Efficacy of artemisinin-based combination therapies and prevalence of molecular markers associated with artemisinin, piperaquine and sulfadoxine-pyrimethamine resistance in Sierra Leone

Samuel J Smith,Anitta R.Y Kamara,Foday Sahr,Mohamed Samai,Alpha S Swaray,Didier Menard,Marian Warsame

doi:10.1016/j.actatropica.2018.06.016

Samuel J Smith, Anitta R.Y Kamara + Show 5 more

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https://doi.org/10.1016/j.actatropica.2018.06.016

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Abstract

Currently, the national malaria control programme (NMCP) of Sierra Leone recommends artesunate–amodiaquine (ASAQ) and artemether–lumefantrine (AL) as first- and second-line treatment for uncomplicated malaria, respectively, and artesunate + sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment during pregnancy and for infants. In 2016, the NMCP conducted a study to assess the clinical and parasitological responses of children under five years to ASAQ, AL and dihydroartemisinin–piperaquine (DHA/PPQ) according to the WHO protocol. Day-0 samples were tested for mutations in the Kelch 13 gene (pfk13) and dihydrofolate reductase/dihydropteroate synthase (pfdhfr/pfdhps) genes associated with artemisinin and SP resistance, respectively, and amplification in the pfplasmepsin2 gene for piperaquine resistance. A total of 295 (ASAQ = 128, AL = 64 and DHA/PPQ = 103) eligible children were enrolled at three sites. PCR-corrected 100% adequate clinical and parasitological response and no parasitaemia on day-3 were observed for all patients in each treatment group. Of the 278 samples with interpretable molecular data, only 2.2% carried non-synonymous pfk13 mutants (A578S, I646T), which are not associated with artemisinin resistance. None of the 103 day-0 samples from the DAH/PPQ group had pfplasmepsin2 gene amplification, confirming the absence of piperaquine resistance. The prevalence of the triple pfdhfr mutant (N51I/C59R/S108N) was close to or reached fixation (97.4–100%). For combined pfdhfr/pfdhps mutation, 55–71% carried the quadruple (N51I/C59R/S108N+A437G) mutant and about 10% the quintuple mutant N51I/C59R/S108N+A437G/K540E. Our findings confirm that ASAQ, AL and DHA/PPQ were highly effective for the treatment of uncomplicated malaria in the study areas, and neither pfk13 validated mutations nor pfplasmepsin2 multiple copies were found. The very low prevalence of the quintuple mutant in this study supports the NMCP’s decision to introduce intermittent preventive treatment for infants with SP in the districts with high malaria transmission.

Highlights

Effective antimalarial therapy is necessary to cure malaria infection, prevent progression to severe disease and save lives
WHO recommends intermittent preventive treatment with SP in pregnancy (IPTp) and in infants (IPTi) living in settings with moderate-to-high malaria transmission in order to mitigate the adverse consequences of malaria infection in these risk groups (WHO, 2010a, 2014)
Recent studies show high treatment failure rates with DHA/PPQ as well as piperaquine and/or artemisinin resistance in several countries in the subregion (Leang et al, 2015; Thanh et al, 2017; Phuc et al, 2017; Imwong et al, 2017). These developments indicate the importance of vigilance in malaria-endemic countries for the possible emergence of resistance to artemisinin and partner drugs and treatment failures with artemisinin-based combination therapy (ACT)

Summary

Introduction

Effective antimalarial therapy is necessary to cure malaria infection, prevent progression to severe disease and save lives. To counteract the resistance of Plasmodium falciparum first to chloroquine and later to other monotherapies such as sulfadoxine–pyrimethamine (SP), WHO recommends artemisinin-based combination therapy (ACT) for the treatment of uncomplicated P. falciparum malaria (WHO, 2015) These drugs are artesunate–amodiaquine (ASAQ), artemether–lumefantrine (AL), artesunate–sulfadoxine–pyrimethamine (ASSP), dihydroartemisinin–piperaquine (DHA/PPQ) and artesunate–mefloquine (ASMQ). Recent studies show high treatment failure rates with DHA/PPQ as well as piperaquine and/or artemisinin resistance in several countries in the subregion (Leang et al, 2015; Thanh et al, 2017; Phuc et al, 2017; Imwong et al, 2017) These developments indicate the importance of vigilance in malaria-endemic countries for the possible emergence of resistance to artemisinin and partner drugs and treatment failures with ACT. The recently identified copy number variation of pfplasmepsin has been associated with piperaquine resistance (Witkowski et al, 2017; Amato et al, 2017)

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