Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal

Daria Van Tyne,Souleymane Mboup,Dyann F Wirth,Omar Ndir,Baba Dieye,Elizabeth J Hamilton,Amanda K Lukens,Mouhamadou Ndiaye,Daouda Ndiaye,Rachel F Daniels,Sarah K Volkman,Amy K Bei,Yaye Die Ndiaye,Papa Diogoye Sène,Clarissa Valim

doi:10.1186/1475-2875-12-441

Abstract

BackgroundMalaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance.MethodsParasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay. Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1.ResultsParasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin.ConclusionsDirectly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples. Furthermore, these data suggest that the use of amodiaquine and artemisinin derivatives in combination therapies is selecting for increased drug tolerance within this population.

Highlights

Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites
Among the 831 patients with uncomplicated malaria screened at the Section de Lutte Antiparasitaire (SLAP) clinic between 2008 and 2011, a subset of 397 patient samples were tested for parasite drug response using the DAPI ex vivo assay (Table 1)
DAPI ex vivo assay validation The usefulness of the DAPI-based ex vivo assay for monitoring drug sensitivity among the parasites circulating in Thiès, Senegal was assessed by measuring the dynamic range and reliability of the assay

Summary

Introduction

Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance. Malaria drug resistance monitoring involves directly measuring parasite drug responses, or indirectly measuring the prevalence of resistance-associated mutations within a parasite population. Ex vivo drug resistance assays measure drug response in parasites taken directly from infected patients, without prior culture adaptation. These assays allow the components of combination therapies to be tested individually against parasites, and they can detect decreases in drug efficacy before resistance becomes clinically evident and widespread [5]. Monitoring the prevalence of these mutations consistently over several years can reveal trends in allele selection within a population over time, and can extend the therapeutic life of current and future treatments [15,16]

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