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Dolutegravir safe and highly effective in older children
Carole Leach-Lemens, 2016-02-25 13:40:00
Dolutegravir (DTG) plus optimised
background regimen (OBR) is safe, well tolerated and provides virologic
efficacy in HIV-infected children from six to 12 years of age at 48 weeks, Andrew
Wiznia presenting on behalf of the IMPAACT1093 study group told participants at
the Conference on Retroviruses and Opportunistic Infections (CROI 2016) on Wednesday
Close to 80% (18 out of 23)
of the children achieved virologic success defined as HIV RNA under 400
copies/ml, (95% CI: 56.3 to 92.5%), with 17 of the 23 (73.9%) having a viral
load under 50 copies/ml, (95% CI: 51.5 to 89.8%).
Dolutegravir (DTG), an
integrase inhibitor, is approved for treatment-naïve and experienced adults and
adolescents 12 years of age and above. Found to have a high barrier to the
development of drug resistance, it is an important option for adults and in
particular adolescents and children who have failed treatment with other
antiretrovirals, most notably in resource-poor settings.
There are 2.6 million children who are in
need of ART. Almost half are currently on a sub-optimal regimen.
Young children do respond
well to antiretroviral therapy with high rates of virological suppression on
first-line treatment. However, acquired drug resistance among young children
after failure on a first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)
based regimen is extremely high. Suppression may be achieved with a second line
protease-inhibitor (PI) (lopinavir/ritonavir) based regimen. However, while
drug resistance mutations are limited among young children failing a first-line
PI based regimen the potential for re-suppression when switching to an NNRTI is
For children failing first-
or second-line PI-based treatment in resource-poor settings alternatives are
lacking. The need to improve second- and third-line options is critical. Despite
efforts, development of new drugs and appropriate formulations continues to be
Integrase inhibitors may play
an important role for children failing a first-line PI-based regimen. Dolutegravir
is of particular interest. It is well tolerated, taken once a day and has a
higher barrier to resistance than raltegravir. Determining the best sequencing
of this class of drugs and improving their availability in resource-poor
settings is key. Integral to this will be substantive price reduction and/or
generic production. ViiV Healthcare agreed licences in 2014 with the Medicines
Patent Pool that will allow generic production of dolutegravir for adults and
children in lower-and middle-income countries.
IMPAACT 1093 is an ongoing
phase 1/11 multi-centre open-label pharmacokinetic (PK), safety and efficacy
study of DTG plus OBR in children and adolescents in age-defined cohorts.
treatment-experienced integrase-naïve children ≥ six to < 12 years of age on
a failing antiretroviral regimen (with a viral load of or over 1000 copies/ml)
were enrolled into Stage 1, an intensive PK evaluation performed between days
five and ten. The children received DTG tablets (10, 25, 50 mg) at 1mg/kg once a
day, based on defined weight bands, which were added to a stable failing
regimen with an OBR added after the intensive PK or in Stage 2 where children
received dolutegravir with an OBR at study entry.
The primary objective was to
evaluate safety, tolerability, CD4 cell count and viral load at week 48. Based
on the Food and Drug Administration (FDA) logarithm virologic success was
defined as a viral load under 400 copies/ml with a secondary outcome of viral
load under 50 copies/ml.
Twenty-three children were enrolled: 11
at Stage 1 and 12 at Stage 2. Of these, 21 (91.3%) completed the 48-week study
The median age of the children
was 10 years (IQR: 8-11) with a median weight of 30 kg (IQR: 18-54). The
majority were male and African American, 70% (16) and 52% (12), respectively.
Caucasians accounted for 17% (4) and Hispanics 26% (6). Median time on prior
ART was 9.3 years (IQR: 6.4-10.4) with close to half triple-class experienced.
Median baseline CD4 cell
count and percentage were 645 cells/mm3 (IQR: 466-732) and 24%
(IQR: 14.3% to 28.7%), respectively. Median viral load at baseline was 5.0 log10
copies/mL (IQR: 4.5-5.5).
In accordance with paediatric
weight band dosage at 1mg/kg, one child (weight > 40kg) received 70 mg, five
children (weight > 40kg) received 50 mg, six (weight 30-40kg) 35 mg and eight
(weight 20-30 kg) 25 mg dolutegravir and three (weight 15-20 kg) 20mg once
The preliminary 24-week study
results presented in 2014 at CROI (poster 118) showed adequate PK safety and
Median CD4 cell count and
percentage gain at week 48 were 387 cells/mm3 (IQR: 49-575) and 9%
(IQR: 7-14), respectively.
Dolutegravir was well
tolerated. There were no Grade 4 adverse events, serious adverse events or
discontinuation due to adverse events.
Three participants had
Two children went off study,
one due to virological failure and the other lost to follow-up.
DTG with an optimised
background regimen had a favourable safety profile in HIV-infected children
aged six to 12 years; excellent and sustained virologic efficacy with
significant improvement in CD4 cell counts and percentages.
The study is continuing with
evaluation of dolutegravir down to four weeks of age.
The future direction is
weight-band dosing so avoiding an age-staggered approach that leads to the
delay in approval for the youngest, a discussion highlighted. The study, Dr.
Wiznia explained, inherited a structure of regulatory requirements involving
age cohorts. The World Health Organization later issued recommendations for
paediatric treatment using weight-band dosing. While switching patient
populations in the middle of the study was not feasible, another version of the
study is to be released in a month or so with another preparation of DTG as a
dispersible 5mg tablet.