title: A trial of combination antimalarial therapies in children from Papua New Guinea.
abstract: BACKGROUND
  Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species, such as in Papua New Guinea.
  
  
  METHODS
  Between April 2005 and July 2007, we conducted an open-label, randomized, parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria. The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum, after correction for reinfections identified through polymerase-chain-reaction (PCR) genotyping of polymorphic loci in parasite DNA. Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping.
  
  
  RESULTS
  Of 2802 febrile children screened, 482 with falciparum malaria and 195 with vivax malaria were included. The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group (95.2%), as compared with 81.5% in the chloroquine-sulfadoxine-pyrimethamine group (P=0.003), 85.4% in the artesunate-sulfadoxine-pyrimethamine group (P=0.02), and 88.0% in the dihydroartemisinin-piperaquine group (P=0.06). The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group (69.4%) was more than twice that in each of the other three treatment groups. The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50% correlated significantly (P<0.001). Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine (P=0.004 for both comparisons).
  
  
  CONCLUSIONS
  The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax. The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine. (Australian New Zealand Clinical Trials Registry number, ACTRN12605000550606.)
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia.
authors.forename: Harin A
authors.initials: HA
authors.lastname: Karunajeewa
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Michele
authors.initials: M
authors.lastname: Senn
authors.forename: Enmoore
authors.initials: E
authors.lastname: Lin
authors.forename: Irwin
authors.initials: I
authors.lastname: Law
authors.forename: P Servina
authors.initials: PS
authors.lastname: Gomorrai
authors.forename: Olive
authors.initials: O
authors.lastname: Oa
authors.forename: Suzanne
authors.initials: S
authors.lastname: Griffin
authors.forename: Kaye
authors.initials: K
authors.lastname: Kotab
authors.forename: Penias
authors.initials: P
authors.lastname: Suano
authors.forename: Nandao
authors.initials: N
authors.lastname: Tarongka
authors.forename: Alice
authors.initials: A
authors.lastname: Ura
authors.forename: Dulcie
authors.initials: D
authors.lastname: Lautu
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Rina
authors.initials: R
authors.lastname: Wong
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use; D000077332:Artesunate; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D016780:Malaria, Vivax / Q000188:drug therapy*; D008297:Male; D016016:Proportional Hazards Models; D011739:Pyrimethamine / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D012008:Recurrence; D013413:Sulfadoxine / Q000627:therapeutic use; D010879:Piperazines
chemical_list: D000962:Antimalarials; D000077549:Artemether; D037621:Artemisinins; D000077332:Artesunate; D002738:Chloroquine; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; C039060:artenimol; C034759:piperaquine; D010879:Piperazines