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

Bell, David J.; Nyirongo, Suzgo K.; Mukaka, Mavuto; Zijlstra, Ed E.; Plowe, Christopher V.; Molyneux, Malcolm E.; Ward, Steve A. and Winstanley, Peter A. (2008) Sulfadoxine-pyrimethamine–based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in malawi. PLoS ONE, 3 (2). Article Number: 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:Article
Additional Information:Published February 13, 2008. 8 pages. Citation: Bell DJ, Nyirongo SK, Mukaka M, Zijlstra EE, Plowe CV, et al. (2008) Sulfadoxine-Pyrimethamine–Based Combinations for Malaria: A Randomised Blinded Trial to Compare Efficacy, Safety and Selection of Resistance in Malawi. PLoS ONE 3(2): e1578. doi:10.1371/journal.pone.0001578
Uncontrolled Keywords:Plasmodium falciparum; chloroquine; prophylaxis; Amodiaquine; agranulocytosis; falciparum malaria; SP; CQ+SP; artesunate; (ART)+SP; AQ+SP; prophylaxis; neutrophil
Subjects:R Medicine > R Medicine (General)
Departments, Research Centres and Related Units:Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Clinical Sciences
Academic Faculties, Institutes and Research Centres > Liverpool School of Tropical Medicine
DOI:10.1371/journal.pone.0001578
Publisher's Statement:Copyright: © 2008 Bell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related URLs:
Refereed:Yes
Status:Published
ID Code:845
Deposited On:25 Jul 2008 11:30
Last Modified:09 Mar 2012 14:14

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