title: Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children.
abstract: The optimal treatment of malaria in human immunodeficiency virus (HIV)-infected children requires consideration of critical drug-drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes.
  
  
  
  We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated.
  
  
  
  One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART.
  
  
  
  The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted.
authors.affiliation: Yale School of Public Health, New Haven, Connecticut.
authors.forename: Sunil
authors.initials: S
authors.lastname: Parikh
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Richard
authors.initials: R
authors.lastname: Kajubi
authors.affiliation: University of California, San Francisco, and San Francisco General Hospital.
authors.forename: Liusheng
authors.initials: L
authors.lastname: Huang
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Joshua
authors.initials: J
authors.lastname: Ssebuliba
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kiconco
authors.affiliation: University of California, San Francisco, and San Francisco General Hospital.
authors.forename: Qin
authors.initials: Q
authors.lastname: Gao
authors.affiliation: University of California, San Francisco, and San Francisco General Hospital.
authors.forename: Fangyong
authors.initials: F
authors.lastname: Li
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Were
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Abel
authors.initials: A
authors.lastname: Kakuru
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Jane
authors.initials: J
authors.lastname: Achan
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Norah
authors.initials: N
authors.lastname: Mwebaza
authors.affiliation: University of California, San Francisco, and San Francisco General Hospital.
authors.forename: Francesca T
authors.initials: FT
authors.lastname: Aweeka
mesh_terms: D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000493:pharmacokinetics*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D060085:Coinfection; D004338:Drug Combinations; D004347:Drug Interactions; D004983:Ethanolamines / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D008288:Malaria / Q000150:complications / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D044966:Anti-Retroviral Agents; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes
keywords: HIV; antimalarial; antiretroviral; malaria; pharmacokinetics