title: Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity.
abstract: Dihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact on Plasmodium falciparum drug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed for P. falciparum parasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y in pfmdr1 and K76T in pfcrt) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. For pfmdr1 N86Y and pfcrt K76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [P = 0.03]; 76T, 96.0% versus 86.1% [P = 0.05]), suggesting selective pressure of DP. Full sequencing of pfcrt in a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harbor pfmdr1 and pfcrt polymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.).
authors.affiliation: Department of Internal Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda Infectious Diseases Research Collaboration, Kampala, Uganda jnankabirwa@yahoo.co.uk.
authors.forename: Joaniter I
authors.initials: JI
authors.lastname: Nankabirwa
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Conrad
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tukwasibwe
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tumwebaze
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Wandera
authors.affiliation: London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Brooker
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.affiliation: Department of Internal Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Sam L
authors.initials: SL
authors.lastname: Nsobya
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000293:Adolescent; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology*; D002648:Child; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D065129:Pre-Exposure Prophylaxis; D015800:Protozoan Proteins / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D014454:Uganda; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C039060:artenimol; C034759:piperaquine; D010879:Piperazines