Background
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. 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. PQ may also cause life-threatening hemolytic anemia in G6PD deficient 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 G6PD deficiency.

In addition, since 2012, the WHO has recommended adding single low-dose PQ to standard artemisinin-based combination therapy (ACT) to reduce transmission of P. falciparum in areas of low malaria endemicity and emerging ACT resistance.

Goal
Impaired PQ hypnozoiticidal and gametocytocidal efficacy has far-reaching implications for P. vivaxand P. falciparum case management, respectively, and the feasibility of malaria elimination. Evidence on the role of poor PQ metabolism, however, remains limited and opportunistic. Rigorous investigation is greatly needed to enable developing optimal PQ treatment in endemic populations. The major question is, Do CYP2D6 genetic polymorphisms, and potential modifiers elsewhere in the genome, significantly influence PQ metabolism and hence efficacy against P. vivax (hypnozoites) and P. falciparum (gametocytes) infection? For this, a tiered approach to evaluate PQ metabolism, addressing knowledge gaps at every level, is urgently needed – (1) a better understanding of the population genetics of host factors known to affect PQ metabolism; (2) a better understanding of the PQ metabolism through in vivo assessment; and (3) correlation of PQ metabolism and CYP2D6 genetics with PQ efficacy in patients treated for P. vivax and P. falciparum malaria according to standard of care. Studies conducted on these lines will address the knowledge gap between PQ metabolism and killing of P. vivax hypnozoites and P. falciparum gametocytes that will enable optimization of PQ treatment across human genetic diversity.

Scope and Information for Authors
Major themes:
• Current and future status of PQ use to achieve malaria elimination-
a. Use of PQ against P. vivax hypnozoites
b. Use of PQ against P. falciparum gametocytes
• Current status of PQ metabolism – characterization of its major and functional (anti-malarial) metabolites
• Current status of the role of drug-metabolizing enzyme (CYP2D6, etc,.) gene polymorphisms in affecting PQ efficacy
• Population genetic diversity, admixture, and anti-malarial treatment outcome
• PQ treatment and untangling the complexity of recurrent P.vivax infections – differentiating relapse, reinfection, and recrudescence

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Frontiers in Pharmacology

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