title: Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.
abstract: BACKGROUND
  Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy.
  
  
  METHODS
  An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints.
  
  
  RESULTS
  A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery.
  
  
  CONCLUSIONS
  AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Thailand. jul@shoklo-unit.com
authors.forename: Julien
authors.initials: J
authors.lastname: Zwang
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Hubert
authors.initials: H
authors.lastname: Barennes
authors.forename: Maryline
authors.initials: M
authors.lastname: Bonnet
authors.forename: Philippe
authors.initials: P
authors.lastname: Brasseur
authors.forename: Hasifa
authors.initials: H
authors.lastname: Bukirwa
authors.forename: Sandra
authors.initials: S
authors.lastname: Cohuet
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
authors.forename: Abdulaye
authors.initials: A
authors.lastname: Djimdé
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
authors.forename: Sally
authors.initials: S
authors.lastname: Hamour
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: Claude
authors.initials: C
authors.lastname: Rwagacondo
authors.forename: Issaka
authors.initials: I
authors.lastname: Sagara
authors.forename: Albert
authors.initials: A
authors.lastname: Same-Ekobo
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.forename: Ingrid
authors.initials: I
authors.lastname: van den Broek
authors.forename: Adoke
authors.initials: A
authors.lastname: Yeka
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Milijaona
authors.initials: M
authors.lastname: Randrianarivelojosia
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D000368:Aged; D000369:Aged, 80 and over; D000655:Amodiaquine / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000302:isolation & purification; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine
references.citation: Trop Med Int Health. 2004 Apr;9(4):438-44
references.pmid: 15078261
references.citation: Malar J. 2007 May 22;6:67
references.pmid: 17519019
references.citation: PLoS Med. 2005 Jul;2(7):e190
references.pmid: 16033307
references.citation: Malar J. 2006 May 16;5:43
references.pmid: 16704735
references.citation: Am J Trop Med Hyg. 2008 Mar;78(3):455-61
references.pmid: 18337343
references.citation: Malar J. 2007 Nov 15;6:150
references.pmid: 18005408
references.citation: Trans R Soc Trop Med Hyg. 2006 Dec;100(12):1105-11
references.pmid: 16766006
references.citation: Trop Med Int Health. 2004 Jun;9(6):673-9
references.pmid: 15189457
references.citation: Malar J. 2007 Sep 06;6:118
references.pmid: 17822531
references.citation: Lancet. 2002 Apr 20;359(9315):1365-72
references.pmid: 11978332
references.citation: Malar J. 2006 Nov 24;5:113
references.pmid: 17125496
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120
references.citation: Lancet. 2004 Nov 27-Dec 3;364(9449):1950-7
references.pmid: 15567011
references.citation: Am J Trop Med Hyg. 2006 Jul;75(1):143-5
references.pmid: 16837721
references.citation: Trans R Soc Trop Med Hyg. 2005 Jul;99(7):485-92
references.pmid: 15876443
references.citation: Malar J. 2009 Jun 08;8:125
references.pmid: 19505304
references.citation: Trop Med Int Health. 2006 Oct;11(10):1503-11
references.pmid: 17002724
references.citation: Am J Trop Med Hyg. 2006 Nov;75(5):836-42
references.pmid: 17123974
references.citation: Trop Med Int Health. 2006 Jul;11(7):1017-21
references.pmid: 16827702
references.citation: Am J Trop Med Hyg. 1999 Jan;60(1):14-21
references.pmid: 9988316
references.citation: Malar J. 2007 Sep 06;6:119
references.pmid: 17822532
references.citation: Malar J. 2005 Feb 24;4:14
references.pmid: 15730557
references.citation: BMJ. 2001 Jul 7;323(7303):42-6
references.pmid: 11440947
references.citation: Malar J. 2008 Aug 09;7:154
references.pmid: 18691429
references.citation: Am J Trop Med Hyg. 2004 Nov;71(5):531-6
references.pmid: 15569778
references.citation: Gan To Kagaku Ryoho. 2004 Aug;31(8):1187-92
references.pmid: 15332541
references.citation: Malar J. 2007 May 03;6:54
references.pmid: 17477865
references.citation: Cochrane Database Syst Rev. 2009 Jul 08;(3):CD007483
references.pmid: 19588433
references.citation: Trop Med Int Health. 1998 Jun;3(6):490-7
references.pmid: 9657512
references.citation: Malar J. 2009 Mar 16;8:48
references.pmid: 19291301
references.citation: Trop Med Int Health. 2005 Sep;10(9):926-33
references.pmid: 16135201
references.citation: BMJ. 2008 May 24;336(7654):1166-9
references.pmid: 18497415
references.citation: Clin Infect Dis. 2007 Apr 15;44(8):1067-74
references.pmid: 17366451
references.citation: Trop Med Int Health. 2004 Feb;9(2):200-8
references.pmid: 15040556
references.citation: Clin Infect Dis. 2005 Oct 15;41(8):1079-86
references.pmid: 16163624
references.citation: Malar J. 2007 Feb 28;6:25
references.pmid: 17328806
references.citation: Methods Mol Med. 2002;72:189-203
references.pmid: 12125116
references.citation: Bull World Health Organ. 2006 Dec;84(12):956-64
references.pmid: 17242831
references.citation: Malar J. 2008 Jan 19;7:16
references.pmid: 18205945
references.citation: Trop Med Int Health. 2004 Oct;9(10):1091-8
references.pmid: 15482401
references.citation: Trop Med Int Health. 2005 Jun;10(6):521-9
references.pmid: 15941414
references.citation: JAMA. 2007 May 23;297(20):2210-9
references.pmid: 17519410
references.citation: PLoS Clin Trials. 2006 May;1(1):e7
references.pmid: 16871329
references.citation: Lancet. 1996 Jun 15;347(9016):1654-8
references.pmid: 8642959
references.citation: Trans R Soc Trop Med Hyg. 2005 Jul;99(7):548-54
references.pmid: 15869770
references.citation: Ann Trop Med Parasitol. 2007 Mar;101(2):95-102
references.pmid: 17316495