Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger

Lise Denoeud-Ndam, Alassane Dicko, Elisabeth Baudin, Ousmane Guindo, Francesco Grandesso, Halimatou Diawara, Sibiri Sissoko, Koualy Sanogo, Seydou Traoré, Sekouba Keita, Amadou Barry, Martin de Smet, Estrella Lasry, Michiel Smit, Lubbe Wiesner, Karen I Barnes, Abdoulaye A Djimde, Philippe J Guerin, Rebecca F Grais, Ogobara K Doumbo, Jean-François Etard, Lise Denoeud-Ndam, Alassane Dicko, Elisabeth Baudin, Ousmane Guindo, Francesco Grandesso, Halimatou Diawara, Sibiri Sissoko, Koualy Sanogo, Seydou Traoré, Sekouba Keita, Amadou Barry, Martin de Smet, Estrella Lasry, Michiel Smit, Lubbe Wiesner, Karen I Barnes, Abdoulaye A Djimde, Philippe J Guerin, Rebecca F Grais, Ogobara K Doumbo, Jean-François Etard

Abstract

Background: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without.

Methods: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF - Plumpy'Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7.

Results: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8-100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4-99.7 %) at day 28 and 98.3 % (95.6-99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04-4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049).

Conclusions: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7.

Trial registration: ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013.

Keywords: Artemether-lumefantrine; Mali; Niger; Pharmacokinetics; Plasmodium falciparum malaria; Severe acute malnutrition; Treatment outcome.

Figures

Fig. 1
Fig. 1
Study profile. SAM, severe acute malnutrition, mITT, modified intent-to-treat, PP, per protocol, PK, pharmacokinetics
Fig. 2
Fig. 2
Kaplan–Meier curves of reinfection-free survival until day 42 in severe acute malnutrition (SAM) and non-SAM children, stratified by age. a Children ≤ 21 months. b Children > 21 months. Results are displayed for the modified intent-to-treat population (N = 397). Age strata are defined by the median value of 21 months. The log-rank tests for equality of survival functions are displayed hereafter: aP = 0.4836 at day 28, P = 0.7845 at day 42. bP = 0.0131 at day 28, P = 0.1684 at day 42
Fig. 3
Fig. 3
Boxplots of lumefantrine concentration by nutritional status. a On different time points. b On day 7 after stratification by age group. Boxplots show median and interquartile range, outside values are not shown. SAM severe acute malnutrition, ns not significant (for comparison between SAM and non-SAM). * P < 0.05; ** P < 0.01

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