Primaquine metabolism and treatment of P. vivax in Madagascar

间日疟原虫对消灭疟疾提出了独特的挑战，因为它 产生催眠虫，休眠的肝脏阶段，导致复发感染数周至数年， 蚊子传播。如果不治疗，催眠虫代表一个疾病水库，其程度是未知的。 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，表现出超越以前认识到的重大障碍的能力。 此时，人们也更加认识到间日疟的临床严重性和 尽管有蚊帐和针对血液期寄生虫的药物，这种寄生虫仍然存在。到 应对这一重大公共卫生挑战和消除疟疾的威胁，努力的重点必须是 减少了催眠虫的储存量伯氨喹（PQ）是世界卫生组织推荐的唯一一种能够 杀灭催眠虫，达到根治间日疟原虫目的。然而，必须考虑许多因素 关于最佳使用这种重要的抗疟疾药物。基因编码的遗传变异 人细胞色素P450同工酶2D 6（CYP 2D 6）与通过P. 间日疟在接受标准PQ治疗（0.25-0.50 mg/kg体重， 每日口服14天）。PQ也可能导致危及生命的溶血性贫血G6 PD缺乏 （G6 PDd）的人，如果药物治疗没有减少后，溶血的迹象变得明显（通常 血尿）。这些观察结果强调了制定有效策略来使用PQ的重要性 和其它8-氨基喹啉药物（他非诺喹; TQ）。TQ作为单剂量治疗（最近 FDA批准;尚未WHO推荐）将提高依从性，但其半衰期更长（PQ 15小时; TQ 15天），这使得它在最严重的人中特别危险。 酶病在这里，我们重点关注优化PQ治疗的必要性。我们的初步结果显示 CYP 2D 6基因的复杂多态性，与CYP 2D 6基因相关的活性评分的显著变化， 探针药物美沙芬（DM），并增加了PQ对间日疟原虫有效性的变化。我们 我们将通过以下具体目标来应对这些挑战。目的1：评价CYP 2D 6双体型 和基因组变异，以鉴定待研究的个体，用于鉴定PQ代谢的修饰剂， 制定一个全球框架来评估PQ的有效性。目的2：评价PQ代谢表型 和CYP 2D 6二倍型关联。目的3：评价PQ根治间日疟原虫的效果 vs.与CYP 2D 6和马达加斯加研究参与者的基因组变异相关的复发。近 2.5 10亿人面临间日疟原虫疟疾的风险。人类遗传变异使基于人口的 在间日疟原虫流行区使用PQ治疗。拟议的研究将调查CYP 2D 6遗传 变异，混淆了PQ的最佳使用，以制定基于种群的策略，以消除间日疟原虫。

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.