a cohort of three to 12 year-old HIV-infected Ugandan children taking
once-daily efavirenz according to 2006 World Health Organization (WHO)
weight-band dosing recommendations, lower and highly variable amounts of drug
entered their bloodstream compared to adults, investigators from the
AntiRetroviral Research fOr Watoto (ARROW) trial team report in the advance
online edition of the Journal of Acquired
Immune Deficiency Syndromes.
Fillekes and collleagues suggest these findings highlight the increased risk of
virological failure and urgently advocate for paediatricians in both
resource-rich and resource-poor settings to move to WHO 2010 dosing guidelines
2010 guidelines for HIV-infected children aged three and above recommend the
use of two nucleoside reverse transcriptase inhibitors (NRTIs) and one
non-nucleoside reverse transcriptase inhibitor (NNRTI). Efavirenz, an NNRTI,
suitable for once-daily dosing because of its long half-life and potent
antiviral activity is one of the most preferred first-line ARVs for
They recommend that efavirenz should be dosed by weight, according to the following formula:
Liquid: 19.5mg/kg per day
Tablet: 15mg/kg once a day
Weight more than 40kg: 600mg once daily
The guidelines also note that the 200mg tablet version of efavirenz is scored, and can be split. Capsules can be opened and added to a small amount of food or liquid.
is known about how efavirenz is absorbed in children, especially in African
children. Several studies have shown that a high proportion of children have
sub-optimal levels blood levels of efavirenz.
World Health Organization made weight-based dosing recommendations for children
in 2006, largely based on data acquired from studies in adults.
the paucity of studies supporting international weight-band dosing for
efavirenz, the authors undertook a pharmacokinetic (PK) sub-study to see if
children in the ARROW trial were absorbing the full amount of drug when dosing according
to the 2006 WHO recommendations.
an open-label randomised trial in Uganda and Zimbabwe, is comparing routine
laboratory to clinically driven monitoring strategies as well as comparing
three different NRTI-based ART regimens in 1,206 HIV-infected infants and
HIV-infected Ugandan children from three to 12 years of age at two Ugandan ARROW
centres taking lamivudine and abacavir twice daily with once-daily efavirenz
for at least 36 weeks were enrolled in a two-period, cross-over open label
pharmacokinetic study comparing twice to once daily lamivudine and abacavir.
The children were not anticipated to change weight-bands within the following
was dosed according to 2006 WHO recommendations at 200, 250, 300 and 350 mg for
children weighing 10<15,15<20, 20<25 and 25<30 kg, respectively;
capsules of 200 and 50 mg were used, or unscored 600 mg tablets that were cut
in the pharmacy.
week 36 blood samples were taken immediately before taking ART and then at
1,2,4,6,8 and 12 hours later. After the sample evaluation (PK1) the children
were switched to a once-daily (morning) regimen. Four weeks later (at week 40)
sampling (PK2) was repeated and a further 24-hour sample
week 36 the median age and body weight were 7.6 (IQR: 5.6-9.1) years and 20.0
(IQR: 16.6-23.0) kg, respectively. Most were moderately stunted and wasted.
authors reference Marzolini’s study looking at efavirenz efficacy and toxicity
in adults, supporting a minimum target of 1.0 mg/L 8-12 hours after taking a
dose and a maximum of 4.0 mg/L.
levels could be determined for all 41 children at PK1 and for 39 at PK2.
area under the curve (AUC) is a measure used to estimate the concentrations of
active drug available over time to suppress HIV. If the AUC falls too low virus
levels may increase, leading to virologic rebound and the development of
authors identified two studies suggesting that an AUC in children above 50
h.mg/L was associated with virological efficacy. In the ARROW sub-study 63%
(26/41) at week 36 (PK1) and 51% (20/39) at week 40 (PK2) had an efavirenz
exposure less than 50 h.mg/L. The mean AUC was 50.8 (90.8%) and 55.5 (82.7%)
h.mg/L at PK1 and PK2, respectively.
(7/41) of the children had sub-therapeutic levels (under 1.0mg/L) of the drug
eight hours and/or at 12 hours after taking the drug on one or both PK days;
these findings are consistent with other studies.
(22/37) at PK1 and 38% at PK2 (15/39) of the children had sub-therapeutic
levels of the drug 24 hours after taking it.
toxic levels of the drug (more than 4.0 mg/L) were found in 29% (12) at eight
and/or 12 hours after taking the drug: 10 children at week 36 (PK1) and 11 at
week 40 (PK2).
authors note the large number of children with efavirenz exposure outside of
the therapeutic range; only 54% (22/41) were given adequate dosage (1.0-4.0
mg/L) determined by absorption eight to 12 hours after taking the drug. This is
consistent with two other studies in African children with percentages of 47
and 66, they add.
differences were seen across weight-bands suggesting use of half-tablets is
2010 WHO recommendations have higher doses than those evaluated in this study
or licensed for children in the 14<20, 25<30, 30<35 and 35<40 kg
weight range; a result of both under-dosing found in two other studies and 50
mg capsules no longer being available. This will bring greater virological
efficacy, but it also means over a third of children will be exposed to
potentially toxic levels, note the authors.
authors conclude “higher paediatric efavirenz doses, as per WHO 2010
recommendations should be used and investigated further, but may risk
increasing the proportion of children with potentially toxic levels.”