MOLECULAR ANALYSIS OF PLASMODIUM FALCIPARUM FROM DRUG TREATMENT FAILURE PATIENTS IN PAPUA NEW GUINEA

GERARD J. CASEY Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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MEZA GINNY Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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MEROLYN URANOLI Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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IVO MUELLER Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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JOHN C. REEDER Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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BLAISE GENTON Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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ALAN F. COWMAN Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Swiss Tropical Institute, Basel, Switzerland

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A study was conducted in Papua New Guinea to analyze Plasmodium falciparum drug resistance polymorphisms in patients presenting with resistant malaria. One hundred ninety-nine P. falciparum-positive patients were recruited at two sites, Madang and Maprik. Exposure to the 4-aminoquinolines chloroquine and amodiaquine was uniformly high, at 84% overall. However, 59% of these were taken in various combinations of sulfadoxine/pyrimethamine and/or primaquine and/or quinine. Two markers for 4-aminoquinoline resistance, P. falciparum chloroquine resistance transporter 76T and P. falciparum multidrug resistance 1, were fixed in the population and two markers for pyrimethamine resistance, dihydrofolate reductase (dhps) 59R and 108N, were found at moderate to high levels, overall 60% and 75%, respectively. No polymorphisms in dhps associated with sulfadoxine resistance were present. Differences between the two sites are analyzed. The study period encompasses a change in standard malaria treatment policy. These findings stress the need for regular monitoring of the effects of standard drug treatment of uncomplicated malaria in Papua New Guinea.

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  • 1

    Grimmond TR, Donovan KO, Riley ID, 1976. Chloroquine resistant malaria in Papua New Guinea. P N G Med J 19 :184–185.

  • 2

    Dulay IS, Gibson FD, Eyeson-Annan MB, Narara A, 1987. Chloroquine resistance in Plasmodium falciparum and its geographical distribution in Papua New Guinea. P N G Med J 30 :281–290.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Trenholme KR, Kum DE, Raiko AK, Gibson N, Narara A, Alpers MP, 1993. Resistance of Plasmodium falciparum to amodiaquine in Papua New Guinea. Trans R Soc Trop Med Hyg 87 :464–466.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    al-Yaman F, Genton B, Mokela D, Narara A, Raiko A, Alpers MP, 1996. Resistance of Plasmodium falciparum malaria to amodiaquine, chloroquine and quinine in the Madang Province of Papua New Guinea, 1990–1993. P N G Med J 39 :16–22.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Darlow B, Vrbova H, Stace J, Heywood P, Alpers M, 1980. Fansidar-resistant falciparum malaria in Papua New Guinea (letter). Lancet 2 :1243.

  • 6

    Darlow B, Vrbova H, Gibney S, Jolley D, Stace J, Alpers M, 1982. Sulfadoxine-pyrimethamine for the treatment of acute malaria in children in Papua New Guinea. I. Plasmodium falciparum.Am J Trop Med Hyg 31 :1–9.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Lamont G, Darlow B, 1982. Comparison of in vitro pyrimethamine assays and in vivo response to sulphadoxine-pyrimethamine in Plasmodium falciparum from Papua New Guinea. Trans R Soc Trop Med Hyg 76 :797–799.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Reeder JC, Rieckmann KH, Genton B, Lorry K, Wines B, Cowman AF, 1996. Point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and cycloguanil of Plasmodium falciparum isolates from Papua New Guinea. Am J Trop Med Hyg 55 :209–213.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sidhu AB, Verdier-Pinard D, Fidock DA, 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 :210–213.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum.Nature 403 :906–909.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Babiker HA, Pringle SJ, Abdel-Muhsin A, Mackinnon M, Hunt P, Walliker D, 2001. High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. J Infect Dis 183 :1535–1538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, bir Singh Sidhu A, Naude B, Deitsch KW, Su X, Wootton JC, Roepe PD, Wellems TE, 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6 :861–871.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum.Nature 345 :255–258.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Duraisingh MT, Drakeley CJ, Muller O, Bailey R, Snounou G, Targett GA, Greenwood BM, Warhurst DC, 1997. Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine. Parasitology 114 :205–211.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Mehlotra RK, Fujioka H, Roepe PD, Janneh O, Ursos LM, Jacobs-Lorena V, McNamara DT, Bockarie MJ, Kazura JW, Kyle DE, Fidock DA, Zimmerman PA, 2001. Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc Natl Acad Sci USA 98 :12689–12694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Triglia T, Menting JGT, Wilson C, Cowman AF, 1997. Mutations of dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum.Proc Natl Acad Sci USA 94 :13944–13949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Triglia T, Wang P, Sims PFG, Hyde JE, Cowman AF, 1998. Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria. EMBO J 17 :3807–3815.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Zolg JW, Plitt JR, Chen GX, Palmer S, 1989. Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum.Mol Biochem Parasitol 36 :253–262.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Cowman AF, Morry MJ, Biggs BA, Cross GAM, Foote SJ, 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.Proc Natl Acad Sci USA 85 :9109–9113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Doumbo OK, Kayentao K, Djimde A, Cortese JF, Diourte Y, Konare A, Kublin JG, Plowe CV, 2000. Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis. J Infect Dis 182 :993–996.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Thaithong S, Ranford-Cartwright LC, Siripoon N, Harnyuttanakorn P, Kanchanakhan NS, Seigprm A, Rungsihirunrat K, Cravo PV, Beale GH, 2001. Plasmodium falciparum: gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine. Exp Parasitol 98 :59–70.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wang P, Read M, Sims PFG, Hyde JE, 1997. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilisation. Mol Microbiol 23 :979–986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Peterson DS, Di SS, Povoa M, Calvosa VS, Do RV, Wellems TE, 1991. Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazon. Am J Trop Med Hyg 45 :492–497.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Duraisingh MT, Curtis J, Warhurst DC, 1998. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol 89 :1–8.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Nagesha HS, Din-Syafruddin D, Casey GJ, Susanti AI, Fryauff DJ, Reeder JC, Cowman AF, 2001. Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in vivo drug resistance in West Papua, Indonesia. Trans R Soc Trop Med Hyg 95 :1–7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    van Weert AW, Geuze HJ, Groothuis B, Stoorvogel W, 2000. Primaquine interferes with membrane recycling from endosomes to the plasma membrane through a direct interaction with endosomes which does not involve neutralisation of endosomal pH nor osmotic swelling of endosomes. Eur J Cell Biol. 79 :394–399.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Plowe CV, Djimde A, Wellems TE, Diop S, Kouriba B, Doumbo OK, 1996. Community pyrimethamine-sulfadoxine use and prevalence of resistant Plasmodium falciparum genotypes in Mali: a model for deterring resistance. Am J Trop Med Hyg 55 :467–471.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mueller I, Bockarie M, Alpers M, Smith T, 2003. The epidemiology of malaria in Papua New Guinea. Trends Parasitol 19 :253–259.

  • 29

    Spencer M, 1994. Malaria, the Australian Experience, 18431991. Townsville, Queensland, Australia: Australian College of Tropical Medicine.

    • PubMed
    • Export Citation
  • 30

    Chen P, Lamont G, Elliott T, Kidson C, Brown G, Mitchell G, Stace J, Alpers M, 1980. Plasmodium falciparum strains from Papua New Guinea: culture characteristics and drug sensitivity. Southeast Asian J Trop Med Public Health 11 :435–440.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Ngo T, Duraisingh M, Reed M, Hipgrave D, Biggs B, Cowman AF, 2003. Analysis of Pfcrt, Pfmdr1, dhfr, and dhps mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin. Am J Trop Med Hyg 68 :350–356.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RAG, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Ghimpeni P, Taylor TE, Plowe CV, 2002. Molecular markers for treatment failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone for falciparum malaria and a model for practical application in Africa. J Infect Dis 185 :380–388.

    • PubMed
    • Search Google Scholar
    • Export Citation
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