Nevirapine dose escalation for children may risk treatment failure

Carole Leach-Lemens
Published: 03 June 2013

Full-dose nevirapine should be considered for HIV-positive children under two years of age in Africa, to simplify ART initiation and reduce the risk of suboptimal dosing, researchers reporting on a pharmacokinetic sub-study from the CHAPAS-1 trial argue in the advance online edition of AIDS.

This retrospective, randomised trial, comprising 162 children with a median age of 5.2 years (IQR: 1.5-8.7), is the first and only one to look at plasma nevirapine concentrations under full-dose or dose-escalation strategies in children during their first two weeks on ART. 

Among HIV-positive infants and children in resource-poor settings, nevirapine is the most frequently used non-nucleoside reverse transcriptase inhibitor (NNRTI). It is often the only choice available for first-line combination ART in those not perinatally exposed to nevirapine.

Advantages include its relative inexpensiveness, extensive use with good virological efficacy, an acceptable safety profile and availability in paediatric fixed-dose combination (FDC) tablets. 

Without dose escalation, high plasma concentrations occur within the first weeks of treatment. Such levels have been linked to an increased risk of rash and liver damage. While a dose-escalation strategy is recommended in the first two weeks to minimise such adverse events, it may be less relevant for young children who metabolise nevirapine faster than adults and older children.

“On the contrary, dose-escalation in young children may result in lower and suboptimal nevirapine levels during the dose-escalation period which might increase the potential for slower viral load suppression or virological failure,” write the authors. 

The authors looked at nevirapine pharmacokinetics with and without dose-escalation strategies in Zambian HIV-positive infants and children, and the effects on safety and efficacy.

CHAPAS-1, an open, randomised trial, investigated appropriate dosing of paediatric FDC tablets: Triomune Baby (50 mg nevirapine, 6mg stavudine and 30 mg lamivudine), Junior (double the dose of Baby) and Lamivir S Baby (30 mg lamivudine and 6mg stavudine) among Zambian children aged three months to 14 years. The trial enrolled participants from June 2006 to June 2008 and followed up children until October 2008, when the trial closed. 

The children were randomised to start ART with either full-dose nevirapine taken twice a day or dose escalation for the first two weeks of treatment, then continuing with full-dose nevirapine.

A single blood sample was taken three to four hours after the morning dose, two weeks after starting ART. Viral load of available stored samples was measured at weeks 4 and 48.

Nevirapine plasma concentrations were compared between full-dose and dose-escalation groups – under and over two years of age, viral load under and over 250 copies/ml, and with and without adverse events.

Of the 77% (162) of children with week-2 samples, median weight and CD4% at the start of ART were 13.0kg (IQR: 8.1-19.0) and 13% (IQR: 8-18), respectively.  Eighty-one (50%) were male. 

The children were moderately to severely stunted and wasted. The median prescribed daily nevirapine doses at enrolment were 362 mg/m2 (IQR: 344-400) and 175 mg/m2 (IQR: 152-193) in the full-dose and dose-escalation groups, respectively.

Children under two years of age on dose escalation had greater subtherapeutic plasma concentrations (defined as under 3.0 mg/l) three to four hours after dose than older children: 7/22 (32%) compared to 7/57 (12%). This supports earlier studies which found quicker nevirapine systemic clearance in younger children. 

Conversely, on full-dose nevirapine few children, under or over two years of age, had subtherapeutic nevirapine levels: 3/23 (13%) and 4/60 (7%), respectively.

Younger children had a lower risk for rash. Of the 11/162 (7%) of children who developed a grade 1 or 2 rash, all were over two years of age and all but one were in the full-dose arm. 

There was no difference in nevirapine levels among children with viral loads greater than 250 copies/ml, compared to those under 250 copies/ml, at week 4 or week 48.

Lending support to their argument for full-dose nevirapine in children under two years of age, the authors cite the P1060 trial, which found nevirapine, regardless of perinatal exposure, less favourable compared to lopinavir/ritonavir (Kaletra) among young children with a median age of 1.7 years; virological failure, including death, was significantly higher among those on nevirapine. 

They note that, while no pharmacokinetic data were available, it was hypothesised that dose escalation in infants under two years of age was a potential contributing factor to the poor response to nevirapine treatment. Since viral load was not tested at 24 weeks, the authors were unable to directly compare their results with P1060.

Eleven per cent of those on full-dose nevirapine had higher viral suppression at week 4. The sample size was small (62), so chance cannot be excluded, the authors write. This result does suggest, however, that starting with full-dose nevirapine may have some virological benefits, they add. 

Pointing out that all rashes were in children over two years of age, the authors note that this is the “first pharmacokinetic-pharmacodynamic association between high nevirapine plasma concentrations and rash, since all those with rash had high week two levels (most over 10mg/L) in the potentially toxic range”.

The authors propose a third argument for starting ART with full-dose nevirapine in young children, namely convenience. Using three different liquid formulations can be confusing and expensive, as well as impractical, for caregivers, they add. 

They note that other studies have shown that carers preferred tablets to syrup in children of two to three years of age.

The authors caution against using a half-dose of Triomune Baby/Junior when starting ART as the “resulting substantial initial lamivudine underdosing at a time when very young children have very high viral loads could lead to early resistance development given its low genetic barrier”. 

They suggest, as in CHAPAS-1, that using one morning dose of Triomune Baby/Junior and one evening dose of Lamivir-S Baby/Junior in the first two weeks of ART provides a safe and simple dose escalation rather than cutting parts of adult FDCs. Using full-dose nevirapine when starting ART is less complicated, they note.

“Children over two could continue to get dose-escalation to avoid development of rash, or have easy access to clinics for timely review if rashes recur with temporary discontinuation and nevirapine re-initiation at half-dose.”

 

 

Reference

Fillekes Q et al. Is nevirapine dose escalation appropriate in young, African, HIV-infected children? AIDS 27, published ahead of print, doi: 10.1097/QAD.0b013e3283620811, 2013.