Artesunate plus amodiaquine and artesunate plus sulphadoxine-pyrimethamine for treatment of uncomplicated malaria in Democratic Republic of Congo: a clinical trial with determination of sulphadoxine and pyrimethamine-resistant haplotypes


Swarthout, TD; van Den Broek, IV; Kayembe, G; Montgomery, J; Pota, H; Roper, C; (2006) Artesunate plus amodiaquine and artesunate plus sulphadoxine-pyrimethamine for treatment of uncomplicated malaria in Democratic Republic of Congo: a clinical trial with determination of sulphadoxine and pyrimethamine-resistant haplotypes. Tropical medicine & international health , 11 (10). pp. 1503-1511. ISSN 1360-2276 DOI: 10.1111/j.1365-3156.2006.01710.x

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Abstract

We undertook a trial of artesunate + amodiaquine (AS + AQ) and artesunate + sulphadoxine-pyrimethamine (AS + SP) in 180 children of age 6-59 months with uncomplicated malaria in Democratic Republic of Congo. Children were randomly allocated to receive 3 days observed treatment of AS + AQ (n = 90) or 3 days of AS + SP (n = 90). Primary efficacy outcomes were 28-day parasite recurrence rates, and recrudescence rates were adjusted by genotyping to distinguish new infection and recrudescence. In addition, we determined the prevalence of molecular markers of resistance to sulphadoxine and pyrimethamine. Day 28 parasite recurrence rates were 16.9% (14/83; 95% CI: 9.5-26.7) in the AS + AQ group and 34.6% (28/81; 95% CI: 24.3-46.0) in the AS + SP group (P = 0.009). After PCR correction, recrudescence rates were 6.7% (5/74; 95% CI: 2.2-15.1) for AS + AQ and 19.7% (13/66; 95% CI: 10.9-31.3) for AS + SP (P = 0.02). There was no significant difference between the two arms in time to parasite clearance, fever clearance and gametocyte clearance. Parasite genotyping showed high frequencies of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) molecular SP-resistance markers, with 57% of the samples showing more than three mutations linked to SP resistance, and 27% with triple-dhfr/double-dhps haplotype, confirming that SP treatment failure rates are likely to be high. AS + AQ had significantly higher efficacy than AS + SP. These results contributed to the subsequent change to AS + AQ as first-line regimen in the country. Efforts to properly implement the new protocol and maintain adherence at acceptable levels should include health staff and patient sensitization. The 6.8% recrudescence rate indicates that AS + AQ should be monitored closely until a more effective artemisinin combination therapy regimen is needed and can be introduced.

Item Type: Article
Keywords: malaria, efficacy, sulphadoxine-pyrimethamine, amodiaquine, artesunate, resistance haplotype, Democratic Republic of Congo, PLASMODIUM-FALCIPARUM MALARIA, ARTEMETHER-LUMEFANTRINE, MOLECULAR, MARKERS, DIHYDROPTEROATE SYNTHASE, DIHYDROFOLATE-REDUCTASE, COMBINATION, THERAPY, AFRICAN CHILDREN, RANDOMIZED-TRIAL, SIERRA-LEONE, EFFICACY, Amodiaquine, therapeutic use, Animals, Antimalarials, therapeutic use, Artemisinins, therapeutic use, Child, Preschool, DNA, Protozoan, genetics, Democratic Republic of the Congo, epidemiology, Drug Combinations, Drug Resistance, genetics, Drug Therapy, Combination, Female, Haplotypes, Humans, Infant, Malaria, drug therapy, epidemiology, Malaria, Falciparum, drug therapy, epidemiology, Male, Plasmodium, genetics, Polymerase Chain Reaction, methods, Pyrimethamine, therapeutic use, Sesquiterpenes, therapeutic use, Sulfadoxine, therapeutic use, Treatment Outcome
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Antimicrobial Resistance Centre (AMR)
Malaria Centre
PubMed ID: 17002724
Web of Science ID: 240681100004
URI: http://researchonline.lshtm.ac.uk/id/eprint/10542

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