Over 80% of treatment-experienced
children with HIV aged three to six years from ten sites in Argentina,
Brazil, India, Kenya and South Africa receiving darunavir/ritonavir (DRV/r) with
an optimised background regimen were virologically suppressed (viral
loads under 50 copies/ml) by week 48, Avy Violari, reporting on behalf of the
ARIEL trial, told participants at the 7th International AIDS Society
Conference (IAS 2013) in Kuala Lumpur last week.
The safety profile was
favourable. While almost all children (95%) experienced at least one grade 1 or
above adverse event (AE), only one child (4.8%) had a grade 1 adverse event possibly
related to darunavir.
Darunavir/ritonavir is approved for
children and adolescents with HIV aged three to under 18, either for
weight-based dosing of darunavir oral suspension with ritonavir liquid, or for
weight-based dosing of darunavir tablets with ritonavir capsules or tablets.
Dosing is also adjusted to twice-daily dosing if one or more primary darunavir-associated
resistance mutations is present.
Findings from the initial
24-week analysis were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections
(CROI) in 2011. Fifty-seven per cent had viral loads under 50 copies/ml at week 24 with a
safety profile comparable to adults. These results compare to a 75% virologic
success rate (under 50 copies/ml at 24 weeks) among 6-12 year olds and 39%
among those aged 12 to 18 years. This led to the approval of DRV/r for
treatment-experienced children aged three to six weighing at least 10kg.
The trial comprised children aged
three to six years, weighing 10 to under 20kg who were failing
their current antiretroviral regimens (viral load over 1000 copies/ml), had fewer
than three DRV resistance-associated mutations (RAM) at screening and had been
on ART for at least 12 weeks.
Participants were given
darunavir oral suspension (100mg/ml) initially dosed at 20mg per kg plus 3mg
of ritonavir per kg twice a day with an investigator-selected optimised background regimen (more than
two active nucleoside reverse transcriptase inhibitors).
After a pharmacokinetic
analysis at week two and following Data Safety Monitoring Board recommendations,
the dose used in this study was increased to darunavir 25mg per kg combined
with 3mg ritonavir per kg for children under 15kg given twice daily. Children
weighing from 15 to under 20kg received darunavir/ritonavir 375/50mg per kg twice
This analysis comprised 21
children, of whom just under half were male, with a median age of 4.4 years at
screening, a baseline mean log10 viral load of 4.34 copies/ml and
median CD4 cell count of 927 cells/mm3 (IQR:209-2429) and median CD4
percentage of 27.7% (IQR: 15,6-51.1).
Eighty per cent of children did not have
any significant protease inhibitor (PI) RAMs. Fifty per cent had non-nucleoside reverse
transcriptase (NNRTI) mutations. The majority (70-80%) had nucleoside
resistance, predominantly in the form of the lamivudine-associated M184V
antiretrovirals included lopinavir/r (76%), lamivudine (100%), stavudine (57%)
and nevirapine (48%).
Ninety per cent (19) of children had two
nucleoside reverse transcriptase inhibitors (NRTIs) in the optimised background regimen (OBR), while 10% (2)
had three. These included: 62% (13) lamivudine, 62% (13) zidovudine, 38% (8)
abacavir, 38% (8) stavudine, 5% (1) didanosine and 5% (1) tenofovir disoproxil
The most common AEs were
upper respiratory tract infections, diarrhoea, tinea capitis and cough. Two
children had grade 4 AEs, stenosing tenosynovitis and asthmatic crisis, while
serious they were not treatment-related.
Only one child stopped
treatment (at week 24) because of grade 2 vomiting believed to be due to
With the exception of one
grade 3 laboratory abnormality (neutropenia), present at baseline and not considered
treatment related, all others were grade 1. There were no lipid abnormalities
above a grade 1.
At baseline, mean age-adjusted
z-scores for child growth were below normal population values. At week 48, the
mean increase from baseline was 5cm in height, 1.7kg in weight and 0.1kg/m2
in body mass index
By week 48, virologic response
(under 50 copies/ml) was high increasing from 12 (57.1%) at week 24 to 17
(81%); the mean (standard error SE) increase in CD4 cell count at week 48 was 187
(76,7) cells/mm3 from a mean increase of 109 at week 24.
While it took longer for a
significant proportion to reach viral suppression (under 50 copies/ml), Dr
Violari noted it is important to recognise that using viral suppression below
400 copies/ml as a cut off, over 80% of the participants had a good response at
By week 48 over 90% had 1 log10
or more drop in viral load.
Two children with baseline
DRV RAMs (L33F/L+L76V  and L76V ) had viral load under 50 copies/ml at
weeks 24 and 48.
Of the three children (14.3%)
with virologic failure, two never suppressed viral load and one experienced
viral rebound. Of these, neither of the two children with paired baseline/endpoint
genotypes developed PI or NRTI RAMs.
Dr Violari concluded
treatment-experienced children three to six years of age receiving darunavir/ritonavir with an OBR had a high rate of virologic response and favourable
safety profile at 48 weeks. No development of resistance was seen in those
experiencing virologic failure.