title: Parasite Clearance and Artemether Pharmacokinetics Parameters Over the Course of Artemether-Lumefantrine Treatment for Malaria in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Ugandan Children.
abstract: BACKGROUND
  Artemisinins are primarily responsible for initial parasite clearance. Antimalarial pharmacokinetics (PK), human immunodeficiency virus (HIV) infection, and antiretroviral therapy have been shown to impact treatment outcomes, although their impact on early parasite clearance in children has not been well characterized.
  
  
  METHODS
  Parasite clearance parameters were generated from twice-daily blood smears in HIV-infected and HIV-uninfected Ugandan children treated with artemether-lumefantrine (AL). Artemether and dihydroartemisinin (DHA) area-under-the-curve from 0-8 hours (AUC0-8hr) after the 1st AL dose was compared with AUC0-8hrafter the last (6th) dose in a concurrently enrolled cohort. The association between post-1st dose artemisinin AUC0-8hrand parasite clearance was assessed.
  
  
  RESULTS
  Parasite clearance was longer in HIV-infected versus HIV-uninfected children (median, 3.5 vs 2.8 hours;P= .003). Artemether AUC0-8hrwas 3- to 4-fold lower after the 6th dose versus the 1st dose of AL in HIV-infected children on nevirapine- or lopinavir/ritionavir-based regimens and in HIV-uninfected children (P≤ .002, 1st vs 6th-dose comparisons). Children on efavirenz exhibited combined post-1st dose artemether/DHA exposure that was significantly lower than those on lopinavir/ritonavir and HIV-uninfected children. Multiple regression analysis supported that the effect of artemether/DHA exposure on parasite clearance was significantly moderated by HIV status.
  
  
  CONCLUSIONS
  Parasite clearance rates remain rapid in Uganda and were not found to associate with PK exposure. However, significant decreases in artemisinin PK with repeated dosing in nearly all children, coupled with small, but significant increase in parasite clearance half-life in those with HIV, may have important implications for AL efficacy, particularly because reports of artemisinin resistance are increasing.
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.
authors.forename: Richard
authors.initials: R
authors.lastname: Kajubi
authors.affiliation: University of California-San Francisco, San Francisco General Hospital.
authors.forename: Liusheng
authors.initials: L
authors.lastname: Huang
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Were
authors.affiliation: University of California-San Francisco, San Francisco General Hospital.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kiconco
authors.affiliation: Yale University School of Public Health and Medicine , New Haven, Connecticut.
authors.forename: Fangyong
authors.initials: F
authors.lastname: Li
authors.affiliation: University of California-San Francisco, San Francisco General Hospital.
authors.forename: Florence
authors.initials: F
authors.lastname: Marzan
authors.affiliation: University of California-San Francisco, San Francisco General Hospital.
authors.forename: David
authors.initials: D
authors.lastname: Gingrich
authors.affiliation: Institute for Global Health, University of Maryland Baltimore School of Medicine.
authors.forename: Myaing M
authors.initials: MM
authors.lastname: Nyunt
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.
authors.forename: Joshua
authors.initials: J
authors.lastname: Ssebuliba
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.
authors.forename: Norah
authors.initials: N
authors.lastname: Mwebaza
authors.affiliation: University of California-San Francisco, San Francisco General Hospital.
authors.forename: Francesca T
authors.initials: FT
authors.lastname: Aweeka
authors.affiliation: Yale University School of Public Health and Medicine , New Haven, Connecticut.
authors.forename: Sunil
authors.initials: S
authors.lastname: Parikh
keywords: HIV; antimalarial; antiretroviral; artemisinin combination therapy; malaria