Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania

Abstract

BackgroundThis study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.MethodsMen and non-pregnant, non-lactating women aged ≥1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart™) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm.ResultsOverall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [6.8, 95 % confidence interval (CI) 4.67–8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of ≥25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention.ConclusionThe findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania.Trial registration number NCT02090036Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1341-3) contains supplementary material, which is available to authorized users.

Sustained High Cure Rate of Artemether–Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania

“…23 The first trial was an AL pharmacokinetics and pharmacodynamics study conducted in 2006, 24 the second trial was a supervised treatment arm of the two arms AL efficacy and effectiveness clinical trial carried out in 2007-2008, 4 the third trial was an AL efficacy trial conducted in 2012-2013 (unpublished data), and the fourth trial was a two arms AL and AL plus a single low-dose primaquine (PQ) efficacy and safety clinical trial carried out in 2014. 25 The PQ arm was included since there was no statistically significant difference in the cure rate between AL and AL + PQ arm. 26 The first study was conducted 6 months before implementation of AL treatment policy, whereas the second, third, and fourth studies were conducted 1, 6, and 8 years after the implementation of AL in Bagamoyo district, respectively.…”

“…The subjects inclusion and exclusion criteria are described elsewhere. 4,24,25 Patients with microscopically confirmed P. falciparum infection were enrolled, admitted during the first 3 days, treated and then followed up for 3 (2006), 28 (2014), 42 (2012-2013), or 56 (2007)(2008) days for clinical and laboratory evaluation. However, for the current study, the treatment outcomes were assessed by day 28.…”

“…For the 2014 cohort, a 0.25 mg/kg single-dose PQ was administered together with the first AL dose among patients in the AL + PQ arm. 25 All doses were directly observed. Patients were observed for 30 minutes after each drug dose and treatment was readministered in case of vomiting within this period.…”

“…Haemoglobin concentration was measured using a portable spectrophotometer HemoCue Hb 201+ (HemoCue AB,Ängelholm, Sweden), with a precision of ± 0.3 g/dL. 25 Thick blood smears and filter papers were processed as previously described. 4,24,25 Parasite clearance half-life was estimated using the parasite clearance estimator developed by World Wide Antimalarial Resistance Network (Oxford, United Kingdom).…”

Optimal timing of primaquine to reduce Plasmodium falciparum gametocyte carriage when co-administered with artemether–lumefantrine

“…This may be explained by acute haemolysis of parasitized blood cells after treatment with ACT [22]. Previous studies in uncomplicated P. falciparum patients have demonstrated similar haemoglobin drops following ACT treatment with or without 0.75 mg/kg or 0.25 mg/kg single dose of primaquine [23][24][25]. Slow haemoglobin recovery in primaquine day 1 arm may be explained by the effect of primaquine administration on the first day of treatment that may worsen the natural drop in haemoglobin which is typically seen shortly after clearance of malaria parasite [11].…”