title: Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999-2009.
abstract: BACKGROUND
  Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene
  
  
  METHODS
  Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis.
  
  
  RESULTS
  Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3.In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) - 6.135, r(2) = 0.94) in ASAQ recipients was 31 hours.
  
  
  CONCLUSIONS
  Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes.
authors.forename: Julien
authors.initials: J
authors.lastname: Zwang
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: Umberto
authors.initials: U
authors.lastname: d'Alessandro
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimde
authors.forename: Philippe
authors.initials: P
authors.lastname: Brasseur
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.affiliation: UNICEF/UNDP/WB/WHO Special Programme for Research & Training in Tropical Diseases (TDR), Geneva, Switzerland. olliarop@who.int.
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
mesh_terms: D017954:Africa South of the Sahara; D000655:Amodiaquine / Q000008:administration & dosage / Q000627:therapeutic use*; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D006801:Humans; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D016017:Odds Ratio; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine