Randomized Trial of Safety and Effectiveness of Chlorproguanil-Dapsone and Lumefantrine-Artemether for Uncomplicated Malaria in Children in The Gambia

Abstract

BackgroundChlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.Methods1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3.FindingsOne third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%–16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%–3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrolment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3.InterpretationAL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon.Trial RegistrationClinicaltrials.gov NCT00118794

Intervention to Promote Patients' Adherence to Antimalarial Medication: A Systematic Review

“…Out of the 1,813 potential articles, 16 fulfilled the inclusion criteria ( Figure 1) [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and comprised a total of 9,247 patients. Of these, two studies included two different interventions.…”

“…18,22 Studies were published from 1998 to 2011. Ten studies (62.5%) were undertaken in Africa [20][21][22][23][24][25][26]29,31,32 and the remainder were set in Asia. [17][18][19]27,28,30 All the studies were based in the public healthcare sectors (12 in a hospital 17,19 -22,24 -31 and 4 in a community setting) 18,23,25,32 but one study also included a group from the private sector.…”

“…20,22,23,25,26,29,31,32 The other studies enrolled adults or patients at all ages. [17][18][19]21,24,27,28,30 In 14 studies (87.5%), the patients were infected with falciparum malaria [18][19][20][21][22][23][24][25][26][27][28][29]31,32 and the remaining studies used patients with vivax malaria. 17,30 Six studies (37.5%) used chloroquine, [20][21][22][23][24][25] five studies (31.2%) used artemisinin-based combination therapy (ACT).…”

Reassessing an old claim: Natural selection of hemizygotes and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

“…A mutation in The Gambia had already been reported at surprisingly low frequency level (less than 2%) in 2004 [7]. The real frequency of this mutation in Gambian males was subsequently confirmed to be 2-3% [5,8], not 5.9% as reported by Ruwende et al The reason why they found such an inflated frequency is unknown. 3.…”

Can Rapid Diagnostic Testing for Malaria Increase Adherence to Artemether–Lumefantrine?: A Randomized Controlled Trial in Uganda

“…For example, patients may not understand how to correctly take the medication, 45,56-60 they may forget to take their pills, 18,56,58,59 they may be saving some pills for a future malaria episode, 45,56 or they may stop taking the medication once they feel better. 61,62 In our study, we found no relationship between literacy or education and adherence, and we also found that 91% of patients took the first two doses of AL with the correct number of pills at approximately the correct time (data not shown).…”