Is nevirapine dose-escalation appropriate in young, African, HIV-infected children?

OBJECTIVES: 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. DESIGN: 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. CONCLUSION: 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.