title: Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.
abstract: BACKGROUND
  Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy.
  
  
  METHODS
  Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only.
  
  
  RESULTS
  Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used.
  
  
  CONCLUSIONS
  The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.
authors.affiliation: Epicentre, Paris, France. elizabeth.ashley@epicentre.msf.org
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Loretxu
authors.initials: L
authors.lastname: Pinoges
authors.forename: Eleanor
authors.initials: E
authors.lastname: Turyakira
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Francesco
authors.initials: F
authors.lastname: Checchi
authors.forename: Hasifa
authors.initials: H
authors.lastname: Bukirwa
authors.forename: Ingrid
authors.initials: I
authors.lastname: van den Broek
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.forename: Pedro Pablo Palma
authors.initials: PP
authors.lastname: Urruta
authors.forename: Michel
authors.initials: M
authors.lastname: van Herp
authors.forename: Suna
authors.initials: S
authors.lastname: Balkan
authors.forename: Walter R
authors.initials: WR
authors.lastname: Taylor
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
mesh_terms: D000349:Africa; D000655:Amodiaquine / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D002675:Child, Preschool; D019992:Databases as Topic / Q000706:statistics & numerical data; D004338:Drug Combinations; D004983:Ethanolamines / Q000627:therapeutic use; D005449:Fluorenes / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007223:Infant; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; C031327:artemisinin; D000077549:Artemether; D000078102:Lumefantrine; D011739:Pyrimethamine