One in eight children and
adolescents receiving HIV treatment at major HIV clinics in Europe experienced
failure of three classes of antiretroviral drugs after five years of treatment,
highlighting the need for formulations of new antiretroviral drugs to be
developed that are suitable for children, European researchers report in The Lancet.
Triple-class failure implies
that a child has experienced the failure of at least two antiretroviral
regimens, one containing a non-nucleoside reverse transcriptase inhibitor
combined with a nucleoside analogue, and one containing a protease inhibitor
combined with a nucleoside analogue. It also implies a degree of cross-resistance to other drugs in the same class.
Children were twice as likely as adults with HIV in Europe to experience failure of their first antiretroviral regimen.
The PLATO II investigators
for the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) reported a retrospective cohort study of
1007 children, among whom over one-third (33%) had started a third drug class
after a median of 4.2 years (of which 105 (44% or 10% overall) were on a
About 25% of those who
developed triple-class virological failure had never achieved viral suppression
(a viral load measurement under 500 copies/ml).
The longer the children were
on ART the greater the risk of triple-class virological failure: after five
years the risk was 12% (95% CI: 9.4-14.6).
Approximately 2 million
children are living with HIV, the majority infected through perinatal
transmission. An estimated 700 children die every day because of AIDS-related
causes. Without treatment an estimated 50% will die before they reach the age
Antiretroviral therapy has
dramatically improved the prognosis for HIV-infected children. Children have
responded well to protease inhibitors (PIs) and non-nucleoside reverse
transcriptase inhibitors (NNRTIs). Guidelines now recommend starting treatment
as soon as possible after HIV diagnosis.
Results from adults treated,
in both resource-poor and resource-rich settings, with all three classes of
antiretrovirals (PIs, NNRTIs and nucleoside reverse transcriptase inhibitors
(NRTIs) suggest that long-term viral suppression is possible and virological
failure happens slowly. It is unclear whether the same is true for children who
will need to maintain viral suppression the longest.
The major challenge in
treating children is to minimise virological failure and the development of
drug resistance so that children will continue to have treatment options
throughout adolescence and adulthood.
Alexandra Calmy and Nathan
Ford from Médecins Sans Frontières in an accompanying Comment stress the
potential difficulties for children, notably in resource-poor settings where
90% of HIV-infected children live: limited availability of current and
effective treatment regimens, unclear strategies for the best drug sequencing
as well as difficulties in maintaining good adherence from infancy to
adulthood, all of which may contribute to drug resistance and virological
The authors looked at the
rate and predictors of triple-class virological failure to the three original
drug classes in children.
From 1998 to 2008, in COHERE, the rate of triple-class failure was analysed in children under 16 years
of age infected perinatally who started antiretroviral therapy with three or more
drugs. 1007 children from 14 COHERE cohorts were identified with over 90% from
the UK and Ireland, Spain,
Holland and France.
Incidence of triple-class
virological failure increased over time, reaching close to 20% after eight
years. The authors note that the rate
of triple-class failure was steepest in the first two years after
having started ART, after which it continued
to rise, but more gradually.
Older age (10-15) when
starting ART was associated with an increased risk of failure.
Calmy and Ford suggest these
findings be understood in context. Close to a quarter of the children had started
ART in 2000 when less effective regimens were in use and standardised treatment
However, Calmy and Ford note
the findings give cause for concern.
The overall virological
failure rate is comparatively low. Nonetheless when the analysis is limited to
children exposed to boosted PIs the cumulative proportion of failure is twice
that of adults in the same cohort collaboration, 8.2% (95% CI: 5.1-11.2)
compared to 4.2% (95% CI: 3.8-4.6) HR
2.2 (95% CI: 1.6-3.0, p<0.0001).
This raises the critical
issue of treatment durability. Calmy and Ford add that no matter what the age
the goal is to achieve and maintain sustained virological suppression. The fact
that a significant number of children experiencing virological failure had
never achieved virological suppression is disturbing, they add.
Reasons include: the
complexities around adherence, particularly in very young children who depend
on caregivers; very limited and often poorly adapted treatment options.
In young children and
adolescents the authors note overlapping social issues: stigma, secrecy and
guilt, disclosure as well as sexual development all contribute to poor
adherence. Few studies, they add, have looked at these issues.
While they welcome the World
Health Organization’s (WHO) efforts to issue user-friendly dosing tablets, Calmy
and Ford express concern “that paediatric antiretrovirals are not currently a
part of WHO’s work on priority medicines for maternal and child health.”
Calmy and Ford stress the
urgency of developing new fixed-drug formulations for children. The absence of
clinical data on the use of specific drugs in children hinders the process.
Calling upon researchers and
drug developers to “prioritise the pursuit of paediatric indications for
antiretroviral drugs” they note, “…children [notably in resource-poor settings]
receive a lower standard of care than do adults.”
They conclude “The fact that
the Drugs for Neglected Diseases Initiative…has recently included paediatric
HIV/AIDS in its portfolio is telling: paediatric HIV/AIDS is a neglected