Modulation of TB-HIV drug interaction by host genetic influences

结核病和艾滋病毒是世界范围内感染导致死亡的主要原因，同时感染是常见的，两种流行病相互助长。同时治疗两种疾病是必要的，但由于药物相互作用而复杂。在使用以利福平（RIF）为基础的结核病治疗方案时，依非韦伦（EFV）是首选的抗艾滋病毒药物，而且在可预见的未来可能仍然如此。RIF减少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：基因（主要是细胞色素P450 CYP2B6）的药物遗传变异是这些差异的主要原因。CYP2B6变异基因在一些人群中特别普遍，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。我们想研究在CYB2B6代谢不良的人群中，RIF对EFV暴露的影响是否不同。我们的假设是，在这些个体中，EFV消除的附属通路因此更重要，并且？第二次打击吗?通过另一种结核病药物（异烟肼）的抑制作用，或其他损害这些途径的常见遗传变异的附加作用，使这些个体在将RIF添加到EFV中时表现不同。我们将首先通过给接受EFV+RIF的健康志愿者异烟肼的相互作用研究来评估这一假设，其中CYP2B6基因型已被表征。其次，我们将对多达347名接受EFV+RIF治疗的hiv阳性患者的DNA进行基因分型，以及同等数量接受EFV但不接受RIF治疗的hiv阳性患者的DNA进行基因分型，以检查继发性暴露修饰遗传效应。该提案结合了利物浦的研究专长和新加坡强大的临床试验环境，以及CYP2B6代谢不良者普遍存在的理想研究人群。所研究的相互作用具有巨大的临床重要性。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）方法或针对高危人群分层治疗策略的方法来优化疾病管理。如果得到证实，这些强大的药理学影响也将影响结核病新治疗方案的配套药物的设计和选择。

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.