Plasmodium falciparum Drug Resistance in Madagascar: Facing the Spread of Unusual pfdhfr and pfmdr-1 Haplotypes and the Decrease of Dihydroartemisinin Susceptibility

ABSTRACT The aim of this study was to provide the first comprehensive spatiotemporal picture of Plasmodium falciparum resistance in various geographic areas in Madagascar. Additional data about the antimalarial resistance in the neighboring islands of the Comoros archipelago were also collected. We assessed the prevalence of pfcrt, pfmdr-1, pfdhfr, and pfdhps mutations and the pfmdr-1 gene copy number in 1,596 P. falciparum isolates collected in 26 health centers (20 in Madagascar and 6 in the Comoros Islands) from 2006 to 2008. The in vitro responses to a panel of drugs by 373 of the parasite isolates were determined. The results showed (i) unusual profiles of chloroquine susceptibility in Madagascar, (ii) a rapid rise in the frequency of parasites with both the pfdhfr and the pfdhps mutations, (iii) the alarming emergence of the single pfdhfr 164L genotype, and (iv) the progressive loss of the most susceptible isolates to artemisinin derivatives. In the context of the implementation of the new national policy for the fight against malaria, continued surveillance for the detection of P. falciparum resistance in the future is required.

[1]  W. Stein,et al.  Polymorphisms within PfMDR1 alter the substrate specificity for anti‐malarial drugs in Plasmodium falciparum , 2008, Molecular microbiology.

[2]  S. Briolant,et al.  Antimalarial drug use in general populations of tropical Africa , 2008, Malaria Journal.

[3]  D. Ménard,et al.  Dihydrofolate Reductase I164L Mutation in Plasmodium falciparum, Madagascar , 2008, Emerging infectious diseases.

[4]  Jonathan Cox,et al.  Emergence of a dhfr mutation conferring high-level drug resistance in Plasmodium falciparum populations from southwest Uganda. , 2008, The Journal of infectious diseases.

[5]  D. Ménard,et al.  Assessment of the efficacy of antimalarial drugs recommended by the National Malaria Control Programme in Madagascar: Up-dated baseline data from randomized and multi-site clinical trials , 2008, Malaria Journal.

[6]  J. E. Hyde,et al.  Antifolate resistance in Africa and the 164-dollar question. , 2008, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[7]  D. Ménard,et al.  Performance and reliability of the SYBR Green I based assay for the routine monitoring of susceptibility of Plasmodium falciparum clinical isolates. , 2008, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[8]  D. Ménard,et al.  Accuracy and reliability of malaria diagnostic techniques for guiding febrile outpatient treatment in malaria-endemic countries. , 2008, The American journal of tropical medicine and hygiene.

[9]  D. Ménard,et al.  Drug-Resistant Malaria Parasites Introduced into Madagascar from Comoros Islands , 2007, Emerging infectious diseases.

[10]  Carol Hopkins Sibley,et al.  World Antimalarial Resistance Network (WARN) II: In vitro antimalarial drug susceptibility , 2007, Malaria Journal.

[11]  H. Joshi,et al.  World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria , 2007, Malaria Journal.

[12]  R. Price,et al.  World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs , 2007, Malaria Journal.

[13]  A. Mårtensson,et al.  Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. , 2007, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[14]  B. Pradines,et al.  Antimalarial drug susceptibility and point mutations associated with drug resistance in 248 Plasmodium falciparum isolates imported from Comoros to Marseille, France in 2004 2006. , 2007, The American journal of tropical medicine and hygiene.

[15]  Conner I. Sandefur,et al.  Pyrimethamine-resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro. , 2007, Molecular and biochemical parasitology.

[16]  P. Rosenthal,et al.  Resistance-Mediating Plasmodium falciparum pfcrt and pfmdr1 Alleles after Treatment with Artesunate-Amodiaquine in Uganda , 2007, Antimicrobial Agents and Chemotherapy.

[17]  Georgina S. Humphreys,et al.  Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria , 2006, Antimicrobial Agents and Chemotherapy.

[18]  D. Fidock,et al.  First evidence of pfcrt mutant Plasmodium falciparum in Madagascar. , 2006, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[19]  D. Fidock,et al.  Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. , 2006, The Journal of infectious diseases.

[20]  J. Tchen,et al.  [Epidemiology and prevention of malaria in the southwestern islands of the Indian Ocean]. , 2006, Medecine tropicale : revue du Corps de sante colonial.

[21]  D. Parzy,et al.  Chimiosensibilité de Plasmodium falciparum importé des Comores à Marseille en 2002–2003 , 2005 .

[22]  T. Anderson,et al.  The origins and spread of antimalarial drug resistance: lessons for policy makers. , 2005, Acta tropica.

[23]  Manoj T Duraisingh,et al.  Contribution of the pfmdr1 gene to antimalarial drug-resistance. , 2005, Acta tropica.

[24]  R. Migliani,et al.  Plasmodium falciparum resistant to chloroquine and to pyrimethamine in Comoros. , 2004, Parasite.

[25]  M. Randrianarivelojosia,et al.  Monitoring susceptibility to sulfadoxine–pyrimethamine among cases of uncomplicated, Plasmodium falciparum malaria in Saharevo, Madagascar , 2004, Annals of tropical medicine and parasitology.

[26]  B. Sharp,et al.  Intercontinental Spread of Pyrimethamine-Resistant Malaria , 2004, Science.

[27]  R. Price,et al.  Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number , 2004, The Lancet.

[28]  P. Rasoanaivo,et al.  Decreasing clinical efficacy of chloroquine in Ankazobe, Central Highlands of Madagascar. , 2004, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[29]  U. d’Alessandro,et al.  History, Dynamics, and Public Health Importance of Malaria Parasite Resistance , 2004, Clinical Microbiology Reviews.

[30]  S. Picot,et al.  Simultaneous identification of the four human Plasmodium species and quantification of Plasmodium DNA load in human blood by real-time polymerase chain reaction. , 2003, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[31]  J. Le bras,et al.  The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum , 2003, Fundamental & clinical pharmacology.

[32]  M. Randrianarivelojosia,et al.  Monitoring the drug-sensitivity of Plasmodium falciparum in coastal towns in Madagascar by use of in vitro chemosensitivity and mutation detection tests. , 2002, Parasite.

[33]  C. Rogier,et al.  Current absence of pyrimethamine resistance of Plasmodium falciparum in Madagascar. , 2002, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[34]  C. Rogier,et al.  Combating malaria in Africa. , 2002, Trends in parasitology.

[35]  M. Randrianarivelojosia,et al.  Mapping of a Plasmodium falciparum pfcrt K76T mutation: a useful strategy for controlling chloroquine resistance in Madagascar. , 2002, The Journal of infectious diseases.

[36]  I. Chemin,et al.  A new viral agent, SEN virus (SENV), has been detected in patients from several countries: the pathogenic role of SENV in coinfections with hepatitis B virus or hepatitis C virus should be investigated. , 2002, The Journal of infectious diseases.

[37]  J. Kublin,et al.  Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. , 2002, The Journal of infectious diseases.

[38]  R. Snow,et al.  The past, present and future of childhood malaria mortality in Africa. , 2001, Trends in parasitology.

[39]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[40]  K. Kirk,et al.  Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum , 2000, Nature.

[41]  W. Jarra,et al.  Biased distribution of msp1 and msp2 allelic variants in Plasmodium falciparum populations in Thailand. , 1999, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[42]  A. Cowman,et al.  Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum , 1990, Nature.

[43]  M. Wahlgren,et al.  Chloroquine-resistant falciparum malaria in Madagascar and Kenya. , 1981, Annals of tropical medicine and parasitology.

[44]  J. Juliano,et al.  Lessons learnt from the six decades of chloroquine use (1945-2005) to control malaria in Madagascar. , 2009, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[45]  B. Pradines,et al.  [Chemosusceptibility analysis of Plasmodium falciparum imported from Comoros to Marseilles, France in 2001-2003]. , 2005, Médecine et maladies infectieuses.

[46]  R. Snow,et al.  Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria , 2003 .