Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate-amodiaquine fixed dose combination or artemether-lumefantrine in Liberia.
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.



The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.



High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.



Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments. The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.
Institut de Médecine et d'Epidémiologie Appliquée, Bichat-C. Bernard Hospital, Paris, France. sabina.dahlstrom@gmail.com.|WorldWide Antimalarial Resistance Network, Oxford, UK. sabina.dahlstrom@gmail.com.|Johnson C. Smith University, Charlotte, NC, 28216, USA. sabina.dahlstrom@gmail.com.
Sabina Dahlström
0000-0001-5042-7924
SD
Otienoburu
Institut de Médecine et d'Epidémiologie Appliquée, Bichat-C. Bernard Hospital, Paris, France.|Bernhard Nocht Institute for Tropical Medicine, 20359, Hamburg, Germany.
Oumou
O
Maïga-Ascofaré
Epicentre, 75012, Paris, France.
Birgit
B
Schramm
INSERM U1129, Service de Pharmacologie, Hôpital Européen Georges Pompidou, Université Paris Descartes, 75015, Paris, France.
Vincent
V
Jullien
National Malaria Control Programme, Ministry of Health and Social Welfare, Monrovia, Liberia.
Joel J
JJ
Jones
National Malaria Control Programme, Ministry of Health and Social Welfare, Monrovia, Liberia.
Yah M
YM
Zolia
AP-HP, Saint-Louis Hospital Biochemistry Laboratory, Paris, France.
Pascal
P
Houzé
Epicentre, 75012, Paris, France.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
Elizabeth A
EA
Ashley
Drugs for Neglected Diseases Initiative, Geneva, Switzerland.
Jean-René
JR
Kiechel
WorldWide Antimalarial Resistance Network, Oxford, UK.|Epicentre, 75012, Paris, France.|Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
Philippe J
PJ
Guérin
Institut de Médecine et d'Epidémiologie Appliquée, Bichat-C. Bernard Hospital, Paris, France.|IRD UMR216, Paris-Descartes University, Paris, France.|Parasitology Laboratory-French National Malaria Reference Centre, AP-HP, Bichat-C. Bernard Hospital, Paris, France.
Jacques
J
Le Bras
IRD UMR216, Paris-Descartes University, Paris, France.|Parasitology Laboratory-French National Malaria Reference Centre, AP-HP, Bichat-C. Bernard Hospital, Paris, France.
Sandrine
S
Houzé
D000655:Amodiaquine / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002675:Child, Preschool; D016054:DNA, Protozoan / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000627:therapeutic use*; D005449:Fluorenes / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D007223:Infant; D007988:Liberia; D016778:Malaria, Falciparum / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D015800:Protozoan Proteins / Q000235:genetics*; D012641:Selection, Genetic
D000655:Amodiaquine; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D016054:DNA, Protozoan; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C515299:amodiaquine, artesunate drug combination
Antimalarial agents; Artemisinin-based combination therapy; Drug resistance; Malaria; Plasmodium falciparum; Selection; pfcrt; pfmdr1; pfmrp1