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Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, bUniversity Teaching Hospital, Lusaka, Zambia, and
MRC Clinical Trials Unit, London, UK.
Correspondence to Quirine Fillekes, MSc, Department of Pharmacy, Radboud University Nijmegen Medical Centre, P.O. Box
9101, 6500 HB Nijmegen, The Netherlands.
Tel: +31 24 3616408; fax: +31 24 3668755; e-mail: Q.Fillekes@akf.umcn.nl
Received: 15 March 2013; accepted: 4 April 2013.
c
DOI:10.1097/QAD.0b013e3283620811
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
2111
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2112
AIDS
2013, Vol 27 No 13
Introduction
In resource-limited settings, nevirapine is generally the
most frequently used nonnucleoside reverse transcriptase
inhibitor (NNRTI) and is frequently the only option
available for first-line combination antiretroviral therapy
(cART) of HIV-infected infants/children (if not perinatally exposed to nevirapine) [1]. The drug has many
advantages, as it is relatively inexpensive, has been used
extensively with good virological efficacy and an
acceptable safety profile, and is available in pediatric
fixed-dose combination (FDC) tablets.
At nevirapine initiation, a dose-escalation strategy (half
nevirapine dose for the first 14 days) is recommended [1]
to minimize the risk of early adverse reactions [2].
Nevirapine induces its own metabolism, and without
dose-escalation, high plasma concentrations occur during
the first weeks of therapy. Elevated nevirapine levels have
been associated with higher risks of rash and hepatotoxicity [3,4].
However, young children metabolize nevirapine more
rapidly than older children or adults [57], and hence, the
impact of auto-induction on nevirapine pharmacokinetics may be less relevant. Indeed, early nevirapineinduced adverse events have been reported to be less
frequent among children, particularly the youngest,
compared with adults [5]. On the contrary, doseescalation in young children may result in lower and
suboptimal nevirapine levels during the dose-escalation
period that might increase the potential for slower viral
load suppression or virological failure [8]. Here, we
evaluate the pharmacokinetics of nevirapine with and
without dose-escalation strategy in Zambian HIVinfected infants and children, and investigate its
relationship with safety and efficacy.
Results
Two hundred and eleven HIV-infected children were
randomized to full-dose versus dose-escalation. One
hundred and sixty-two (77%) children had week-2
samples available for determining nevirapine plasma
concentrations, 79 (49%) of them randomized to the
dose-escalation group. At ART initiation, median
[interquartile range (IQR)] age, weight and CD4% in
the 162 included children were 5.2 (1.58.7) years, 13.0
(8.119.0) kg and 13 (818)%, respectively (very similar
to the whole trial [7]). Eighty-one (50%) children were
male. They were moderately to severely stunted and
wasted [median (IQR) height-for-age z-score 3.23
(4.09, 2.26); weight-for-age z-score 3.09 (4.15,
2.17)]. The median (IQR) prescribed daily nevirapine
doses at enrolment were 362 (344400) and 175 (152
193) mg/m2 in the full-dose and dose-escalation groups,
respectively.
Two weeks after ART initiation at enrolment, median
(IQR) nevirapine plasma concentrations were 9.2
(6.412) versus 4.9 (3.66.4) mg/l in the full-dose
versus dose-escalation groups, respectively (P < 0.001;
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2113
Discussion
This randomized trial is the first, and currently only, to
evaluate plasma nevirapine concentrations under fulldose or dose-escalation strategies during the initial
2 weeks of treatment in children. Despite the relatively
small sample size, with nevirapine dose-escalation at
cART initiation, more subtherapeutic nevirapine plasma
concentrations 34 h postdose were observed in children
less than 2 years of age than in older children. This finding
is compatible with earlier studies describing more rapid
nevirapine systemic clearance in younger than in older
children [5,6].
Of note, the P1060 trial [8] found less favourable outcomes
with nevirapine compared with ritonavir-boosted lopinavir among young children (median 1.7 years of age),
regardless of whether they were previously exposed to
nevirapine or not; virological failure (including deaths)
by 24 weeks was significantly (15.6 percentage points)
higher with nevirapine versus ritonavir-boosted lopinavir.
Although no pharmacokinetic data were available, doseescalation in infants was hypothesized to be a potential
contributing factor for inferior response to nevirapine
therapy [8]. We did not find evidence for an association
between week-2 nevirapine plasma concentrations with
short (week 4) or longer term (week 48) viral load
suppression (which might be due, at least in part, to small
numbers of samples assayed), but the high observed
proportion of subtherapeutic nevirapine plasma concentrations 2 weeks after cART initiation in young children
supports the hypothesis from the P1060 trial that the
nevirapine dose-escalation strategy might be suboptimal in
children less than 2 years of age. Unfortunately, we did not
assay viral load in 24-week samples, so we are unable to
directly compare our results with P1060. Interestingly,
however, we observed 11% higher viral load suppression of
less than 250 copies/ml in the full-dose group at week 4;
although the small number of samples that could be assayed
(n 62) precluded us from excluding chance as an
explanation, this does suggest that it is plausible that
full-dose initiation could have some virological benefits.
5.3 (4.29.0)
4.8 (2.96.4)
0.14
10.0 (7.912.2)
5.0 (3.96.6)
<0.001
0.001
0.41
3 out of 23 (13%)
7 out of 22 (32%)
0.16
4 out of 60 (7%)
7 out of 57 (12%)
0.35
0.39
0.05
MM
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AIDS
2013, Vol 27 No 13
(a)
30
25
20
15
10
0
DE < 2
FD < 2
DE >= 2
no rash
FD >= 2
no rash
DE >= 2
FD >= 2
(b)
30
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25
20
15
10
0
DE >= 2
rash
FD >= 2
rash
Fig. 1. Nevirapine plasma concentrations of the children in study. (a) Nevirapine plasma concentrations, dosing groups and age.
(b) Nevirapine plasma concentrations and rash. DE, dose-escalation; FD, full-dose.
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Acknowledgements
The authors would like to thank the families and children,
and staff from the University Teaching Hospital and
School of Medicine, Lusaka, Zambia, for their participation in the study. Laboratory technologists from
the Department of Pharmacy, Radboud University
Nijmegen Medical Centre, Nijmegen, are thanked for
analysing the pharmacokinetic samples, and from the
CIDRZ, Lusaka, Zambia, for assaying samples for HIV
viral load. The CHAPAS-1 study was funded by the
European and Developing Countries Clinical Trials
Partnership (grant CHINTU 2004.01.H.d2.33011) and
sponsored by the Medical Research Council, UK. The
study medication was supplied by Cipla Pharmaceuticals,
India.
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Conflicts of interest
There are no conflicts of interest.
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