Full-dose nevirapine may lead to rash in children with HIV

Mulenga V. Clin Infect Dis. 2010;51:1081-1089.

A full-dose regimen of stavudine, lamivudine and nevirapine was linked to high rates of rash but only a 12% rate of clinical toxicity, according to study results.

The fixed-dose combination of scored, dispersible stavudine, lamivudine and nevirapine (Triomune Baby/Junior, Cipla Pharmaceuticals) has correct dose ratios for children with HIV, including a full dose of nevirapine. However, this regimen can not be used to escalate doses of nevirapine.

In the current study, children were randomly assigned antiretroviral therapy initiation with the full-dose nevirapine regimen in the morning and evening or a regimen involving escalating dose of nevirapine — which was determined to be the Triomune formulation in the morning and stavudine-lamivudine (Lamivir, Cipla) in the evening — for 14 days, followed by full dosing thereafter.

The primary outcome measure was clinical or laboratory grade 3 or 4 adverse events related to nevirapine.

The 211 children in the final analysis — 105 in the full-dose arm and 106 in the dose-escalation arm — had a median age of 5 years (interquartile range [IQR], 2-9 years) and a median CD4 cell percentage of 13% (IQR, 8%-18%). Follow-up was conducted for a median of 92 weeks (IQR, 68-116 weeks).

Thirty-one grade 3 or 4 adverse events that were definitely/probably or uncertainly associated with nevirapine were observed in the full-dose group (18 per 100 child-years) vs. 29 in the dose-escalation group (16.5 per 100 child-years), for an incidence rate ratio of 1.09 (95% CI, 0.63-1.87). All adverse events reported were asymptomatic.

Elevations in aminotransferase or aspartate aminotransferase levels were observed in 11 children in the full-dose group and three children in the escalating-dose group. All of these events were resolved without a change or interruption in nevirapine dosing.

No children developed grade 3 or 4 rashes, but 15 children developed grade 1 or 2 rashes. When rash occurred, efavirenz was substituted in two children in the full-dose group and one child in the dose-escalation group; three children in the full-dose group continued nevirapine after rash; eight children in the full-dose group and one child in the dose-escalation group temporarily interrupted nevirapine and then achieved successful dose escalation.

Older age (P=.003) and higher CD4 cell counts for age (P=.03) predicted rash.

There were 22 deaths; 12 in the full-dose group and 10 in the dose-escalation group. One death in the full-dose group and one death in the dose-escalation group occurred before 4 weeks of follow-up. Independent review determined that none of the deaths were drug-related.

“Dual pediatric stavudine-lamivudine minitablets are preferred for safe and simple [dose escalation],” the researchers wrote. “If unavailable, initiating [full dose] Triomune requires timely review for rash, which could be managed by temporary reduction to half-dose Triomune or efavirenz substitution.”

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