Primaquine metabolism and treatment of P. vivax in Madagascar

项目摘要-间日疟原虫对消除疟疾构成独特的挑战，因为它 产生催眠药，休眠的肝脏阶段，导致复发感染，从几周到几年没有 蚊子传播。如果不治疗，催眠虫就代表着一种疾病宿主，其程度尚不清楚。 我们在马达加斯加的研究提供了证据，证明间日疟原虫现在能够感染达菲的红细胞- 消极的人，展示了超越以前认识到的重大障碍的能力。 此时，人们也更多地认识到间日疟的临床严重性和 尽管有针对血液期寄生虫的蚊帐和药物，这种寄生虫仍将持续存在。至 应对这一重大的公共卫生挑战和对消除疟疾的威胁，努力必须集中在 减少催眠药储藏量。伯喹(PQ)是世界卫生组织推荐的唯一一种能够 杀灭催眠虫，实现间日疟根治。然而，必须考虑一些因素。 关于最佳使用这种重要的抗疟疾药物。编码该基因的遗传变异 人类细胞色素P450同工酶2D6(CYP2D6)通过P。 接受标准PQ治疗(0.25-0.50毫克/公斤体重)的人中间日疟复发 连续14天每天张口)。PQ也可能导致G6PD缺乏者发生危及生命的溶血性贫血 (G6PDd)如果溶血迹象明显后不减少药物治疗的人(通常 血尿)。这些观察结果强调了开发有效的策略来使用PQ的重要性 和其他8-氨基喹啉类药物(他苯喹；TQ)。TQ作为单剂治疗提供(最近 FDA批准；还没有WHO推荐)将改善依从性，但其半衰期(PQ)要长得多 ≈5小时；TQ≈15天)使其对患有最严重形式的人特别危险 酶病。在这里，我们将重点放在需要优化PQ治疗上。我们的初步结果显示 CYP2D6基因的复杂多态，活动度评分显著变化与 探测药物右美沙芬(DM)，以及PQ抗间日疟原虫效果的日益变异。我们 将通过以下具体目标应对这些挑战。目的1：评估CYP2D6的二倍型 和基因组变异来确定要研究的个体，以确定PQ新陈代谢的修饰物和 制定一个评估PQ有效性的全球框架。目的2：评估PQ代谢表型 未感染的马拉加西人中存在CYP2D6二倍型关联。目的3：评估间日疟原虫的PQ根治 马达加斯加研究参与者中与CYP2D6和基因组变异相关的复发。差一点 25亿人面临着间日疟原虫疟疾的风险。人类基因变异使以群体为基础的研究复杂化 在间日疟流行区使用PQ进行治疗。拟议的研究将调查CYP2D6基因 这一变异混淆了PQ的最佳使用，以开发基于种群的策略来消灭间日疟原虫。

Project Summary – Plasmodium vivax presents unique challenges to malaria elimination because it produces hypnozoites, dormant liver-stages that cause relapse infections from weeks to years without mosquito transmission. If untreated, hypnozoites represent a disease reservoir whose extent is unknown. Our studies in Madagascar provide evidence that P. vivax is now able to infect red blood cells of Duffy- negative people, demonstrating the capacity to evolve beyond a significant previously recognized barrier. At this time, there is also greater recognition of the clinical severity of vivax malaria and the capacity of this parasite to persist despite availability of bed nets and drugs that target blood stage parasites. To address this substantial public health challenge and threat to malaria elimination, efforts must focus on reducing the hypnozoite reservoir. Primaquine (PQ) is the only WHO-recommended drug that is able to kill hypnozoites and achieve radical cure of P. vivax. However, a number of factors must be considered regarding optimal use of this important antimalarial drug. Genetic variation in the gene encoding the human cytochrome P450 isoenzyme 2D6 (CYP2D6) has been associated with PQ failure through P. vivax relapses in people who have received standard PQ treatment (0.25-0.50 mg/kg body weight by mouth daily for 14 days). PQ may also cause life-threatening hemolytic anemia in G6PD deficient (G6PDd) people if drug treatment is not curtailed after signs of hemolysis become evident (usually hematuria). These observations emphasize the importance of developing effective strategies to use PQ and other 8-aminoquinoline drugs (tafenoquine; TQ). TQ delivered as a single-dose treatment (recently FDA-approved; not yet WHO-recommended) would improve adherence, but its much longer half-life (PQ ≈5 hours; TQ ≈15 days) makes it particularly dangerous in people with the most severe form of this enzymopathy. Here, we focus on the need to optimize PQ treatment. Our preliminary results reveal complex polymorphism in the CYP2D6 gene, significant variation in activity scores associated with the probe drug dextromethorphan (DM), and increasing variation in PQ effectiveness against P. vivax. We will address these challenges through the following Specific Aims. Aim 1: Evaluate CYP2D6 diplotypes and genome variation to identify individuals to be studied for identifying modifiers of PQ metabolism and develop a global framework to estimate PQ effectiveness. Aim 2: Evaluate PQ metabolism phenotype and CYP2D6 diplotype association in uninfected Malagasies. Aim 3: Assess PQ radical cure of P. vivax vs. recurrence in association with CYP2D6 and genomic variation in Malagasy study participants. Nearly 2.5 billion people are at risk of P. vivax malaria. Human genetic variation complicates population-based treatment using PQ in P. vivax-endemic areas. The proposed studies will investigate CYP2D6 genetic variation that confounds optimal use of PQ to develop population-based strategies to eliminate P. vivax.