Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

Bastiaens, Guido J. H.; Tiono, Alfred B.; Okebe, Joseph; Pett, Helmi; Coulibaly, Sam Aboubacar; Gonçalves, Bronner P.; Affara, Muna; Ouédraogo, Alphonse; Bougouma, Edith C.; Sanou, Guillaume S.; Nébié, Issa; Bradley, John; Lanke, Kjerstin; Niemi, Mikko; Sirima, Sodiomon B.; D’Alessandro, Umberto; Bousema, Teun; Drakeley, Chris

doi:10.1371/journal.pone.0190272

Cited by 35 publications

(50 citation statements)

References 45 publications

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“…Pharmacovigilance in this study was planned to ensure training, detection, reporting, management, and follow-up of adverse events by both passive and active surveillance. In line with other studies [ 13 , 14 , 16 , 34 – 37 ], MDA with DP and SLD primaquine was deemed safe, with some transient adverse events and no reports of clinically serious adverse events. In addition, acceptability of the intervention was high with over 90% of survey respondents expressing willingness to participate in future MDAs.…”

Section: Discussionsupporting

confidence: 86%

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting—high coverage and safety, but no significant impact on transmission

Morris

Msellem

Mkali

et al. 2018

BMC Med

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BackgroundMass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting.MethodsA cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.8%. The areas were randomised to eight intervention and eight control clusters. The intervention included two rounds of MDA with dihydroartemisinin-piperaquine and single low-dose primaquine 4 weeks apart in May–June 2016. Primary and secondary outcomes were cumulative confirmed malaria case incidences 6 months post-MDA and parasite prevalences determined by PCR 3 months post-MDA. Additional outcomes included intervention coverage, treatment adherence, occurrence of adverse events, and cumulative incidences 3, 12, and 16 months post-MDA.ResultsIntervention coverage was 91.0% (9959/10944) and 87.7% (9355/10666) in the first and second rounds, respectively; self-reported adherence was 82.0% (881/1136) and 93.7% (985/1196). Adverse events were reported in 11.6% (147/1268) and 3.2% (37/1143) of post-MDA survey respondents after both rounds respectively. No serious adverse event was reported. No difference in cumulative malaria case incidence was observed between the control and intervention arms 6 months post-MDA (4.2 and 3.9 per 1000 population; p = 0.94). Neither was there a difference in PCR-determined parasite prevalences 3 months post-MDA (1.4% and 1.7%; OR = 1.0, p = 0.94), although having received at least the first MDA was associated with reduced odds of malaria infection (aOR = 0.35; p = 0.02). Among confirmed malaria cases at health facilities, 26.0% and 26.3% reported recent travel outside Zanzibar in the intervention and control shehias (aOR ≥ 85; p ≤ 0.001).ConclusionsMDA was implemented with high coverage, adherence, and tolerability. Despite this, no significant impact on transmission was observed. The findings suggest that two rounds of MDA in a single year may not be sufficient for a sustained impact on transmission in a pre-elimination setting, especially when the MDA impact is restricted by imported malaria. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa.Trial registrationClinicalTrials.gov, NCT02721186 (registration date: March 29, 2016)Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1202-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting—high coverage and safety, but no significant impact on transmission

Morris

Msellem

Mkali

et al. 2018

BMC Med

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“…Accumulating evidence from Africa [ 63 – 65 ] and Asia [ 66 ], suggests that single-dose PQ at 0.25 mg/kg as a gametocytocidal drug to block transmission would be safe in areas where G6PD deficiency A− and other type 2 variants predominates, comparable to the settings in this study site. Encouraging evidence from neighbouring Swaziland, a country with a similar G6PD deficiency prevalence profile to South Africa, suggests the roll-out of a low-dose PQ policy with no prior genetic profiling requirement, at least in none G6PD-deficient participants by RDT, is associated with good safety profiles [ 53 ].…”

Section: Discussionmentioning

confidence: 58%

Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa

Awandu

Raman

Makhanthisa

et al. 2018

Malar J

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BackgroundPrimaquine (PQ) is recommended as an addition to standard malaria treatments in pre-elimination settings due to its pronounced activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for onward transmission to mosquitoes. However, PQ may trigger haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. Additional human genetic factors, including polymorphisms in the human cytochrome P450 2D6 (CYP2D6) complex, may negatively influence the efficacy of PQ. This study assessed the prevalence of G6PD deficiency and two important CYP2D6 variants in representative pre-elimination settings in South Africa, to inform malaria elimination strategies.MethodsVolunteers (n = 248) attending six primary health care facilities in a malaria-endemic region of South Africa were enrolled between October and November 2015. G6PD status was determined phenotypically, using a CareStart™ G6PD rapid diagnostic test (RDT), and genotypically for two common African G6PD variants, namely A+ (A376G) and A− (G202A, A542T, G680T & T968C) by PCR, restriction fragment length polymorphisms (RFLP) and DNA sequencing. CYP2D6*4 and CYP2D6*17 variants were determined with PCR and RFLP.ResultsA prevalence of 13% (33/248) G6PD deficiency was observed in the cohort by G6PD RDT whilst by genotypic assessment, 32% (79/248) were A+ and 3.2% were A−, respectively. Among the male participants, 11% (6/55) were G6PD A− hemizygous; among females 1% (2/193) were G6PD A− homozygous and 16% (32/193) G6PD A− heterozygous. The strength of agreement between phenotyping and genotyping result was fair (Cohens Kappa κ = 0.310). The negative predictive value for the G6PD RDT for detecting hemizygous, homozygous and heterozygous individuals was 0.88 (95% CI 0.85–0.91), compared to the more sensitive genotyping. The CYP2D6*4 allele frequencies for CYP2D6*4 (inferred poor metabolizer phenotype) and CYP2D6*17 (inferred intermediate metabolizer phenotype) were 3.2 and 19.5%, respectively.ConclusionsPhenotypic and genotypic analyses both detected low prevalence of G6PD deficiency and the CYP2D6*4 variants. These findings, combined with increasing data confirming safety of single low-dose PQ in individuals with African variants of G6PD deficiency, supports the deployment of single low-dose PQ as a gametocytocidal drug. PQ would pose minimal risks to the study populations and could be a useful elimination strategy in the study area.

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“…Most studies evaluating the safety of PQ intake in G6PDd patients are based on P. falciparum infections receiving a single dose of PQ administered at different concentrations (0.25 or 0.4 mg/kg [ 34 , 35 ]; 0.4–0.5 mg/kg [ 36 ]; 0.1, 0.4, 0.75 mg/kg [ 37 ]; 0.7 mg/kg [ 38 ]). Those studies seem to agree on two points: that the adverse effects of PQ at low doses are usually mild or moderate even in patients with G6PDd; and that safety depends primarily on primaquine doses, as well as the variant of G6PD deficiency.…”

Section: Discussionmentioning

confidence: 99%

G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients

Ávalos

Mejía²,

Banegas³

et al. 2018

Malar J

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BackgroundThe incidence of malaria in the Americas has decreased markedly in recent years. Honduras and the other countries of Mesoamerica and the island of Hispaniola have set the goal of eliminating native malaria by the year 2020. To achieve this goal, Honduras has recently approved national regulations to expand the possibilities of a shortened double dose primaquine (PQ) treatment for vivax malaria. Considering this new shortened anti-malarial treatment, the high frequency of G6PDd genotypes in Honduras, and the lack of routinely assessment of the G6PD deficiency status, this study aimed at investigating the potential association between the intake of PQ and haemolysis in malaria-infected G6PDd subjects.MethodsThis was a prospective cohort and open-label study. Participants with malaria were recruited. Plasmodium vivax infection was treated with 0.25 mg/kg of PQ daily for 14 days. Safety and signs of haemolysis were evaluated by clinical criteria and laboratory values before and during the 3rd and 7th day of PQ treatment. G6PD status was assessed by a rapid test (CareStart™) and two molecular approaches.ResultsOverall 55 participants were enrolled. The frequency of G6PD deficient genotypes was 7/55 (12.7%), where 5/7 (71.4%) were hemizygous A− males and 2/7 (28.6%) heterozygous A− females. Haemoglobin concentrations were compared between G6PD wild type (B) and G6PDd A− subjects, showing a significant difference between the means of both groups in the 3rd and 7th days. Furthermore, a statistically significant difference was evident in the change in haemoglobin concentration between the 3rd day and the 1st day for both genotypes, but there was no statistical difference for the change in haemoglobin concentration between the 7th day and the 1st day. Besides these changes in the haemoglobin concentrations, none of the patients showed signs or symptoms associated with severe haemolysis, and none needed to be admitted to a hospital for further medical attention.ConclusionsThe findings support that the intake of PQ during 14 days of treatment against vivax malaria is safe in patients with a class III variant of G6PDd. In view of the new national regulations in the shortened treatment of vivax malaria for 7 days, it is advisable to be alert of potential cases of severe haemolysis that could occur among G6PD deficient hemizygous males with a class II mutation such as the Santamaria variant, previously reported in the country.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2564-2) contains supplementary material, which is available to authorized users.

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Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

Cited by 35 publications

References 45 publications

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting—high coverage and safety, but no significant impact on transmission

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting—high coverage and safety, but no significant impact on transmission

Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa

G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients

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