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Randomised Trial of Chloroquine / Sulphadoxine-pyrimethamine for Uncomplicated Malaria in Gambian Children: Impact of Multi-Drug Resistant Plasmodium falciparum on Treatment Efficacy

Authors :
Ali Alloueche
Samuel Dunyo
Musa Jawara
Rosalynn Ord
Anna Randall
Gijs Walraven
Colin J. Sutherland
Margaret Pinder
Rachel Hallett
Neal Alexander
Geoffrey A. T. Targett
Source :
PLoS Clinical Trials
Publication Year :
2006

Abstract

Objectives: In the Gambia, chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) is the first-line antimalarial treatment. Plasmodium falciparum parasites carrying mutations associated with resistance to each of these drugs were present in 2001 but did not cause a significant loss of therapeutic efficacy among children receiving the combination CQ/SP. We measured their effect on parasite transmission to Anopheles gambiae mosquitoes. Design: We conducted a single-blind, randomised, controlled trial with follow-up over 28 d. Mosquito feeding experiments were carried out 7, 10, or 14 d after treatment. Setting: The study took place in the town of Farafenni and surrounding villages in the Gambia. Participants: Participants were 500 children aged 6 mo to 10 y with uncomplicated P. falciparum malaria. Interventions: Children were randomised to receive CQ, SP, or CQ/SP. Outcome Measures: Outcomes related to transmission were determined, including posttreatment gametocyte prevalence and density. Infectiousness was assessed by membrane-feeding A. gambiae mosquitoes with blood from 70 gametocyte-positive patients. Mutations at seven loci in four genes associated with drug resistance were measured pre- and posttreatment and in the midguts of infected mosquitoes. Results: After SP treatment, the infectiousness of gametocytes was delayed, compared to the other two treatment groups, despite comparable gametocyte densities. Among bloodmeal gametocytes and the midguts of infected mosquitoes, the presence of the four-locus multidrug-resistant haplotype TYRG (consisting of mutations pfcrt-76T, pfmdr1-86Y, pfdhfr-59R, and pfdhps-437G) was associated with significantly higher oocyst burdens after treatment with the combination CQ/SP. Conclusions: Parasites with a multidrug-resistant genotype had a substantial transmission advantage after CQ/SP treatment but did not have a significant impact on in vivo efficacy of this drug combination. Protocols that include measuring transmission endpoints as well as therapeutic outcomes may be a useful strategy when monitoring the evolution of drug resistance in malaria parasites in vivo.<br />Editorial Commentary Background: In an accompanying paper published in PLoS Clinical Trials [15], the investigators report the effects of treating uncomplicated malaria in young children in the Gambia with the combination of chloroquine and sulfadoxine-pyrimethamine, as compared to either treatment individually. As an addition to the main trial results, the researchers also wanted to find out how the different treatment regimens affected the ability of the malaria parasite to generate sexual forms (gametocytes) in the participants' blood, and to what extent the parasites are then transmitted to mosquitoes. The researchers also tested whether malaria parasites had a specific genotype, termed TYRG, comprising mutations in four distinct genes associated with resistance to chloroquine and sulfadoxine-pyrimethamine, and whether that affected transmission of the parasites back to mosquitoes. What the trial shows: In this trial it was found that children treated with chloroquine and sulfadoxine-pyrimethamine were no more or less likely to carry sexual forms of the malaria parasite compared to children treated with chloroquine, over 28 days of follow-up. Transmission of the malaria parasites back to mosquitoes also did not differ significantly between children treated with chloroquine and sulfadoxine-pyrimethamine versus chloroquine alone. Parasites bearing the TYRG genotype, associated with drug resistance, were more likely to be transmitted to mosquitoes from children treated with chloroquine/sulfadoxine-pyrimethamine than from chloroquine treated children. Strengths and limitations: The addition of data about parasite transmission within the setting of a randomized trial is valuable and can provide information about the evolution of drug resistance. However, the results may not completely represent the current situation, as the trial was originally conducted in 2001 and levels of resistance may now be higher in the Gambia. Contribution to the evidence: This follow-up study to a randomized trial provides additional evidence that treatment with chloroquine and sulfadoxine-pyrimethamine, as compared to chloroquine, does not reduce the extent to which malaria parasites can produce sexual forms and transmit them back to mosquitoes. The finding that parasites bearing the TYRG genotype are more likely than other parasites to be transmitted back to mosquitoes following chloroquine and sulfadoxine-pyrimethamine treatment is also novel.

Details

Language :
English
ISSN :
15555887
Database :
OpenAIRE
Journal :
PLoS Clinical Trials
Accession number :
edsair.doi.dedup.....3023b4ad3f486df5405d7c102dc96ccd