title: Increased gametocytemia after treatment: an early parasitological indicator of emerging sulfadoxine-pyrimethamine resistance in falciparum malaria.
abstract: BACKGROUND
  Although malaria treatment aims primarily to eliminate the asexual blood stages that cause illness, reducing the carriage of gametocytes is critical for limiting malaria transmission and the spread of resistance.
  
  
  METHODS
  Clinical and parasitological responses to the fixed-dose combination of sulfadoxine and pyrimethamine in patients with uncomplicated falciparum malaria were assessed biannually since implementation of this treatment policy in 1998 in Mpumalanga Province, South Africa.
  
  
  RESULTS
  Despite sustained cure rates of > 90% (P = .14), the duration of gametocyte carriage increased from 3 to 22 weeks (per 1000 person-weeks) between 1998 and 2002 (P < .001). The dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance were the most important drivers of the increased gametocytemia, although these mutations were not associated with increased pretreatment asexual parasite density or slower asexual parasite clearance times. The geometric mean gametocyte duration and area under the gametocyte density time curve (per 1000 person-weeks) were 7.0 weeks and 60.8 gametocytes/microL per week, respectively, among patients with wild-type parasites, compared with 45.4 weeks (P = .016) and 1212 gametocytes/microL per week (P = .014), respectively, among those with parasites containing 1-5 dhfr/dhps mutations.
  
  
  CONCLUSIONS
  An increased duration and density of gametocyte carriage after sulfadoxine-pyrimethamine treatment was an early indicator of drug resistance. This increased gametocytemia among patients who have primary infections with drug-resistant Plasmodium falciparum fuels the spread of resistance even before treatment failure rates increase significantly.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen I
authors.initials: KI
authors.lastname: Barnes
authors.forename: Francesca
authors.initials: F
authors.lastname: Little
authors.forename: Aaron
authors.initials: A
authors.lastname: Mabuza
authors.forename: Nicros
authors.initials: N
authors.lastname: Mngomezulu
authors.forename: John
authors.initials: J
authors.lastname: Govere
authors.forename: David
authors.initials: D
authors.lastname: Durrheim
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: Bill
authors.initials: B
authors.lastname: Watkins
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology*; D008297:Male; D020125:Mutation, Missense; D018512:Parasitemia; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use*; D013019:South Africa; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine