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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, Stephen 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, Vol 3, Issue 2, e1578.

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Abstract

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 ≤0.5×103 cells/µl 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
Subjects: ?? R1 ??
QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 38 Drug action.
QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs
QX Parasitology > Protozoa > QX 135 Plasmodia
WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WB Practice of Medicine > Therapeutics > WB 330 Drug therapy
WB Practice of Medicine > Medical Climatology > WB 710 Diseases of geographic areas
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
WS Pediatrics > WS 20 Research (General)
WS Pediatrics > By Age Groups > WS 430 Infancy
WS Pediatrics > By Age Groups > WS 440 Preschool child
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.pone.0001578
Depositing User: Mary Creegan
Date Deposited: 25 Jul 2008 10:30
Last Modified: 06 Feb 2018 13:00
URI: http://archive.lstmed.ac.uk/id/eprint/985

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