title: Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination "baby pills" in Zambia: a randomized controlled trial.
abstract: BACKGROUND
  Fixed-dose combination scored dispersible stavudine, lamivudine, and nevirapine minitablets (Triomune Baby and Junior; Cipla Ltd) are simpler and cheaper than liquid formulations and have correct dose ratios for human immunodeficiency virus-infected children. However, they cannot be used for dose escalation (DE) of nevirapine.
  
  
  METHODS
  Children were randomized to initiate antiretroviral therapy with full-dose (FD) nevirapine (Triomune Baby or Junior in the morning and evening) versus DE (half-dose nevirapine for 14 days [Triomune in the morning and stavudine-lamivudine {Lamivir-S} in the evening], then FD), in accordance with World Health Organization weight-band dosing tables. The primary end point was nevirapine-related clinical or laboratory grade 3 or 4 adverse events (AEs).
  
  
  RESULTS
  In total, 211 children (median [interquartile range {IQR}] age, 5 [ 2-9 ] years; median [IQR] CD4 cell percentage, 13% [8%-18%]) were enrolled and followed up for a median (IQR) of 92 (68-116) weeks. There were 31 grade 3 or 4 AEs that were definitely/probably or uncertainly related to nevirapine in the FD group (18.0 per 100 child-years), compared with 29 in the DE group (16.5 per 100 child-years) (incidence rate ratio, 1.09; 95% confidence interval, 0.63&#x2013;1.87; P = .74). All were asymptomatic; 11 versus 3 were single grade 3 or 4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, all of which resolved without a change in nevirapine dose or interruption. Thirteen (12%) FD versus 2 (2%) DE children had grade 1 (2 in FD) or grade 2 (11 in FD and 2 in DE) rashes. Three (2 in FD and 1 in DE) substituted efavirenz, 3 (FD) continued FD nevirapine, and 9 (8 in FD and 1 in DE) temporarily interrupted nevirapine, followed by successful DE. Predictors of nevirapine rash were older age (P = .003) and higher CD4 cell count for age (P = .03). Twenty-two children died (12 in FD and 10 in DE), 1 FD and 5 DE children at <4 weeks; none were considered to be drug related by independent review.
  
  
  CONCLUSIONS
  Rash was more frequent with FD nevirapine, but 88% had no clinical toxicity; elevated AST or ALT levels were transient and resolved spontaneously, suggesting that routine laboratory monitoring has limited value. Dual pediatric stavudine-lamivudine minitablets are preferred for safe and simple DE; if unavailable, initiating FD Triomune requires timely review for rash, which could be managed by temporary reduction to half-dose Triomune or efavirenz substitution.
  
  
  BACKGROUND
  Current Controlled Trials identifier: ISRCTN31084535 .
authors.affiliation: University Teaching Hospital, Lusaka, Zambia.
authors.forename: V
authors.initials: V
authors.lastname: Mulenga
authors.forename: A
authors.initials: A
authors.lastname: Cook
authors.forename: A S
authors.initials: AS
authors.lastname: Walker
authors.forename: D
authors.initials: D
authors.lastname: Kabamba
authors.forename: C
authors.initials: C
authors.lastname: Chijoka
authors.forename: A
authors.initials: A
authors.lastname: Ferrier
authors.forename: C
authors.initials: C
authors.lastname: Kalengo
authors.forename: C
authors.initials: C
authors.lastname: Kityo
authors.forename: C
authors.initials: C
authors.lastname: Kankasa
authors.forename: D
authors.initials: D
authors.lastname: Burger
authors.forename: M
authors.initials: M
authors.lastname: Thomason
authors.forename: C
authors.initials: C
authors.lastname: Chintu
authors.forename: D M
authors.initials: DM
authors.lastname: Gibb
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005076:Exanthema / Q000139:chemically induced; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D019829:Nevirapine / Q000008:administration & dosage* / Q000009:adverse effects*; D018119:Stavudine / Q000494:pharmacology; D015024:Zambia
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase