A trial of combination antimalarial therapies in children from Papua New Guinea.
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.)
Karunajeewa
Harin A
HA
School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia.
Mueller
Ivo
I
Senn
Michele
M
Lin
Enmoore
E
Law
Irwin
I
Gomorrai
P Servina
PS
Oa
Olive
O
Griffin
Suzanne
S
Kotab
Kaye
K
Suano
Penias
P
Tarongka
Nandao
N
Ura
Alice
A
Lautu
Dulcie
D
Page-Sharp
Madhu
M
Wong
Rina
R
Salman
Sam
S
Siba
Peter
P
Ilett
Kenneth F
KF
Davis
Timothy M E
TM
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
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