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.
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.
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
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
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
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.
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
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,
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.
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
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
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
“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.”