title: Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naïve areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976-78.
abstract: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naïve Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P. falciparum resistance after 2 years of treatment are reported.
  
  
  
  Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods.
  
  
  
  Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069ACT→ACGsynonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001).
  
  
  
  Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069ACGand a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden. irina.jovel@ki.se.
authors.forename: Irina T
authors.identifier: 0000-0002-2651-6772
authors.initials: IT
authors.lastname: Jovel
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.affiliation: Department of Women's and Children's Health, International Maternal and Child Health Unit, Uppsala University, Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.|Department of Infectious Diseases, Danderyds Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ursing
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000008:administration & dosage*; D004351:Drug Resistance; D006801:Humans; D007988:Liberia; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011739:Pyrimethamine / Q000008:administration & dosage*; D012641:Selection, Genetic
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D002738:Chloroquine; C007030:chlorproguanil; D002727:Proguanil; D011739:Pyrimethamine
keywords: Liberia; Malaria; Plasmodium falciparum; Resistance; pfcrt; pfdhfr; pfdhps; pfmdr1; pfmrp1; pfnhe1