Sulfadoxine-Pyrimethamine-Based Combinations for Malaria: A Randomised Blinded Trial to Compare Efficacy, Safety and Selection of Resistance in Malawi

被引:30
作者
Bell, David J. [1 ,5 ]
Nyirongo, Suzgo K. [2 ]
Mukaka, Mavuto [2 ]
Zijlstra, Ed E. [3 ]
Plowe, Christopher V. [4 ]
Molyneux, Malcolm E. [2 ]
Ward, Steve A. [1 ]
Winstanley, Peter A. [5 ]
机构
[1] Univ Liverpool, Liverpool Sch Trop Med, Dept Mol & Biochem Parasitol, Liverpool L3 5QA, Merseyside, England
[2] Malawi Liverpool Wellcome Trust Clin Res Prog, Blantyre, Malawi
[3] Univ Malawi, Coll Med, Dept Med, Blantyre, Malawi
[4] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD USA
[5] Univ Liverpool, Sch Clin Sci, Liverpool, Merseyside, England
来源
PLOS ONE | 2008年 / 3卷 / 02期
基金
英国惠康基金;
关键词
D O I
10.1371/journal.pone.0001578
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ) since sulfadoxine-pyrimethamine (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 # 0.5 x 10(3) 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.
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页数:8
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