title: Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance.
abstract: BACKGROUND
  Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance.
  
  
  RESULTS
  We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50 km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively.
  
  
  CONCLUSIONS
  A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials.
authors.affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.
authors.forename: Jamie T
authors.initials: JT
authors.lastname: Griffin
authors.forename: Matthew
authors.initials: M
authors.lastname: Cairns
authors.forename: Azra C
authors.initials: AC
authors.lastname: Ghani
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: David
authors.initials: D
authors.lastname: Schellenberg
authors.forename: Ilona
authors.initials: I
authors.lastname: Carneiro
authors.forename: Robert D
authors.initials: RD
authors.lastname: Newman
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.forename: Daniel
authors.initials: D
authors.lastname: Chandramohan
authors.forename: Roly D
authors.initials: RD
authors.lastname: Gosling
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000962:Antimalarials / Q000627:therapeutic use*; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000188:drug therapy* / Q000469:parasitology / Q000517:prevention & control*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D000426:Alcohol Dehydrogenase; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine