title: Is nevirapine dose-escalation appropriate in young, African, HIV-infected children?
abstract: OBJECTIVE
  Young children metabolize nevirapine faster than older children/adults. We evaluated nevirapine pharmacokinetics with or without dose-escalation in Zambian, HIV-infected infants/children and its relationship with safety/efficacy.
  
  
  METHODS
  A retrospective pharmacokinetic substudy of the CHAPAS-1 trial.
  
  
  METHODS
  HIV-infected, Zambian children were randomized to initiate antiretroviral therapy (ART) with full-dose twice-daily nevirapine versus 2-week nevirapine dose-escalation. Samples taken 3-4 h postmorning-dose 2 weeks after nevirapine initiation were assayed for nevirapine levels. Viral load was measured on available samples at weeks 4 and 48; adverse events were prospectively reported.
  
  
  RESULTS
  Of 162 (77%) children with week-2 samples, 79 (49%) were randomized to nevirapine dose-escalation. At ART initiation, median [interquartile range (IQR)] age, weight and CD4% were 5.2 (1.5-8.7) years, 13.0 (8.1-19.0) kg and 13 (8-18)%, respectively; 81 (50%) were male. With full dose, few children aged less than 2 years (3/23, 13%) or more than 2 years (4/60, 7%) had subtherapeutic nevirapine levels (defined as <3.0 mg/l), but with dose-escalation, seven out of 22 (32%) aged less than 2 years versus seven out of 57 (12%) more than 2 years had subtherapeutic nevirapine levels (P=0.05). There was no difference between week-2 nevirapine levels in those with viral load more than 250 versus less than 250 copies/ml at week 4 (P=0.97) or week 48 (P=0.40). Eleven out of 162 children had grade 1/2 rash; all were more than 2 years of age (P=0.04), and 10 were randomized to full dose.
  
  
  CONCLUSIONS
  Subtherapeutic nevirapine levels 3-4 h postdose were more frequent in young children on dose-escalation. Younger children were at lower risk for rash. To simplify ART initiation and reduce the risk of suboptimal dosing, full-dose nevirapine at ART initiation should be considered for African HIV-infected children less than 2 years of age.
authors.affiliation: aRadboud University Nijmegen Medical Centre, Nijmegen, The Netherlands bUniversity Teaching Hospital, Lusaka, Zambia cMRC Clinical Trials Unit, London, UK.
authors.forename: Quirine
authors.initials: Q
authors.lastname: Fillekes
authors.forename: Veronica
authors.initials: V
authors.lastname: Mulenga
authors.forename: Desiré
authors.initials: D
authors.lastname: Kabamba
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Thomason
authors.forename: Adrian
authors.initials: A
authors.lastname: Cook
authors.forename: Chifumbe
authors.initials: C
authors.lastname: Chintu
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005076:Exanthema / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D019829:Nevirapine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D019562:Viral Load; D015024:Zambia
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine