title: No seasonal accumulation of resistant P. falciparum when high-dose chloroquine is used.
abstract: BACKGROUND
  Potentially chloroquine resistant P. falciparum, identified by the 76T haplotype in the chloroquine resistance transporter (pfcrt 76T), are highly prevalent throughout Africa. In Guinea-Bissau, normal and double dose chloroquine have respective efficacies of 34% and 78% against P.falciparum with pfcrt 76T and approximately three times the normal dose of chloroquine is routinely taken. Proportions of pfcrt 76T generally increase during high transmission seasons, as P.falciparum with pfcrt 76T commonly survive treatment with normal dose chloroquine. In Guinea-Bissau, there should be no seasonal increase of pfcrt 76T if the high doses of CQ commonly used are effective.
  
  
  RESULTS
  P. falciparum parasite density, age, sex, the proportion of chloroquine resistance associated haplotypes pfcrt 76T and P. falciparum multidrug resistance gene 1 86Y were assessed in 988 samples collected from children between 2002 and 2007. There was no seasonal accumulation of any allele. During the high and low transmission periods the pfcrt 76T proportions were 24% (95% CI, 21-27%) and 26% (95% CI, 20-33%). There was no significant change of pfcrt 76T (OR 1.05, 95% CI; 0.94-1.16 p = 0.39) or pfmdr1 86Y (OR 0.92, 95%CI; 0.83-1.01 p = 0.08) proportions between 2003 and 2007. Lower median parasite density (P.falciparum/microl) was associated with pfcrt 76T (15254 [95% CI, 12737-17772]; n = 164) compared to pfcrt 76K (18664 [95% CI, 16676-20653]; p = 0.003; n = 591). Similarly, pfmdr1 86Y was associated with a lower median parasite density (16320 [95% CI, 13696-18944]; n = 224) compared to pfmdr1 86N, (18880 [95% CI, 16701-21059]; P = 0.018; n = 445).
  
  
  CONCLUSIONS
  In contrast to the rest of Africa, P. falciparum parasites resistant to normal dose chloroquine do not have a selective advantage great enough to become the dominant P.falciparum type in Guinea-Bissau. This is most likely due to the efficacy of high-dose chloroquine as used in Guinea-Bissau, combined with a loss of fitness associated with pfcrt 76T.
authors.affiliation: Malaria Research, Department of Infectious Diseases, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. johan.ursing@ki.se
authors.forename: Johan
authors.initials: J
authors.lastname: Ursing
authors.forename: Poul-Erik
authors.initials: PE
authors.lastname: Kofoed
authors.forename: Amabelia
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Lars
authors.initials: L
authors.lastname: Rombo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D015810:Linkage Disequilibrium; D026901:Membrane Transport Proteins / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics; D012621:Seasons
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine