title: The usefulness of twenty-four molecular markers in predicting treatment outcome with combination therapy of amodiaquine plus sulphadoxine-pyrimethamine against falciparum malaria in Papua New Guinea.
abstract: BACKGROUND
  In Papua New Guinea (PNG), combination therapy with amodiaquine (AQ) or chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000.
  
  
  METHODS
  We assessed in vivo treatment failure rates with AQ+SP in two different areas in PNG and twenty-four molecular drug resistance markers of Plasmodium falciparum were characterized in pre-treatment samples. The aim of the study was to investigate the association between infecting genotype and treatment response in order to identify useful predictors of treatment failure with AQ+SP.
  
  
  RESULTS
  In 2004, Day-28 treatment failure rates for AQ+SP were 29% in the Karimui and 19% in the South Wosera area, respectively. The strongest independent predictors for treatment failure with AQ+SP were pfmdr1 N86Y (OR = 7.87, p < 0.01) and pfdhps A437G (OR = 3.44, p < 0.01). Mutations found in CQ/AQ related markers pfcrt K76T, A220S, N326D, and I356L did not help to increase the predictive value, the most likely reason being that these mutations reached almost fixed levels. Though mutations in SP related markers pfdhfr S108N and C59R were not associated with treatment failure, they increased the predictive value of pfdhps A437G. The difference in treatment failure rate in the two sites was reflected in the corresponding genetic profile of the parasite populations, with significant differences seen in the allele frequencies of mutant pfmdr1 N86Y, pfmdr1 Y184F, pfcrt A220S, and pfdhps A437G.
  
  
  CONCLUSIONS
  The study provides evidence for high levels of resistance to the combination regimen of AQ+SP in PNG and indicates which of the many molecular markers analysed are useful for the monitoring of parasite resistance to combinations with AQ+SP.
authors.affiliation: Swiss Tropical Institute, Socinstrasse 57, P,O, Box, CH-4002 Basel, Switzerland. jutta.marfurt@gmail.com
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.forename: Ivo
authors.initials: I
authors.lastname: Müller
authors.forename: Albert
authors.initials: A
authors.lastname: Sie
authors.forename: Olive
authors.initials: O
authors.lastname: Oa
authors.forename: John C
authors.initials: JC
authors.lastname: Reeder
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Smith
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D004338:Drug Combinations; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D010219:Papua New Guinea / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D015415:Biomarkers; D004338:Drug Combinations; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine