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Sulfadoxine-pyrimethamine–based combinations for malaria : a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi

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Bell, David J., Nyirongo, Suzgo K., Mukaka, Mavuto, Zijlstra, Ed E., Plowe, Christopher V., Molyneux, Malcolm E., Ward, Steve A. and Winstanley, Peter. (2008) Sulfadoxine-pyrimethamine–based combinations for malaria : a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi. PLoS ONE, Vol.3 (No.2). e1578. ISSN 1932-6203

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Abstract

Background: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ) since sulfadoxinepyrimethamine
(SP) replaced CQ as first line treatment for uncomplicated malaria. When used for prophylaxis, Amodiaquine
(AQ) was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa. Here
we compare the efficacy, safety and selection of resistance using SP or CQ+SP or artesunate (ART)+SP or AQ+SP for the
treatment of uncomplicated falciparum malaria.
Methodology and Findings: 455 children aged 1–5 years were recruited into a double-blinded randomised trial comparing
SP to the three combination therapies. Using intention to treat analysis with missing outcomes treated as successes, and
without adjustment to distinguish recrudescence from new infections, the day 28 adequate clinical and parasitological
response (ACPR) rate for SP was 25%, inferior to each of the three combination therapies (p,0.001). AQ+SP had an ACPR
rate of 97%, higher than CQ+SP (81%) and ART+SP (70%), p,0.001. Nineteen children developed a neutropenia of
#0.56103 cells/ml by day 14, more commonly after AQ+SP (p = 0.03). The mutation pfcrt 76T, associated with CQ resistance,
was detected in none of the pre-treatment or post-treatment parasites. The prevalence of the pfmdr1 86Y mutation was
higher after treatment with AQ+SP than after SP, p = 0.002.
Conclusions: The combination AQ+SP was highly efficacious, despite the low efficacy of SP alone; however, we found
evidence that AQ may exert selective pressure for resistance associated mutations many weeks after treatment. This study
confirms the return of CQ sensitivity in Malawi and importantly, shows no evidence of the re-emergence of pfcrt 76T after
treatment with CQ or AQ. Given the safety record of AQ when used as a prophylaxis, our observations of marked falls in
neutrophil counts in the AQ+SP group requires further scrutiny.

Item Type: Journal Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Plasmodium falciparum -- Treatment -- Malawi, Antimalarials
Journal or Publication Title: PLoS ONE
Publisher: Public Library of Science
ISSN: 1932-6203
Official Date: 13 February 2008
Volume: Vol.3
Number: No.2
Page Range: e1578
Identification Number: 10.1371/journal.pone.0001578
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: Wellcome Trust (London, England)
Grant number: 066681 (WT)
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URI: http://wrap.warwick.ac.uk/id/eprint/36678

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