Project Title

Single low-dose primaquine efficacy and safety for treatment of uncomplicated Plasmodium falciparum malaria based on cytochrome P450 2D6 activity in Bagamoyo district, Tanzania.

EDCTP Project Call

Career Development Fellowship (CDF)

Project Objectives

Broad Objective To compare the safety and efficacy of a 0.25 mg/kg single-dose PQ added to a standard artemether-lumefantrine regimen for clearance and transmission-blocking of P. falciparum gametocytes in patients with reduced/null compared to those with normal/increased CYP2D6 isoenzyme activities. Specific Objectives 1. To determine the prevalence of patients with reduced activities of CYP2D6 with the intention to treat malaria. 2. To determine the safety of 0.25 mg/kg single-dose PQ added to the first dose of artemether-lumefantrine in patients with reduced/null vs. normal/increased activities of CYP2D6. 3. To determine the prevalence of G6PD deficiency in patients with reduced/null vs. normal/increased activities of CYP2D6. 4. To determine the safety of 0.25 mg/kg single-dose PQ added to the first dose of artemether-lumefantrine in patients with G6PD deficiency and reduced/null vs. normal/increased activities of CYP2D6 5. To determine the efficacy of 0.25 mg/kg single-dose PQ added to the first dose of artemether-lumefantrine in the clearance of gametocytes in patients with reduced/null vs. normal/increased activities of CYP2D6. 6. To determine the efficacy of 0.25 mg/kg single-dose PQ added to the first dose of artemether-lumefantrine in blocking the transmission of P. falciparum gametocytes in patients with reduced/null vs. normal/increased activities of CYP2D6.

Study Design

Study Design There is no rapid diagnostic test that could be used to test and group participants based on their CYP2D6 status, therefore, this was a single-arm clinical trial to assess the safety and efficacy of a 0.25 mg/kg single-dose PQ added to standard artemether-lumefantrine treatment in individuals with CYP2D6 reduced or no activity compared to those with normal or increased activity for clearance and blocking transmission of P. falciparum gametocytes. Patients with microscopically confirmed uncomplicated P. falciparum mono-infection were enrolled in the study, treated with a standard artemether-lumefantrine regimen plus 0.25 mg/kg single-dose PQ, and then followed up until day 28 after treatment initiation for clinical and parasitological assessment. Only CYP2D6 alleles common in African Tanzanians were genotyped. Individuals with reduced CYP2D6 activity were defined as those with CYP2D6*17 and CYP*29 alleles, whereas those with no activity were those with CYP2D6*4 and CYP2D6*5, and normal individuals were those with CYP2D6*1, while those with CYP2D6*2 were defined as having increased activity [26,33]. However, a previous study indicated a very low prevalence of poor metabolizers, which probably wouldn't lead to a significant conclusion [33]. Therefore, poor metabolizers were combined with those with reduced CYP2D6 activity to form one group, the reduced CYP2D6 activity group.

Project Summary

Background: The World Health Organization (WHO) recommends the addition of a single low-dose (0.25 mg/kg) of primaquine to standard artemisinin-based combination therapy (ACT) for the elimination of Plasmodium falciparum malaria in low transmission settings and for containment in areas threatened by artemisinin resistance. The drug has shown to be safe and efficacious, and can probably be employed in malaria endemic sub-Saharan Africa for control of the infection. However, primaquine is metabolized mainly by an enzyme (cytochrome P450 (CYP) 2D6), which is known to be highly polymorphic. This polymorphism has led to people having either, no, reduced, normal, or increased enzyme activity. The polymorphic nature of the enzyme is thought to compromise the safety and efficacy of primaquine, particularly in individuals with reduced or no CYP2D6 enzyme activity. This trial, therefore, assessed the safety and efficacy of 0.25 mg/kg single-dose of primaquine when added to a standard artemether-lumefantrine regimen for clearance and blocking the transmission of P. falciparum gametocytes in patients with no/reduced enzyme activity as compared to those with normal/increased enzyme activity in Bagamoyo district, Tanzania. Methods: Between June 2019 and January 2020 children aged 1-10 years, attending at Yombo dispensary, Bagamoyo district, with confirmed microcopy-determined uncomplicated P. falciparum malaria were enrolled in the study. The enrolled patients were treated with a standard artemether-lumefantrine regimen plus 0.25 mg/kg single-dose primaquine and followed up for 28 days for clinical and laboratory assessment. Primaquine was administered with the first dose of artemether-lumefantrine. Safety assessment involved direct questioning and recording of the nature and incidence of clinical signs and symptoms, and measurement of hemoglobin (Hb) concentration. Blood samples collected from 100 patients were used for assessment of post-treatment infectiousness on day 7 using mosquito membrane feeding assays. Molecular methods were used to determine CYP2D6 and glucose-6-phosphate dehydrogenase (G6PD) status. The primary outcome was the safety of 0.25 mg/kg single-dose primaquine based on CYP2D6 status. Results: In total, 157 children (median age 6.4 (Interquartile range 4.0-8.2) years) were recruited, of whom 21.0% (33/157) and 12.7% (20/157) had reduced CYP2D6 and deficient G6PD activity, respectively. Day 3 mean absolute Hb concentration reduction was 1.50 g/dL (95% confidence interval [CI]: 1.10-1.90) and 1.51 g/dL (95%CI:1.31-1.71) in reduced and normal CYP2D6 patients, respectively (t=0.012, p=0.990). The day 3 mean absolute Hb concentration reduction in G6PD deficient, G6PD normal and heterozygous female was 1.82 g/dL (95%CI: 1.32-2.32), 1.48 g/dL (95%CI: 1.30-1.67) and 1.47 g/dL (95%CI: 0.76-2.18), respectively (F=0.838, p=0.435). Sixteen percent (16/98) of the patients each infected at least one mosquito on day 7, and of these, 10.0% (2/20) and 17.9% (14/78) had reduced and normal CYP2D6 enzyme activity, respectively (x2= 0.736, p=0.513). Conclusion: Single-dose 0.25 mg/kg primaquine was safe and sufficient for reducing transmission of P. falciparum gametocytes regardless of CYP2D6 or G6PD status.

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Current Organisation

Tropical Pesticides Research Institute

Current Job Title

Research Scientist

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