title: Molecular genotyping in a malaria treatment trial in Uganda - unexpected high rate of new infections within 2 weeks after treatment.
abstract: Polymerase chain reaction (PCR) genotyping of malaria parasites in drug efficacy trials helps differentiate reinfections from recrudescences. A combination therapy trial of one (n = 115) or three (n = 117) days artesunate (1AS, 3AS 4 mg/kg/day) plus sulphadoxine-pyrimethamine (SP) vs. SP alone (n = 153) was conducted in Mbarara, a mesoendemic area of western Uganda. All paired recurrent Plasmodium falciparum parasitaemias on days 7, 14, 21 and 28 post-treatment were genotyped by PCR amplification and analysis of glutamate-rich protein (glurp) and merozoite surface proteins (msp) 1 and 2 genes to distinguish recrudescent from new infections. A total of 156 (1AS = 61, 3AS = 35, SP alone = 60) of 199 paired recurrent samples were successfully analysed and were resolved as 79 recrudescences (1AS = 32, 3AS = 8, SP = 39) and 77 as new infections (1AS = 29, 3AS = 27, SP = 21). The ratios of proportions of new to recrudescent infections were 0.2, 0.9, 1.4 and 1.9 on days 7, 14, 21 and 28, respectively (P < 0.001, chi(2) test for linear trend). Unexpected high new infection rates were observed early in follow-up on days 7 [5/26 (19.2%)] and 14 [24/51 (47.1%)]. These results impact significantly on resistance monitoring and point to the value of genotyping all recurrent infections in antimalarial trials.
authors.affiliation: Ifakara Health Research and Development Centre, Ifakara, Tanzania.
authors.forename: Kefas
authors.initials: K
authors.lastname: Mugittu
authors.forename: Gerardo
authors.initials: G
authors.lastname: Priotto
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Guthmann
authors.forename: James
authors.initials: J
authors.lastname: Kiguli
authors.forename: Martin
authors.initials: M
authors.lastname: Adjuik
authors.forename: Georges
authors.initials: G
authors.lastname: Snounou
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Hassan
authors.initials: H
authors.lastname: Mshinda
authors.forename: Piero L
authors.initials: PL
authors.lastname: Olliaro
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D002648:Child; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D019353:Endemic Diseases; D017125:Genes, Protozoan / Q000235:genetics; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology; D020066:Merozoite Surface Protein 1 / Q000032:analysis; D018512:Parasitemia / Q000188:drug therapy / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D015800:Protozoan Proteins / Q000032:analysis; D011739:Pyrimethamine / Q000008:administration & dosage*; D012008:Recurrence; D012717:Sesquiterpenes / Q000008:administration & dosage*; D013413:Sulfadoxine / Q000008:administration & dosage*; D014454:Uganda / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; D012717:Sesquiterpenes; C072492:glutamate-rich protein, Plasmodium; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D011739:Pyrimethamine