Prevalence of glucose 6-phosphate dehydrogenase deficiency in highly malaria-endemic municipalities in the Brazilian Amazon: A region-wide screening study

Nascimento, Joabi; Brito-Sousa, José Diego; Almeida, Anne Cristine Gomes de; Melo, Marly Marques de; Costa, Mônica Regina Farias; Barbosa, Laila R. A.; Ramos, Reinaldo  Nery; Silva-Neto, Alexandre Vilhena; Balieiro, Patrícia Carvalho da Silva; Figueiredo, Erick Frota Gomes; Silva, Emanuelle Lira; Baía-da-Silva, Djane Clarys; Bassat, Quique; Romero, Gustavo Adolfo Sierra; Melo, Gisely Cardoso de; Sampaio, Vanderson de Souza; Lacerda, Marcus

doi:10.1016/j.lana.2022.100273

Cited by 9 publications

(19 citation statements)

References 32 publications

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“…However, this class of 8-aminoquinolines can cause hemolysis in individuals with low G6PD enzyme activity, which presents an obstacle to the global implementation of drug delivery against vivax malaria (25,26). The prevalence of G6PDd in the male population has been reported in several studies from around the world, and also in the Amazon region, with a frequency of 4.5-10% (12,27,28). The African A-variant (G202A/A376G) was the most common, around 55.6%, followed by the African A+ (A376G) (11.1%) and Mediterranean (C563T) (5.6%) variants.…”

Section: Discussionmentioning

confidence: 77%

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

Macêdo

Almeida

Barbosa

et al. 2023

Preprint

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Background In the Amazon, Plasmodium vivax is the prevalent malaria parasite, and the standard treatment is chloroquine combined with primaquine. However, this regimen is limited because of the risk of acute hemolytic anemia (AHA) in glucose-6-phosphate dehydrogenase deficient individuals (G6PDd). CYP2D6 is a key enzyme that is involved in the metabolism of a large number of drugs. Primaquine is a prodrug that requires conversion by the CYP2D6 enzyme in order to be effective against malaria. Furthermore, interaction with cytochrome P450 (CYP) liver enzymes of some pharmacogenes, such as CYP2C19, CYP2D6 and CYP3A4 associated with PQ metabolism, may enhance, or reduce its biotransformation. Methods A series of cases were followed-up at an infectious diseases reference hospital in the Western Brazilian Amazon. The inclusion criteria were patients of either sex, > 6 months of age, diagnosed with vivax malaria, treated with PQ and presence of hemolysis after treatment. The STANDARD G6PD (SD Biosensor®) assay was used to test G6PD status, and real-time PCR was used to genotype G6PD, CYP2C19, CYP2D6 and CYP3A4. Results Eighteen patients were included, of which 55.6% had the African A- variant (G202A/A376G), 11.1% the African A + variant (A376G), 5.6% the Mediterranean variant (C563T) and 27.8% were the wild type. CYP2C19, CYP2D6 and CYP3A4 genotyping showed no statistically significant differences in the frequency of star alleles between the groups (p > 0.05). Elevated levels of liver and kidney markers in the G6PDd patients were observed in gNM, gRM and gUM of CYP2C19 and CYP2D6 (p < 0.05). Conclusions These findings reinforce the importance of studies on the mapping of G6PD deficiency and CYP2C19, CYP2D6 and CYP3A4 genetic variations. This mapping will allow us to validate the prevalence of CYPs and determining their influence on the hemolytic process in vivax malaria patients, and will aid in decisions regarding the appropriate treatment regimen, thereby avoiding complications caused by the breakdown of PQ by CYP.

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Section: Discussionmentioning

confidence: 77%

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

Macêdo

Almeida

Barbosa

et al. 2023

Preprint

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“…G6PD deficiency, the most common RBC enzymopathy, also affects malaria risk. The relatively mild West African G6PD A− variant (10% to 60% G6PD activity), found in 39.3% of the G6PD-deficient Amazonians [ 56 ], is associated with a significant reduction in the risk of severe falciparum malaria in both male hemizygotes and heterozygous females in Africa. Whether the G6PD A− variant affects the risk of P .…”

Section: Human Genetics Red Blood Cell Invasion and P ...mentioning

confidence: 99%

“…vivax infection and disease is unknown [ 47 ]. Nevertheless, the Mediterranean variant (1% to 10% G6PD activity), which is widely distributed across Europe and Asia [ 26 ] but rare in the Amazon [ 56 ], reduces the risk of symptomatic P . vivax malaria by 76% in hemizygous males and homozygous females of Pashtum ethnicity from Afghanistan [ 57 , 58 ].…”

Section: Human Genetics Red Blood Cell Invasion and P ...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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“…On the other hand, for the radical cure of P. vivax , PQ 0.5 mg/day for 7 days is employed; this shorter, higher dose regimen is being used in several nations, such as Brazil [ 135 ]. The same total dose (0.5 mg/kg/day to 210 mg) administered over 7 days as opposed to 14 days may have little to no difference on P. vivax recurrences [ 127 ].…”

Section: Control Challengesmentioning

confidence: 99%

Plasmodium vivax: the potential obstacles it presents to malaria elimination and eradication

Habtamu

Petros

Yan

2022

Trop Dis Travel Med Vaccines

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Initiatives to eradicate malaria have a good impact on P. falciparum malaria worldwide. P. vivax, however, still presents significant difficulties. This is due to its unique biological traits, which, in comparison to P. falciparum, pose serious challenges for malaria elimination approaches. P. vivax's numerous distinctive characteristics and its ability to live for weeks to years in liver cells in its hypnozoite form, which may elude the human immune system and blood-stage therapy and offer protection during mosquito-free seasons. Many malaria patients are not fully treated because of contraindications to primaquine use in pregnant and nursing women and are still vulnerable to P. vivax relapses, although there are medications that could radical cure P. vivax. Additionally, due to CYP2D6's highly variable genetic polymorphism, the pharmacokinetics of primaquine may be impacted. Due to their inability to metabolize PQ, some CYP2D6 polymorphism alleles can cause patients to not respond to treatment. Tafenoquine offers a radical treatment in a single dose that overcomes the potentially serious problem of poor adherence to daily primaquine. Despite this benefit, hemolysis of the early erythrocytes continues in individuals with G6PD deficiency until all susceptible cells have been eliminated. Field techniques such as microscopy or rapid diagnostic tests (RDTs) miss the large number of submicroscopic and/or asymptomatic infections brought on by reticulocyte tropism and the low parasitemia levels that accompany it. Moreover, P. vivax gametocytes grow more quickly and are much more prevalent in the bloodstream. P. vivax populations also have a great deal of genetic variation throughout their genome, which ensures evolutionary fitness and boosts adaptation potential. Furthermore, P. vivax fully develops in the mosquito faster than P. falciparum. These characteristics contribute to parasite reservoirs in the human population and facilitate faster transmission. Overall, no genuine chance of eradication is predicted in the next few years unless new tools for lowering malaria transmission are developed (i.e., malaria elimination and eradication). The challenging characteristics of P. vivax that impede the elimination and eradication of malaria are thus discussed in this article.

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Prevalence of glucose 6-phosphate dehydrogenase deficiency in highly malaria-endemic municipalities in the Brazilian Amazon: A region-wide screening study

Cited by 9 publications

References 32 publications

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

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

Plasmodium vivax: the potential obstacles it presents to malaria elimination and eradication

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