title: Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria.
abstract: Early rising asexual parasitaemia (ERAP), initially defined as 'an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment' of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs).
  
  
  
  ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1-2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping.
  
  
  
  ERAP occurred in 205 of 416 children. A parasitaemia <100,000/μL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81-130.1) and 2.5 h (95% CI 2.2-2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2-0.3), 1 h (95% CI 0.9-1.1), and 0.9 h-1(95% CI 0.8-1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential.
  
  
  
  ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria.
  
  
  
  Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria. akinsowunmi@hotmail.com.|Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria. akinsowunmi@hotmail.com.|Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. akinsowunmi@hotmail.com.
authors.forename: Akintunde
authors.initials: A
authors.lastname: Sowunmi
authors.affiliation: Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria.
authors.forename: Kazeem
authors.initials: K
authors.lastname: Akano
authors.affiliation: Department of Paediatrics, University of Ibadan, Ibadan, Nigeria.
authors.forename: Adejumoke I
authors.initials: AI
authors.lastname: Ayede
authors.affiliation: Department of Physiology, University of Ibadan, Ibadan, Nigeria.
authors.forename: Elsie O
authors.initials: EO
authors.lastname: Adewoye
authors.affiliation: National Malaria Elimination Programme, Federal Ministry of Health, Abuja, Nigeria.
authors.forename: Godwin
authors.initials: G
authors.lastname: Ntadom
authors.affiliation: World Health Organization, Regional Office for the Western Pacific, Phnom Penh, Cambodia.
authors.forename: Bayo
authors.initials: B
authors.lastname: Fatunmbi
authors.affiliation: Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria.|Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria.
authors.forename: Grace O
authors.initials: GO
authors.lastname: Gbotosho
authors.affiliation: Department of Biological Sciences, Redeemer's University, Ede, Nigeria.|African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer's University, Ede, Nigeria.
authors.forename: Onikepe A
authors.initials: OA
authors.lastname: Folarin
authors.affiliation: Department of Biological Sciences, Redeemer's University, Ede, Nigeria.|African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer's University, Ede, Nigeria.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Happi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000655:Amodiaquine / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002662:Child Health Services; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology* / Q000469:parasitology; D008297:Male; D009549:Nigeria / Q000453:epidemiology; D018512:Parasitemia / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology; D012307:Risk Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine
keywords: Artemisinin-based combination treatments; Children; Early rising asexual parasitaemia; Nigeria