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Commentary: When to start and what to use in

children recommendations and rationale


George Siberrya and Denis Tindyebwab
AIDS 2014, 28 (Suppl 2):S133S135

The 2013 WHO consolidated guidelines recommend


treating all HIV-infected children under the age of 5 years
regardless of CD4 T-cell count or WHO clinical stage,
and treating children aged 5 years and older according to
the same criteria as for adults: WHO clinical stage 3 or 4
or CD4 T-cell count of 500 cells/ml or less [1].
Guideline recommendations for what drugs to use for
initial antiretroviral therapy (ART) vary by age group: less
than 3 years, 310 years and above 10 years.
Table 1 summarizes the criteria for when to start ART in
HIV-infected children; a review of supporting evidence
for these recommendations has been published [2]. The
CHER study [3] provides evidence for treating all
children less than 12 months of age (infants), and
therefore for this age group, the recommendation was
categorized as strong with moderate quality of evidence.
But for children aged 1 to less than 5 years, evidence to
support this recommendation is lacking. The recommendation to treat all children less than 5 years of age
regardless of WHO clinical stage or CD4 T-cell count
was largely driven by programmatic reasons: to scale up
paediatric ART in light of low coverage compared with
adult ART, to simplify treatment especially with limited
access to CD4 T-cell count tests and to improve
retention, as many programmes were reporting poor
follow up of children on pre-ART care. It remains to be
seen whether indeed this recommendation will indeed
increase paediatric ART uptake and retention.
The evidence informing the choice of initial ART
regimens for children under age 3 years and children at
least age 3 years (including adolescents) has been
summarized in systematic reviews [4,5]. The WHO
recommendations for first-line ART in children and
adolescents are summarized in Table 2.
In general, WHO recommends that all children under age
3 years receive a lopinavir/r-based ART regimen;
nevirapine-based ART is recommended only if use of
lopinavir/r is not feasible. The preferred dual nucleoside

reverse transcriptase inhibitor (NRTI) backbone in firstline ART for children under age 3 years is abacavir or
zidovudine in combination with lamivudine; tenofovir
disoproxil fumarate is a recommended NRTI option for
children age 3 to less than 10 years and is the preferred
NRTI for adolescents (ages 1019 years). When secondline therapy is required because of first-line treatment
failure, children who were receiving an NNRTI-based
initial ART regimen should switch nevirapine to
lopinavir/r, continue lamivudine and switch their other
NRTI (abacavir or tenofovir disoproxil fumarate to
zidovudine, zidovudine to abacavir, or, if 2 years old,
zidovudine to tenofovir disoproxil fumarate). Children at
least 3 years old who are failing a lopinavir/r-based initial
ART regimen should receive efavirenz in place of
lopinavir/r, continue lamivudine and switch their other
NRTI (abacavir or tenofovir disoproxil fumarate to
zidovudine, zidovudine to tenofovir disoproxil fumarate
or abacavir). For children less than 3 years old failing a
lopinavir/r-based initial ART regimen, no change in
regimen is recommended unless there is advanced clinical
disease progression or lack of adherence specifically
because of poor palatability of lopinavir/r; in such cases,
an nevirapine-based ART regimen should be considered.
The WHO recommendations emphasize the choice of
lopinavir/r over nevirapine in first-line therapy for
children less than 3 years old, based on randomized
clinical trials that demonstrated superior efficacy of
lopinavir/r, both for infants with and without prior
nevirapine exposure through regimens used for prevention of mother-to-child transmission (PMTCT) [6,7].
The preference for protease inhibitor based initial ART in
this age group is unique, as NNRTI-based therapy is
recommended by WHO as first-line for all other
populations, including older children (3 years old).
However, liquid lopinavir/r presents major logistic
barriers to widespread use, including high cost, coldchain requirement and poor palatability. As a result, the
WHO recommendations advise initiation of a nevirapine-based ART regimen for this age group if lopinavir/r

Maternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland, USA, and bANECCA, Kampala, Uganda.
Correspondence to George K Siberry, MD, MPH Maternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, National Institutes of Health 6100 Executive Boulevard,
Room 4B11H Bethesda, MD 20892-7510, USA.
Tel: +301 496 7350; fax: +301 496 8678; e-mail: siberryg@mail.nih.gov
DOI:10.1097/QAD.0000000000000241

ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

S133

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S134

AIDS

2014, Vol 28 (Suppl 2)

Table 1. Summary of recommendations on when to start antiretroviral therapy in children in the 2013 WHO consolidated guidelines [1].
Age group

Recommendation

All ages

WHO Stage 3 or 4 regardless of CD4 T-cell count

Strong recommendation, moderate quality of evidence

Initiate ART in a child younger than 18 months with


presumptive clinical diagnosis of HIV infection

Strong recommendation, low quality of evidence

<5 years

Initiate ART in all regardless of WHO clinical stage


or CD4 T-cell count

Infants in first year of life strong recommendation,


moderate quality of evidence
1 to <5 years conditional recommendation,
very low quality of evidence

5 years and older

Initiate ART in all with CD4 T-cell count


500 cells/ml

CD4 T-cell count 350 cells/ml strong recommendation,


moderate quality of evidence
CD4 T-cell count between 350 and 500 cells/ml conditional
recommendation, very low quality of evidence

is not available or feasible, as deferring ART completely


would be expected to carry a higher risk of morbidity and
mortality in this age group than initiating therapy with a
regimen that has a somewhat higher risk of virologic
failure. As these guidelines were being finalized, efavirenz
was licensed for infants and young children (3 months
old), but further evaluation will be required in order to
determine whether this drug will assume a role in initial
therapy of children less than 3 years old in the future, as
there remain concerns regarding the pharmacokinetics
and appropriate dosing of efavirenz in young children [8].
Studies underway to evaluate raltegravir and other drugs
in infants and young children offer hope for new and
improved options for initial therapy in the future.
The WHO recommendations include another strategy
to address the difficulties of continued use of lopinavir/
r-based ART in young children. On the basis of the results
of the NEVEREST study [9], the WHO guidelines

Strength of recommendation and quality of evidence

provide an option for substituting an NNRTI for


lopinavir/r in those infants and young children who have
achieved sustained virologic suppression (plasma viral load
<400 copies/ml). This strategy may also preserve protease
inhibitor activity for patients who develop treatment
failure and NNRTI drug resistance later. This approach
depends upon the availability of virologic monitoring,
which may limit the extent of its use.
Tuberculosis remains a major problem for children
with HIV infection, and interactions between antituberculosis and antiretroviral drugs are an even greater
problem for young children who cannot use efavirenz.
On the basis of results of the ARROW trial that
demonstrated high efficacy of triple NRTI therapy
(zidovudine abacavir lamivudine) in maintaining virologic suppression in children who achieved virologic
suppression on a full NNRTI-based ART regimen [10],
there is a new recommendation to use this triple NRTI

Table 2. Summary of recommended ART regimens in the 2013 WHO guidelines [1].
Recommendation

Strength of recommendation/quality of evidence

A lopinavir/ritonavir (lopinavir/r)-based regimen should be used as first-line ART


for all HIV-infected children younger than 3 years (36 months) of age,
regardless of NNRTI exposure. If lopinavir/r is not feasible, treatment
should be initiated with an nevirapine-based regimen

Strong recommendation, moderate-quality evidence

Where viral load monitoring is available, consideration can be given to substituting


lopinavir/r with an NNRTI after virological suppression is sustained

Conditional recommendation, low-quality evidence

In HIV-infected infants and children younger than 3 years of age, abacavir


lamivudine zidovudine is recommended as an option for children who
develop tuberculosis while on an ART regimen containing nevirapine or
lopinavir/r. Once tuberculosis therapy has been completed, this regimen
should be stopped and the original regimen should be restarted

Strong recommendation, moderate-quality evidence

For HIV-infected infants and children younger than 3 years of age, the NRTI
backbone for an ART regimen should be abacavir or zidovudine lamivudine

Strong recommendation, low-quality evidence

For HIV-infected infants and children 3 years and older (including adolescents),
efavirenz is the preferred NNRTI for first-line treatment and nevirapine is the
alternative

Strong recommendation, low-quality evidence

For adolescents infected with HIV (10 to 19 years old) weighing 35 kg or more,
the NRTI backbone for an ART regimen should align with that of adults and be one
of the following, in preferential order: tenofovir disoproxil fumarate lamivudine
(or emtricitabine); zidovudine lamivudine; abacavir lamivudine

Strong recommendation, low-quality evidence

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When to start and what to use in children Siberry and Tindyebwa

strategy temporarily for the duration of tuberculosis


therapy and then resume the original, standard ART
regimen once tuberculosis therapy has been completed.
Other options include optimizing the nevirapine dose,
substituting nevirapine for lopinavir/r or super-boosting
lopinavir/r with additional ritonavir. All of these
approaches have drawbacks, however, and evaluation of
efavirenz and other drug options (e.g. raltegravir) in
children less than 3 years old who are receiving
tuberculosis therapy are warranted. For children more
than 3 years old who develop tuberculosis while on an
ART regimen, no change is required for those already
receiving efavirenz-based regimens and changing
nevirapine or lopinavir/r to efavirenz is a recommended
option, provided there is no history of NNRTI treatment
failure.
The choice of preferred NRTI backbone for children is
limited by those drugs that are available in appropriate
formulations and that have data available for at least safety
and pharmacokinetics to allow appropriate dosing, and
ideally for efficacy as well. Although there is a stated
preference for abacavir over zidovudine based on the
general principle of using nonthymidine analogues (such
as abacavir) in first-line regimens and thymidine
analogues (such as zidovudine) in second-line regimens,
both of these drugs, together with lamivudine, are firstline recommended NRTI backbones for children under
age 3 years. Tenofovir disoproxil fumarate is part of
WHO-recommended first-line regimens for adolescents,
pregnant women and nonpregnant adults and is included
in NRTI options for first-line ART regimens in children
ages 3 to more than 10 years, but there are no safety or
pharmacokinetic data for use of tenofovir disoproxil
fumarate in children under age 2 years and very limited
information about its use in children 23 years old,
though it is licensed for children at least 2 years old. A dual
NRTI backbone of tenofovir disoproxil fumarate in
combination with lamivudine (or emtricitabine) is
generally recommended for people with hepatitis B
(HBV)-HIV coinfection, but for young children with
HBV coinfection, the optimal ART regimen is not
known. Although d4T has been strongly discouraged for
first-line regimen options for adolescents and adults based
on toxicity concerns, it remains an option in first-line
ART for children less than 3 years old in special
circumstances. The currently limited availability of
abacavir, inability to use zidovudine in children with
severe anaemia and lack of other NRTI options mean that
these special circumstances are relatively common.
Recommended second-line ART regimens are also
constrained by limited drug options available for children
under age 3 years. Because resistance is almost uniform
when NNRTI-based regimens fail, lopinavir/r replaces
nevirapine or efavirenz in cases of ART failure. For most
children less than 3 years old who fail first-line lopinavir/

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r-based ART, however, the WHO no longer recommends a change in therapy, because protease inhibitor
resistance takes much longer to accumulate, nevirapine
has relatively poor performance in this age group and no
other options currently exist.
The 2013 WHO guidelines affirm that ART interruption is not recommended for children in this age
group. The guidelines also include a new section
outlining considerations for simplifying and harmonizing ART regimens in children who have no prior
history or current evidence of treatment failure. A
transition to simpler and better tolerated regimens as
children grow older and new drug options become
available will be increasingly commonplace in many
programmes.

Acknowledgements
Conflicts of interest
There are no conflicts of interest.

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