title: Early parasitological response following artemisinin-containing regimens: a critical review of the literature.
abstract: BACKGROUND
  Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.
  
  
  METHODS
  The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.
  
  
  RESULTS
  In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3-95, IQR=30.5-69.2] on Day 1, 6% [range 0-65.9, IQR=2-11.5] on Day 2 and 0 [range 0-12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.
  
  
  CONCLUSIONS
  These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.
authors.affiliation: WorldWide Antimalarial Resistance Network, Oxford, UK.
authors.forename: Debashish
authors.initials: D
authors.lastname: Das
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.forename: Delia
authors.initials: D
authors.lastname: Bethell
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Guerin
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D059208:Parasite Load; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin