Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination "baby pills" in Zambia: a randomized controlled trial.
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 .
Mulenga
V
V
University Teaching Hospital, Lusaka, Zambia.
Cook
A
A
Walker
A S
AS
Kabamba
D
D
Chijoka
C
C
Ferrier
A
A
Kalengo
C
C
Kityo
C
C
Kankasa
C
C
Burger
D
D
Thomason
M
M
Chintu
C
C
Gibb
D M
DM
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
D019380:Anti-HIV Agents; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase