title: Risks of Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficient Infants Exposed to Chlorproguanil-Dapsone, Mefloquine and Sulfadoxine-Pyrimethamine as Part of Intermittent Presumptive Treatment of Malaria in Infants.
abstract: BACKGROUND
  Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimalarial regimens. We sought to examine the joint effects of G6PD status and IPTi antimalarial treatment on incidence of hemolysis in asymptomatic children treated with CD, sulfadoxine-pyrimethamine (SP), and mefloquine (MQ).
  
  
  METHODS
  A secondary analysis of data from a double-blind, placebo-controlled trial of IPTi was conducted. Hemoglobin (Hb) measurements were made at IPTi doses, regular follow-up and emergency visits. G6PD genotype was determined at 9 months looking for SNPs for the A- genotype at coding position 202. Multivariable linear and logistic regression models were used to examine hemolysis among children with valid G6PD genotyping results. Hemolysis was defined as the absolute change in Hb or as any post-dose Hb <8 g/dL. These outcomes were assessed using either a single follow-up Hb on day 7 after an IPTi dose or Hb obtained 1 to 14 or 28 days after each IPTi dose.
  
  
  RESULTS
  Relative to placebo, CD reduced Hb by approximately 0.5 g/dL at day 7 and within 14 days of an IPTi dose, and by 0.2 g/dL within 28 days. Adjusted declines in the CD group were larger than in the MQ and SP groups. At day 7, homo-/hemizygous genotype was associated with higher odds of Hb <8 g/dL (adjusted odds ratio = 6.7, 95% CI 1.7 to 27.0) and greater absolute reductions in Hb (-0.6 g/dL, 95% CI -1.1 to 0.003). There was no evidence to suggest increased reductions in Hb among homo-/hemizygous children treated with CD compared to placebo, SP or MQ.
  
  
  CONCLUSIONS
  While treatment with CD demonstrated greater reductions in Hb at 7 and 14 days after an IPTi dose compared to both SP and MQ, there was no evidence that G6PD deficiency exacerbated the adverse effects of CD, despite evidence for higher hemolysis risk among G6PDd infants.
authors.affiliation: Global Health Group, University of California San Francisco, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Poirot
authors.affiliation: Global Health Group, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Vittinghoff
authors.affiliation: Tanga Medical Research Centre, National Institute for Medical Research, Tanga, United Republic of Tanzania.
authors.forename: Deus
authors.initials: D
authors.lastname: Ishengoma
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, National University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Alifrangis
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Ilona
authors.initials: I
authors.lastname: Carneiro
authors.affiliation: Mwanza Interventions Trial Unit, National Institute for Medical Research, Mwanza, United Republic of Tanzania.
authors.forename: Ramadhan
authors.initials: R
authors.lastname: Hashim
authors.affiliation: Tanga Medical Research Centre, National Institute for Medical Research, Tanga, United Republic of Tanzania.|International Health Unit, Department of Epidemiology, University of Antwerp, Antwerp, Belgium.
authors.forename: Vito
authors.initials: V
authors.lastname: Baraka
authors.affiliation: Mwanza Interventions Trial Unit, National Institute for Medical Research, Mwanza, United Republic of Tanzania.
authors.forename: Jacklin
authors.initials: J
authors.lastname: Mosha
authors.affiliation: Tanga Medical Research Centre, National Institute for Medical Research, Tanga, United Republic of Tanzania.
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chandramohan
authors.affiliation: Global Health Group, University of California San Francisco, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Roland
authors.initials: R
authors.lastname: Gosling
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use; D015331:Cohort Studies; D003622:Dapsone / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics* / Q000378:metabolism; D006454:Hemoglobins / Q000032:analysis; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage* / Q000627:therapeutic use; D015999:Multivariate Analysis; D016017:Odds Ratio; D016012:Poisson Distribution; D020641:Polymorphism, Single Nucleotide; D002727:Proguanil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000627:therapeutic use; D013413:Sulfadoxine / Q000008:administration & dosage* / Q000627:therapeutic use; D013636:Tanzania
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D006454:Hemoglobins; C519882:chloroguanil, dapsone drug combination; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D003622:Dapsone; D005954:Glucosephosphate Dehydrogenase; D002727:Proguanil; D015767:Mefloquine; D011739:Pyrimethamine