The Expert Committee recommended the addition of dolutegravir 50 mg tablets
to the core list of the EMLc for treatment of HIV infection in paediatric patients
weighing 25 kg or more, in combination with an optimized NRTI backbone
regimen, in line with recommendations in current WHO guidelines.
The Committee acknowledged the important need to expand HIV
treatment options for children. The Committee noted the available evidence for
use of dolutegravir in children was largely limited to pharmacokinetic and safety
data from two ongoing paediatric trials, but considered that extrapolation of
efficacy from adult trials was acceptable.
The application requested the addition of dolutegravir to the core list of the EMLc for treatment of HIV infection in paediatric patients weighing 25kg or more.
Dolutegravir was added to the core list of the EML in 2017 for treatment of adult patients.
Public health relevance
There are now 1.8 million children living with HIV, the vast majority in sub-
Saharan Africa. Evidence shows that in the absence of ART, over 50% of HIV-infected
infants progress to AIDS or death by the age of 2 years (1), but the
introduction of paediatric ART has changed HIV infection in children from a
life-threatening illness to a chronic but manageable infection. Despite recognition
of the advantages of early treatment, paediatric treatment coverage still only
reaches 52% of children eligible for treatment (estimated 940 000) and in 2017
an estimated 110 000 HIV/AIDS-related deaths occurred in children <15 years
of age (2).
Although there is limited clinical experience globally with use of
dolutegravir (DTG) in children, it is recommended in this population based
on extrapolation of efficacy from the larger, and more diverse adult studies
(3). Regulatory and normative bodies including the WHO (and its paediatric
working groups) and the US FDA have accepted the concept of extrapolation of
efficacy of ARVs in paediatric patients based on bridging pharmacokinetic (PK)
data and supporting safety information. Thus, the most recent WHO treatment
guidelines for paediatric use of DTG are based primarily on aligning PK data
collected in children receiving DTG in clinical trials to adult PK targets.
Dolutegravir has been shown to be effective in diverse adult patient populations
enrolled in multiple clinical trials conducted internationally. The results of
these adult clinical trials were reviewed in the dossier submitted to support
inclusion of dolutegravir 50 mg as first-line ART in the EML in 2017 and are not
The paediatric data published to date comprises two ongoing clinical
trials and several observational cohort reports. The trials on which WHO
treatment and dosing recommendations are based include the IMPAACT P1093
study, sponsored by the U.S. National Institutes of Health, and the ODYSSEY
study, sponsored by the Paediatric European Network for Treatment of AIDS-ID.
PK and safety data from these trials have been reported and reviewed as new
weight band cohorts have been completed. Both trials are evaluating paediatric
patients as young as 4 weeks of age using a dispersible tablet, but data for the
younger/smaller patients are not available at this time.
IMPAACT P1093 is an ongoing single-arm, open-label trial of DTG in
children with HIV. FDA approval of DTG for use in children weighing as low
as 40 kg was based on data from 23 treatment-experienced, integrase strand
transfer inhibitor (INSTI)-naive adolescents (4). Intensive PK evaluations were
performed on the first 10 participants, nine of whom weighed ≥40 kg and
received dolutegravir 50 mg and one of whom weighed 37 kg and received DTG
35 mg. These doses resulted in exposures comparable to those seen in adults
receiving 50 mg once daily. At 48 weeks, 61% of participants had achieved HIV
RNA concentration <50 copies/mL. By week 144, 39% and 30% of participants
had achieved HIV RNA concentrations <400 copies/mL and <50 copies/mL,
respectively. All who experienced virologic failure were reported to be nonadherent.
A younger cohort of children aged ≥6 to <12 years were also enrolled
in IMPAACT P1093, with those weighing ≥30 kg to <40 kg receiving the 35 mg
dose and those weighing ≥40 kg receiving the 50 mg dose. At 48 weeks, data
from 23 participants demonstrated a favourable safety profile, adequate PK and
virologic efficacy, with HIV RNA concentrations of <50 copies/mL achieved in
74% of participants. These data led to FDA approval of the lower strength filmcoated
tablets (10 mg plus 25 mg) for children with HIV weighing at least 30 kg.
Using similar data, the European Medicines Agency (EMA) approved
the lower strength film-coated tablets for children aged ≥6 years and weighing
≥15 kg based on population PK modelling and simulation analyses (5). The
EMA approved doses of 20 mg for children weighing 15 kg to <20 kg and 25 mg
doses for those weighing 20 kg to <30 kg. Because the available PK data in
these weight bands were very limited and the observed trough concentrations
(Ctrough) were lower than expected, the FDA did not approve dosing for children
weighing <30 kg.
The ODYSSEY trial is enrolling both treatment-naive and -experienced
paediatric patients in the EU, Thailand and several African countries, and initially
evaluated the EMA-approved doses for children weight > 15kg. A total of 674
children <18 years of age were enrolled; 282 starting dolutegravir as first-line
therapy and 392 starting second-line therapy (6). Nested pharmacokinetic substudies
within ODYSSEY are evaluating simplified paediatric dosing aligned with
WHO-recommended weight bands. PK data have been reported from a cohort
of children >25 kg switching to the 50 mg adult tablet (n=27). These children
receiving the 50 mg film-coated tablet achieved exposures similar to those of
adults. When given to children 14 to <25 kg, the DTG 25 mg film-coated tablet
resulted in lower exposure than the adult target exposure, particularly Ctrough.
The lower Ctrough was more marked in the 20 to <25 kg group. Higher doses are
currently under study in these weight bands and doses have been adjusted for
lower weight bands (7, 8).
After careful review and discussion, the WHO-convened Paediatric
Antiretroviral Working Group endorsed the simplified dosing using the
dolutegravir 50 mg tablet in children weighing >25kg.
In the adult clinical studies to date, dolutegravir-based regimens were
either non-inferior or superior in efficacy to comparator regimens containing
other integrase inhibitors, boosted protease inhibitors and NNRTIs, regardless of
patient population. In patients initiating first-line treatment, successful virologic
suppression occurred in more patients receiving DTG than the comparators.
There are no comparative paediatric trials available but both the WHO working
groups and multiple regulatory agencies (including the U.S. FDA and the EMA)
endorse the concept of extrapolating efficacy from well-designed, adequatelypowered
adult trials on the basis of similar pharmacokinetic profile and
supplemental safety data.
A French, retrospective, multicentre cohort study evaluated 50 adolescents who
initiated dolutegravir-based ART. In this cohort, only one patient discontinued
DTG-based treatment because of a significant adverse effects (dizziness and sleep
disturbance) (9). Another cohort of adolescents reported from Barcelona received
the fixed-dose combination product Triumeq (abacavir 600 mg/dolutegravir
50 mg/lamivudine 300 mg). No serious safety concerns were reported, however,
patients complained about the size of the tablet and six reported having to crush
or split the tablet in order to swallow it, potentially contributing to adherence
In the original clinical trials, patients on dolutegravir experienced
significantly fewer incidences of nervous system disorders and psychiatric
disorders than those receiving efavirenz, however, there have been postmarketing
reports of neuropsychiatric events (such as insomnia or depression)
among adults receiving DTG-based treatment since its approval. Causality for
these events has been difficult to determine as many patients are reported to
have a previous history of psychiatric symptoms.
In a surveillance study of birth outcomes among pregnant women
on ART in Botswana, an increased rate of neural tube defects was observed
among infants born to women who were receiving dolutegravir at the time of
conception (11). As children and young adolescents mature, and before they
become sexually active, paediatric and adolescent providers should discuss this
potential risk with patients who are receiving or initiating dolutegravir and their
caregivers. The WHO 2018 interim guidelines (3) note the following in their
guidance on this topic:
– Dolutegravir appears to be safe when started later in pregnancy:
after the period of risk of neural tube defects and after the first
– Adolescent girls and women of childbearing potential who do not
currently want to become pregnant can receive DTG together with
consistent and reliable contraception; hormonal contraception
and DTG have no reported or expected drug–drug interactions
although data are limited.
Cost / cost effectiveness
The indicative average price per patient per year (PPPY) for dolutegravir 50 mg
tablets is approximately US$ 50 for children weighing between 25 and 35 kg.
This price is lower than PPPY for other ARVs suitable for children.
In November 2015, the Clinton Health Access Initiative (CHAI),
UNAIDS, and Unitaid announced a pricing agreement for DTG 50 mg single
tablets that had been brokered with Aurobindo Pharma (12). Under the
agreement, Aurobindo agreed to make generic DTG 50 mg tablets available at a
price of US$ 44.00 PPPY (or US$ 3.67 per pack).
The WHO-recommended dose of DTG in integrase inhibitor treatment naive
adults and paediatric patients weighing more than 25 kg is one tablet (50 mg)
once daily (3). Dolutegravir should be given together with two NRTIs appropriate
for paediatric patients (i.e. abacavir plus lamivudine or zidovudine plus
lamivudine). In addition, the WHO 2018 interim guidelines also recommend
that DTG in combination with an optimized NRTI backbone is the preferred
second-line regimen for children with approved DTG dosing for whom non-
DTG-based regimens are failing.
Dolutegravir 50 mg tablets are manufactured by multiple pharmaceutical
companies, including generic and WHO prequalified manufacturers.
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status and baseline characteristics. Abstract 34. 10th International Working on HIV Pediatrics.
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on film-coated dolutegravir 25mg tablets in the ODYSSEY trial. Abstract 22. 10th International
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Therapy & Infectious Diseases 2018;8:27.
8. Turkova A, Bollen P, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A et al. Steady-state
pharmacokinetics and early safety data in HIV-infected African children weighing ≥25kg after
switching to 50mg film-coated dolutegravir tablets in the ODYSSEY trial. Abstract 3. 10th
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lamivudine works in adolescents, but size matters. J Antimicrob Chemother. 2017;72(10):2958–60.
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12. Three new agreements announced with the potential to expand access to innovative HIV
treatment in low- and middle-income countries [Press Release]. Harare/Geneva: UNAIDS; 2015.
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