Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial.
BACKGROUND
Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment.


METHODS
We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared.


RESULTS
The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment.


CONCLUSIONS
The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.
von Seidlein
L
L
Farafenni Field Station, Medical Research Council Laboratories, The Gambia. lseidlein@mrc.gm
Milligan
P
P
Pinder
M
M
Bojang
K
K
Anyalebechi
C
C
Gosling
R
R
Coleman
R
R
Ude
J I
JI
Sadiq
A
A
Duraisingh
M
M
Warhurst
D
D
Alloueche
A
A
Targett
G
G
McAdam
K
K
Greenwood
B
B
Walraven
G
G
Olliaro
P
P
Doherty
T
T
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D037621:Artemisinins; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005714:Gambia; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000302:isolation & purification; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000009:adverse effects; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000009:adverse effects; D013413:Sulfadoxine / Q000008:administration & dosage* / Q000009:adverse effects
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D011739:Pyrimethamine