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Clinical Therapeutics

pfk13-Independent Treatment Failure in Four Imported Cases of Plasmodium falciparum Malaria Treated with Artemether-Lumefantrine in the United Kingdom

Colin J. Sutherland, Paul Lansdell, Mandy Sanders, Julian Muwanguzi, Donelly A. van Schalkwyk, Harparkash Kaur, Debbie Nolder, Julie Tucker, Hayley M. Bennett, Thomas D. Otto, Matthew Berriman, Trupti A. Patel, Roderick Lynn, Effrossyni Gkrania-Klotsas, Peter L. Chiodini
Colin J. Sutherland
aPublic Health England Malaria Reference Laboratory, London School of Hygiene & Tropical Medicine, London, United Kingdom
bDepartment of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Paul Lansdell
aPublic Health England Malaria Reference Laboratory, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Mandy Sanders
cWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Julian Muwanguzi
bDepartment of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Donelly A. van Schalkwyk
bDepartment of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Harparkash Kaur
bDepartment of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Debbie Nolder
aPublic Health England Malaria Reference Laboratory, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Julie Tucker
aPublic Health England Malaria Reference Laboratory, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Hayley M. Bennett
cWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Thomas D. Otto
cWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Matthew Berriman
cWellcome Trust Sanger Institute, Hinxton, United Kingdom
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Trupti A. Patel
dHospital for Tropical Diseases, London, United Kingdom
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Roderick Lynn
eHaematology Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
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Effrossyni Gkrania-Klotsas
fInfectious Diseases Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
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Peter L. Chiodini
aPublic Health England Malaria Reference Laboratory, London School of Hygiene & Tropical Medicine, London, United Kingdom
dHospital for Tropical Diseases, London, United Kingdom
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DOI: 10.1128/AAC.02382-16
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  • TABLE 1

    Genotyping data from P. falciparum isolates taken from primary and secondary symptomatic malaria episodes in four UK patients

    PatientSex and age (yrs)TravelEpisode 1Episode 2 (elapsed time since previous episode)Mutation(s) or haplotypeWGSf clonality
    pfk13bpfcrtcpfmdr1pfap2mupfubp1
    1Male over 65AngolaAugust 2015 Lys189ThrCVIETTyr184PhedSer160AsnWT
    43 daysLys189ThrCVIETTyr184PheSer160AsnWT
    2Female under 21UgandaJanuary 2016 WTCVIETWTWTGlu1525Gln
    28 days (cultured)aWTCVIETWTWTGlu1525Gln
    3Male over 21LiberiaFebruary 2016 WT Gly112GluCVIET CVMNKTyr184Pheins_Lys233,e ins_Asn233WT≥2 clones
    17 daysGly112GluCVMNKTyr184Pheins_Lys233WT1 clone
    4Female under 21UgandaJanuary 2016 Lys189ThrCVIETWTins_Asn226, ins_Asn326Thr1500Ile
    34 daysLys189ThrCVIETWTins_Asn226, ins_Asn326Thr1500Ile
    • ↵a Parasites from the second malaria episode of patient 2 were successfully established in in vitro culture for estimation of drug susceptibility.

    • ↵b The nomenclature used shows the wild-type (WT) (reference) amino acid encoded at the codon of interest, followed by the amino acid encoded by the observed variant. Mutations in the pfk13 locus previously associated with reduced susceptibility to artemisinin in vitro and in vivo in the Mekong region occur between codon 440 and the 3′ end of the coding region.

    • ↵c The nomenclature used shows the single-letter amino acid code for codons 72 to 76, strongly associated with chloroquine resistance. The CVMNK haplotype has been associated with AL treatment failures in Kenya (5).

    • ↵d The single mutation Tyr to Phe at codon 184 identifies the NFD genotype at codons 86, 184, and 1246 in the pfmdr1 locus, previously associated with AL failure in Tanzania and Kenya (5, 8).

    • ↵e ins, insertion of one amino acid, relative to the reference sequence, after the codon shown.

    • ↵f Whole-genome sequencing results for both parasite isolates from patient 3. In the primary episode, heterozygosity (variant allele frequencies of between 5% and 95% of total reads) was seen in over 4,000 loci. About 50% of reads at informative positions comprised variants also present in the monoclonal recrudescent episode (17 days later).

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pfk13-Independent Treatment Failure in Four Imported Cases of Plasmodium falciparum Malaria Treated with Artemether-Lumefantrine in the United Kingdom
Colin J. Sutherland, Paul Lansdell, Mandy Sanders, Julian Muwanguzi, Donelly A. van Schalkwyk, Harparkash Kaur, Debbie Nolder, Julie Tucker, Hayley M. Bennett, Thomas D. Otto, Matthew Berriman, Trupti A. Patel, Roderick Lynn, Effrossyni Gkrania-Klotsas, Peter L. Chiodini
Antimicrobial Agents and Chemotherapy Feb 2017, 61 (3) e02382-16; DOI: 10.1128/AAC.02382-16

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pfk13-Independent Treatment Failure in Four Imported Cases of Plasmodium falciparum Malaria Treated with Artemether-Lumefantrine in the United Kingdom
Colin J. Sutherland, Paul Lansdell, Mandy Sanders, Julian Muwanguzi, Donelly A. van Schalkwyk, Harparkash Kaur, Debbie Nolder, Julie Tucker, Hayley M. Bennett, Thomas D. Otto, Matthew Berriman, Trupti A. Patel, Roderick Lynn, Effrossyni Gkrania-Klotsas, Peter L. Chiodini
Antimicrobial Agents and Chemotherapy Feb 2017, 61 (3) e02382-16; DOI: 10.1128/AAC.02382-16
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KEYWORDS

antimalarials
artemisinins
drug resistance
Ethanolamines
Fluorenes
Malaria, Falciparum
Parasitemia
Plasmodium falciparum
Protozoan Proteins
imported malaria
treatment failure
parasite genotyping
antimalarial agents
drug resistance mechanisms

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