYP2B6) accounts for most of these differences. CYP2B6 variant genes are particularly prevalent in some populations, such as black Africans, South Indians and SE Asians, and these are populations where HIV-TB coinfection is also widespread. We want to investigate whether the impact of RIF on EFV exposure is different in people who are CYB2B6 poor metabolisers. Our hypothesis is that in these individuals, accessory pathways of EFV elimination are consequently more important, and a ?second hit? on these accessory pathways either through inhibition by another TB drug (isoniazid), or else the added effect of other common genetic variants which impair these pathways, makes these individuals behave differently when RIF is added to EFV. We will evaluate this hypothesis firstly through an interaction study of isoniazid given to healthy volunteers receiving EFV+RIF, in whom CYP2B6 genotype has been characterised. Secondly, we will genotype DNA from up to 347 HIV-positive patients receiving EFV+RIF, together with an equivalent number of HIV-positive patients receiving EFV but not RIF, to examine for secondary exposure-modifying genetic effects. This proposal combines research expertise from Liverpool with a strong clinical trials environment in Singapore, and an ideal study population where CYP2B6 poor metabolisers are prevalent. The interaction studied is of huge clinical importance. Knowledge gained will inform treatment guidelines for HIV-TB coinfection, and allow disease management to be optimised through a personalised medicines (genotyping) approach, or approach which stratifies treatment strategies for at-risk populations. If proven, these strong pharmacogenetic influences will also impact on the design and selection of partner drugs for new TB regimens.

结核病和艾滋病毒是全世界因感染而死亡的主要原因，合并感染很常见，每种流行病都会助长另一种流行病。同时治疗这两种疾病是必要的，但由于药物相互作用而复杂。当使用基于利福平（RIF）的结核治疗方案时，依法韦仑（EFV）是HIV药物的首选，并且在可预见的未来可能仍然如此。RIF降低了EFV暴露，但低于其他HIV药物。然而，尽管标准化剂量，人们在EFV暴露方面存在很大差异：他们基因（主要是细胞色素P450 CYP 2B 6）的药物遗传学变异是这些差异的主要原因。CYP 2B 6变异基因在某些人群中特别普遍，如非洲黑人、南印度人和东南亚人，这些人群中HIV-TB合并感染也很普遍。我们想研究RIF对EFV暴露的影响是否在CYB 2B 6弱代谢者中有所不同。我们的假设是，在这些人中，EFV消除的辅助途径因此更重要，和？第二次打击？通过另一种TB药物（异烟肼）的抑制作用或其他常见的遗传变异对这些辅助途径的附加作用，使这些个体在EFV中加入RIF时表现不同。我们将首先通过对接受EFV+RIF的健康志愿者进行异烟肼相互作用研究来评估这一假设，其中CYP 2B 6基因型已被表征。其次，我们将对347例接受EFV+RIF治疗的HIV阳性患者以及同等数量接受EFV但未接受RIF治疗的HIV阳性患者的DNA进行基因分型，以检查继发性免疫修饰遗传效应。该提案将利物浦的研究专业知识与新加坡强大的临床试验环境以及CYP 2B 6弱代谢者普遍存在的理想研究人群相结合。研究的相互作用具有巨大的临床意义。所获得的知识将为艾滋病毒-结核病合并感染的治疗指南提供信息，并允许通过个性化药物（基因分型）方法或对高危人群的治疗策略进行分层的方法来优化疾病管理。如果得到证实，这些强大的药物遗传学影响也将影响新结核治疗方案的合作药物的设计和选择。