Higher-Dose Primaquine to Prevent Relapse of
            <i>Plasmodium vivax</i>
            Malaria

Chamma-Siqueira, Nathália Nogueira; Negreiros, Suiane C.; Ballard, Sarah-Blythe; Farias, Sâmela; Silva, Sandro P.; Chenet, Stella M.; Santos, Eduardo José Melo dos; Sena, Luann Wendel Pereira de; Costa, Flávia Póvoa da; Cardoso-Mello, Amanda G.N.; Marchesini, Paola; Peterka, Cassio Roberto Leonel; Viana, Giselle Maria Rachid; Oliveira, Alexandre Macedo de

doi:10.1056/nejmoa2104226

Cited by 28 publications

(27 citation statements)

References 26 publications

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“…Here we focus on current knowledge of population genetic variation of CYP2D6 and PQ metabolism in hopes of expanding the population that can use this drug effectively ( Baird et al, 2018a ) to reduce the hypnozoite reservoir. This is consistent with recent clinical trials to test optimal dosing strategies against relapse infections ( Brito-Sousa et al, 2022 ; Chamma-Siqueira et al, 2022 ). An adjoining article by Stewart et al focuses on implications of CYP2D6 and G6PD genetic variation on potential treatment approaches and limitations for P. vivax as well as P. ovale (that also produces hypnozoites) liver stage parasites ( Stewart et al, 2021 ).…”

Section: Introduction—malaria Primaquine and Human Geneticssupporting

confidence: 90%

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

2022

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Clinical trial and individual patient treatment outcomes have produced accumulating evidence that effective primaquine (PQ) treatment of Plasmodium vivax and P. ovale liver stage hypnozoites is associated with genetic variation in the human cytochrome P450 gene, CYP2D6. Successful PQ treatment of individual and population-wide infections by the Plasmodium species that generate these dormant liver stage forms is likely to be necessary to reach elimination of malaria caused by these parasites globally. Optimizing safe and effective PQ treatment will require coordination of efforts between the malaria and pharmacogenomics research communities.

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Section: Introduction—malaria Primaquine and Human Geneticssupporting

confidence: 90%

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

2022

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“…(29) Therefore, highdose primaquine regimens (e.g., 7.0 mg/kg of primaquine over 14 days) may be required to eradicate hypnozoites in this region. (30) Parasite resistance to schizontocidal antimalarials, leading to blood-stage recrudescence shortly after treatment, is unlikely to contribute significantly to the overall vivax malaria burden in the Juruá Valley hotspot of Brazil, where the standard chloroquine-primaquine therapy remains highly efficacious. (31,32) Some of our current findings are at odds with previous observations suggestive of strong antimalarial immunity among rural Amazonians.…”

Section: Discussionmentioning

confidence: 99%

Clinically silent Plasmodium vivax infections in native Amazonians of northwestern Brazil: acquired immunity or low parasite virulence?

Barros

Calil

Rodrigues

et al. 2022

Mem. Inst. Oswaldo Cruz

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BACKGROUND Malaria remains common among native Amazonians, challenging Brazil′s elimination efforts. OBJECTIVES We examined the epidemiology of malaria in riverine populations of the country′s main hotspot - the upper Juruá Valley in Acre state, close to the Brazil-Peru border, where Plasmodium vivax accounts for > 80% of cases. METHODS Participants (n = 262) from 10 villages along the Azul River were screened for malaria parasites by microscopy and genus-specific, cytochrome b ( cytb ) gene-based polymerase chain reaction. Positive samples were further tested with quantitative TaqMan assays targeting P. vivax- and P. falciparum -specific cytb domains. We used multiple logistic regression analysis to identify independent correlates of P. vivax infection. FINDINGS Microscopy detected only one P. vivax and two P. falciparum infections . TaqMan assays detected 33 P. vivax infections (prevalence, 11.1%), 78.1% of which asymptomatic, with a median parasitaemia of 34/mL. Increasing age, male sex and use of insecticide-treated bed nets were significant predictors of elevated P. vivax malaria risk. Children and adults were similarly likely to remain asymptomatic once infected. MAIN CONCLUSIONS Our findings are at odds with the hypothesis of age-related clinical immunity in native Amazonians. The low virulence of local parasites is suggested as an alternative explanation for subclinical infections in isolated populations.

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“…Carriers of low-activity CYP2D6 alleles were found to be at increased risk of P . vivax recurrence following chloroquine-PQ treatment in some [ 32 , 34 , 36 ], although not all, clinical studies [ 35 , 37 ]. Importantly, high-dose PQ treatment may represent a safe and efficacious alternative to circumvent poor or intermediate CYP2D6-mediated metabolization in Brazil [ 37 ].…”

Section: Relapses and Repeated Plasmodium Vivax In...mentioning

confidence: 99%

Individual variation in Plasmodium vivax malaria risk: Are repeatedly infected people just unlucky?

2023

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Extensive research has examined why some people have frequent Plasmodium falciparum malaria episodes in sub-Saharan Africa while others remain free of disease most of the time. In contrast, malaria risk heterogeneity remains little studied in regions where P. vivax is the dominant species. Are repeatedly infected people in vivax malaria settings such as the Amazon just unlucky? Here, we briefly review evidence that human genetic polymorphism and acquired immunity after repeated exposure to parasites can modulate the risk of P. vivax infection and disease in predictable ways. One-fifth of the hosts account for 80% or more of the community-wide vivax malaria burden and contribute disproportionally to onward transmission, representing a priority target of more intensive interventions to achieve malaria elimination. Importantly, high-risk individuals eventually develop clinical immunity, even in areas with very low or residual malaria transmission, and may constitute a large but silent parasite reservoir.

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Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria

Cited by 28 publications

References 26 publications

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

Clinically silent Plasmodium vivax infections in native Amazonians of northwestern Brazil: acquired immunity or low parasite virulence?

Individual variation in Plasmodium vivax malaria risk: Are repeatedly infected people just unlucky?

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