title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013.
authors: Epicentre, Paris, France. lise.denoeud@epicentre.msf.org.
authors: Lise
authors: L
authors: Denoeud-Ndam
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Alassane
authors: A
authors: Dicko
authors: Epicentre, Paris, France.
authors: Elisabeth
authors: E
authors: Baudin
authors: Epicentre, Maradi, Niger.
authors: Ousmane
authors: O
authors: Guindo
authors: Epicentre, Paris, France.
authors: Francesco
authors: F
authors: Grandesso
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Halimatou
authors: H
authors: Diawara
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Sibiri
authors: S
authors: Sissoko
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Koualy
authors: K
authors: Sanogo
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Seydou
authors: S
authors: Traoré
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Sekouba
authors: S
authors: Keita
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Amadou
authors: A
authors: Barry
authors: Medecins Sans Frontieres, Brussels, Belgium.
authors: Martin
authors: M
authors: de Smet
authors: Medecins Sans Frontieres, New York, NY, USA.
authors: Estrella
authors: E
authors: Lasry
authors: Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa.
authors: Michiel
authors: M
authors: Smit
authors: Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa.
authors: Lubbe
authors: L
authors: Wiesner
authors: Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa.|WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.
authors: Karen I
authors: KI
authors: Barnes
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Abdoulaye A
authors: AA
authors: Djimde
authors: WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors: Philippe J
authors: PJ
authors: Guerin
authors: Epicentre, Paris, France.
authors: Rebecca F
authors: RF
authors: Grais
authors: Malaria Research and Training Center, Faculté de Médecine et d'Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali.
authors: Ogobara K
authors: OK
authors: Doumbo
authors: Epicentre, Paris, France.|TransVIHMI UMI 233, Institut de Recherche pour le Développement (IRD) - Inserm U 1175 - Montpellier 1 University, Montpellier, France.
authors: Jean-François
authors: JF
authors: Etard
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002675:Child, Preschool; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008302:Mali; D009548:Niger; D000067011:Severe Acute Malnutrition / Q000378:metabolism* / Q000469:parasitology
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes
keywords: Artemether-lumefantrine; Mali; Niger; Pharmacokinetics; Plasmodium falciparum malaria; Severe acute malnutrition; Treatment outcome