title: The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.
abstract: BACKGROUND
  Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.
  
  
  METHODS
  Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.
  
  
  RESULTS
  Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites.
  
  
  CONCLUSIONS
  There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Adjuik
authors.forename: Richard
authors.initials: R
authors.lastname: Allan
authors.forename: Anupkumar R
authors.initials: AR
authors.lastname: Anvikar
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Mamadou S
authors.initials: MS
authors.lastname: Ba
authors.forename: Hubert
authors.initials: H
authors.lastname: Barennes
authors.forename: Karen I
authors.initials: KI
authors.lastname: Barnes
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Baudin
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.forename: François
authors.initials: F
authors.lastname: Bompart
authors.forename: Maryline
authors.initials: M
authors.lastname: Bonnet
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Brasseur
authors.forename: Hasifa
authors.initials: H
authors.lastname: Bukirwa
authors.forename: Francesco
authors.initials: F
authors.lastname: Checchi
authors.forename: Michel
authors.initials: M
authors.lastname: Cot
authors.forename: Prabin
authors.initials: P
authors.lastname: Dahal
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.forename: Meghna
authors.initials: M
authors.lastname: Desai
authors.forename: Graciela
authors.initials: G
authors.lastname: Diap
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Espié
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Etard
authors.forename: Caterina I
authors.initials: CI
authors.lastname: Fanello
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Faucher
authors.forename: Babacar
authors.initials: B
authors.lastname: Faye
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Flegg
authors.forename: Oumar
authors.initials: O
authors.lastname: Gaye
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gething
authors.forename: Raquel
authors.initials: R
authors.lastname: González
authors.forename: Francesco
authors.initials: F
authors.lastname: Grandesso
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Guerin
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
authors.forename: Sally
authors.initials: S
authors.lastname: Hamour
authors.forename: Armedy Ronny
authors.initials: AR
authors.lastname: Hasugian
authors.forename: Simon I
authors.initials: SI
authors.lastname: Hay
authors.forename: Georgina S
authors.initials: GS
authors.lastname: Humphreys
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Juma
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Jean R
authors.initials: JR
authors.lastname: Kiechel
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
authors.forename: Valérie
authors.initials: V
authors.lastname: Lameyre
authors.forename: Laminou M
authors.initials: LM
authors.lastname: Ibrahim
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: Achille
authors.initials: A
authors.lastname: Massougbodji
authors.forename: Hervé
authors.initials: H
authors.lastname: Menan
authors.forename: Didier
authors.initials: D
authors.lastname: Ménard
authors.forename: Clara
authors.initials: C
authors.lastname: Menéndez
authors.forename: Martin
authors.initials: M
authors.lastname: Meremikwu
authors.forename: Clarissa
authors.initials: C
authors.lastname: Moreira
authors.forename: Carolyn
authors.initials: C
authors.lastname: Nabasumba
authors.forename: Michael
authors.initials: M
authors.lastname: Nambozi
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Frederic
authors.initials: F
authors.lastname: Nikiema
authors.forename: Christian
authors.initials: C
authors.lastname: Nsanzabana
authors.forename: Francine
authors.initials: F
authors.lastname: Ntoumi
authors.forename: Bernhards R
authors.initials: BR
authors.lastname: Ogutu
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Lyda
authors.initials: L
authors.lastname: Osorio
authors.forename: Jean-Bosco
authors.initials: JB
authors.lastname: Ouédraogo
authors.forename: Louis K
authors.initials: LK
authors.lastname: Penali
authors.forename: Mbaye
authors.initials: M
authors.lastname: Pene
authors.forename: Loretxu
authors.initials: L
authors.lastname: Pinoges
authors.forename: Patrice
authors.initials: P
authors.lastname: Piola
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Claude Emile
authors.initials: CE
authors.lastname: Rwagacondo
authors.forename: Albert
authors.initials: A
authors.lastname: Same-Ekobo
authors.forename: Birgit
authors.initials: B
authors.lastname: Schramm
authors.forename: Amadou
authors.initials: A
authors.lastname: Seck
authors.forename: Bhawna
authors.initials: B
authors.lastname: Sharma
authors.forename: Carol Hopkins
authors.initials: CH
authors.lastname: Sibley
authors.forename: Véronique
authors.initials: V
authors.lastname: Sinou
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Frank
authors.initials: F
authors.lastname: Smithuis
authors.forename: Fabrice A
authors.initials: FA
authors.lastname: Somé
authors.forename: Doudou
authors.initials: D
authors.lastname: Sow
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Todd D
authors.initials: TD
authors.lastname: Swarthout
authors.forename: Khadime
authors.initials: K
authors.lastname: Sylla
authors.forename: Ambrose O
authors.initials: AO
authors.lastname: Talisuna
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Temu
authors.forename: Julie I
authors.initials: JI
authors.lastname: Thwing
authors.forename: Emiliana
authors.initials: E
authors.lastname: Tjitra
authors.forename: Roger C K
authors.initials: RC
authors.lastname: Tine
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.forename: Michel T
authors.initials: MT
authors.lastname: Vaillant
authors.forename: Neena
authors.initials: N
authors.lastname: Valecha
authors.forename: Ingrid
authors.initials: I
authors.lastname: Van den Broek
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Adoke
authors.initials: A
authors.lastname: Yeka
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
mesh_terms: D000349:Africa; D000655:Amodiaquine / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine