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Abstract

The recommendation of artemisinin-based combination therapy (ACT) as a first line treatment of malaria continues to be based only on data obtained from single episode treatment rather than repetitive treatment. However, malaria episodes are frequent and there is thus a need to understand the long-term impact of repeated use of ACT to treat consecutive episodes of malaria over successive seasons. My study aimed to define the risk of parasite recurrence as a function of the pharmacokinetic and pharmacodynamic characteristics of ACT partner drugs in patients re-treated for multiple malaria episodes. Participants from Mali were randomized into three treatment arms: dihydroartemisinin-piperaquine (DHA-PPQ), pyronaridine-artesunate (PA), and first-line ACT (either artemether-lumefantrine [AL] or artesunate-amodiaquine [ASAQ]). Participants received the same ACT for each new episode of malaria for two years. Clinical and parasitological data were collected at each visit. Plasma samples were collected at day 7 of follow-up for quantification of drugs using high-performance liquid chromatography methods. In total, study participants experienced 5,260 episodes of malaria during the two-year follow-up period. Major findings were: i) accumulation of desethylamodiaquine (DEAQ), the main and active metabolite of amodiaquine (AQ), in the study population after early (between 25 to 45 days) retreatment with ASAQ; ii) no association of DEAQ concentration on day 7 with treatment outcome; iii) an association between day 7 lumefantrine concentrations and a reduced risk of re-infections within day 28 follow-up (hazard ratio, HR = 0.605, CI (0.50 – 0.74), p < 0.001). This protection of lumefantrine was concentration dependent; a concentration below a threshold of 380 ng/ml did not protect against subsequent re-infection by day 28. Importantly, the majority of the children under five years (84 out of 140; 60%) had lumefantrine day 7 concentrations (median (interquartile range): 305 ng/ml (207 – 490 ng/ml)) below this threshold. In conclusion, my results demonstrated an accumulation of DEAQ in the study population after early re-treatment with ASAQ, and suggest a need of lumefantrine dose optimisation in under five years age group. My analyses also showcase the value of re-treatment studies for improving treatment recommendations.