title: Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy.
abstract: Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Stephan
authors.initials: S
authors.lastname: Karl
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Moses
authors.initials: M
authors.lastname: Laman
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: John
authors.initials: J
authors.lastname: Benjamin
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Tamarah
authors.initials: T
authors.lastname: Koleala
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Clemencia
authors.initials: C
authors.lastname: Ibam
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Bernadine
authors.initials: B
authors.lastname: Kasian
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea Department of Microbiology, Division of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andreea
authors.initials: A
authors.lastname: Waltmann
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia Centre de Recerca en Salut Internacional de Barcelona (CRESIB), Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: School of Physics, University of Western Australia, Crawley, Western Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Woodward
authors.affiliation: School of Physics, University of Western Australia, Crawley, Western Australia.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: St Pierre
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia tim.davis@uwa.edu.au.
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use*; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D016780:Malaria, Vivax / Q000188:drug therapy; D008297:Male; D009285:Naphthoquinones / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D009285:Naphthoquinones; C031327:artemisinin; D000077549:Artemether; D000078102:Lumefantrine