title: Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa.
abstract: BACKGROUND
  Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology vs other anti-malarials is needed in view of potential safety liabilities.
  
  
  METHODS
  Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.
  
  
  RESULTS
  4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, p = 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.
  
  
  CONCLUSIONS
  The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.
authors.affiliation: Drugs for Neglected Diseases Initiative (DNDi), Geneva, Switzerland. zwang@free.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Zwang
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ndiaye
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimdé
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D000368:Aged; D000655:Amodiaquine / Q000008:administration & dosage* / Q000009:adverse effects*; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects*; D000077332:Artesunate; D001773:Blood Cells / Q000187:drug effects; D001774:Blood Chemical Analysis; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine; D000077332:Artesunate