Prevalence of Glucose 6-phosphate Dehydrogenase Deficiency in Highly Malaria-endemic Municipalities in the Brazilian Amazon: A Region-wide Screening Study

Background: Difficulties associated with the assessment of glucose-6-phosphate dehydrogenase deficiency (G6PDd), particularly in remote areas, hinders the safe use of 8-aminoquinolines such as primaquine (PQ) and tafenoquine against malaria due to the risk of haemolysis.

Methods: This cross-sectional study was conducted in 41 malaria-endemic municipalities of six states in the Brazilian Amazon, between 2014 and 2018. Male individuals were screened for G6PDd using the qualitative Fluorescent Spot Test using fingerpick-collected whole blood samples. Point and interval estimates of the G6PDd prevalence were calculated for each state. Deficient samples were genotyped for the most prevalent variants in the Amazon. Frequencies of malaria recurrences were estimated for G6PDd and non-G6PDd patients.

Interpretation: This is one of the largest surveys ever conducted in Latin America, covering the entire malaria endemic area in the Brazilian Amazon. These results indicate that an important proportion of the population is at risk of hemolysis if exposed to PQ and its congener drug tafenoquine. The adoption of G6PDd screening protocols is essential to ensure the safety of individuals treated with those drugs and should also be considered when implementing malaria elimination strategies.

Findings: A total of 14,847 individuals were included, of which 5.6% presented G6PDd. The state of Acre had the highest G6PDd prevalence (8.3%), followed by Amapá (5.8%), Pará (5.7%), Rondônia (5.4%), Roraima (4.2%) and Amazonas (4.0%). From 828 genotyped samples, African A (6.2%), African A (39.3%) and wild-type (non-African non-Mediterranean; 54.2%) variants were found. A greater proportion of malaria recurrences was found among G6PD deficient individuals [16.7% vs 4.1%, Risk ratio 3.52 (2.16-5.74) < 0.01].

Funding: Brazilian Ministry of Health; Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM).

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References

Chu C, Bancone G, Nosten F, White N, Luzzatto L . Primaquine-induced haemolysis in females heterozygous for G6PD deficiency. Malar J. 2018; 17(1):101. PMC: 5833093. DOI: 10.1186/s12936-018-2248-y. View

Brasil L, Rodrigues-Soares F, Santoro A, Almeida A, Kuhn A, Ramasawmy R . CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study. Malar J. 2018; 17(1):57. PMC: 5795836. DOI: 10.1186/s12936-017-2139-7. View

Mason P, Bautista J, Gilsanz F . G6PD deficiency: the genotype-phenotype association. Blood Rev. 2007; 21(5):267-83. DOI: 10.1016/j.blre.2007.05.002. View

Watson J, Taylor W, Menard D, Kheng S, White N . Modelling primaquine-induced haemolysis in G6PD deficiency. Elife. 2017; 6. PMC: 5330681. DOI: 10.7554/eLife.23061. View

Peixoto H, Brito M, Romero G, Monteiro W, de Lacerda M, de Oliveira M . G6PD deficiency in male individuals infected by Plasmodium vivax malaria in the Brazilian Amazon: a cost study. Malar J. 2015; 14:126. PMC: 4381355. DOI: 10.1186/s12936-015-0647-x. View

Ley B, Alam M, Kibria M, Marfurt J, Phru C, Ami J . Glucose-6-phosphate dehydrogenase activity in individuals with and without malaria: Analysis of clinical trial, cross-sectional and case-control data from Bangladesh. PLoS Med. 2021; 18(4):e1003576. PMC: 8064587. DOI: 10.1371/journal.pmed.1003576. View

Hsu J, Fink D, Langer E, Carter M, Bengo D, Ndidde S . PCR-based allelic discrimination for glucose-6-phosphate dehydrogenase (G6PD) deficiency in Ugandan umbilical cord blood. Pediatr Hematol Oncol. 2013; 31(1):68-75. PMC: 3923300. DOI: 10.3109/08880018.2013.860649. View

Zobrist S, Brito M, Garbin E, Monteiro W, Clementino Freitas S, Macedo M . Evaluation of a point-of-care diagnostic to identify glucose-6-phosphate dehydrogenase deficiency in Brazil. PLoS Negl Trop Dis. 2021; 15(8):e0009649. PMC: 8384181. DOI: 10.1371/journal.pntd.0009649. View

Brito-Sousa J, Murta F, Vitor-Silva S, Sampaio V, Mendes M, Brito M . Real-life implementation of a G6PD deficiency screening qualitative test into routine vivax malaria diagnostic units in the Brazilian Amazon (SAFEPRIM study). PLoS Negl Trop Dis. 2021; 15(5):e0009415. PMC: 8162658. DOI: 10.1371/journal.pntd.0009415. View

10.

Pal S, Bansil P, Bancone G, Hrutkay S, Kahn M, Gornsawun G . Evaluation of a Novel Quantitative Test for Glucose-6-Phosphate Dehydrogenase Deficiency: Bringing Quantitative Testing for Glucose-6-Phosphate Dehydrogenase Deficiency Closer to the Patient. Am J Trop Med Hyg. 2018; 100(1):213-221. PMC: 6335905. DOI: 10.4269/ajtmh.18-0612. View

11.

Domingo G, Satyagraha A, Anvikar A, Baird K, Bancone G, Bansil P . G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests. Malar J. 2013; 12:391. PMC: 3830439. DOI: 10.1186/1475-2875-12-391. View

12.

Luzzatto L . Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica. 2006; 91(10):1303-6. View

13.

Brito-Sousa J, Peixoto H, Devine A, Silva-Neto A, Balieiro P, Sampaio V . Real-life quantitative G6PD screening in Plasmodium vivax patients in the Brazilian Amazon: A cost-effectiveness analysis. PLoS Negl Trop Dis. 2022; 16(3):e0010325. PMC: 8982881. DOI: 10.1371/journal.pntd.0010325. View

14.

Monteiro W, Moura-Neto J, Recht J, Bassat Q, Lacerda M . Fatal Primaquine-Induced Hemolysis in a Patient With Plasmodium vivax Malaria and G6PD A(-) Variant in the Brazilian Amazon. Clin Infect Dis. 2016; 62(9):1188. DOI: 10.1093/cid/ciw039. View

15.

Monteiro W, Franca G, Melo G, Queiroz A, Brito M, Peixoto H . Clinical complications of G6PD deficiency in Latin American and Caribbean populations: systematic review and implications for malaria elimination programmes. Malar J. 2014; 13:70. PMC: 3938641. DOI: 10.1186/1475-2875-13-70. View

16.

Lacerda M, Llanos-Cuentas A, Krudsood S, Lon C, Saunders D, Mohammed R . Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019; 380(3):215-228. PMC: 6657226. DOI: 10.1056/NEJMoa1710775. View

17.

Balieiro A, Siqueira A, Melo G, Monteiro W, Sampaio V, Mueller I . Short-Time Recurrences of Malaria as a Public Health Proxy for Chloroquine-Resistance Surveillance: A Spatio-Temporal Study in the Brazilian Amazon. Int J Environ Res Public Health. 2021; 18(10). PMC: 8150757. DOI: 10.3390/ijerph18105061. View

18.

Brito-Sousa J, Santos T, Avalos S, Fontecha G, Melo G, Val F . Clinical Spectrum of Primaquine-induced Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficiency: A 9-Year Hospitalization-based Study From the Brazilian Amazon. Clin Infect Dis. 2019; 69(8):1440-1442. DOI: 10.1093/cid/ciz122. View

19.

Cappellini M, Fiorelli G . Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008; 371(9606):64-74. DOI: 10.1016/S0140-6736(08)60073-2. View

20.

Santana M, Monteiro W, Costa M, Sampaio V, Brito M, Lacerda M . High frequency of diabetes and impaired fasting glucose in patients with glucose-6-phosphate dehydrogenase deficiency in the Western brazilian Amazon. Am J Trop Med Hyg. 2014; 91(1):74-6. PMC: 4080572. DOI: 10.4269/ajtmh.13-0032. View