If there is a dark cloud on the horizon, it is that these children will
require effective antiretroviral therapy for life — and careful monitoring and
support to make sure that it remains effective.
While the prospect of sustaining lifetime antiretroviral treatment is
daunting enough in adults who may have access to only first-line and
second-line treatment, the prospect is even more challenging in children, who
may experience failure of first-line treatment due to very high viral load,
adherence problems or sub-optimal drug concentrations.
For young children, the options for second-line treatment are limited
due to the lack of suitable formulations for children, and third-line treatment
is even more difficult – and expensive – to piece together. Drug resistance
that develops after the failure of first-line treatment critically restricts
later options and further complicates the assembly of an effective second or
third-line combination..
So issues of adherence, drug resistance, virological monitoring and drug
access are particularly acute in this group of patients.
But monitoring for treatment failure, whether in adults or children in
resource limited settings, is difficult because “current immunological
definitions of immunological failure are poor at detecting viral rebound,” said
Dr Mary-Ann Davies, who presented data on the use of different immunological
criteria to monitor children receiving ART in the South African International Epidemiologic Databases to
Evaluate AIDS (IeDEA) paediatric sites.5
The study included 2513 children below the age of sixteen, whose viral load had
been completely suppressed during the first year on treatment.
These children
were then monitored with CD4 cell count and viral load measurements every six
months to determine sensitivity, specificity, positive and negative predictive
values (PPV) and (NPV) of WHO and US definitions of immunological failure for
identifying virological rebound in a child on ART for at least 18 months.
After following the children out until 3.5 years of ART, the WHO
definition was found to have a very low sensitivity although PPV was better
(42%); the sensitivity was higher for the US definition (though still low), and
the PPV was very low (20%).
To make these definitions work better, Dr Davies said that one could get
another CD4 count to confirm failure, which would increase PPV, but decrease sensitivity.
Furthermore, she noted that this simply isn’t done in practice in South Africa
when viral load is available. So the researchers also looked to see whether the
sensitivity and positive predictive value could be improved by combining the
most sensitive immunological criteria with a single HIV-RNA measurement to
define failure (a targeted viral load strategy). This approach increased the
PPV for both the WHO and US criteria considerably, but the diagnostic accuracy
was still sub-optimal.
Methods for determining immunological failure
WHO 2010
|
USA
|
CD4% <10 (2 – 4 yrs)
|
Sustained decline of CD4% by 5 percentage points
(any age)
|
CD4 absolute <200
(2 – 4 yrs)
|
CD4 absolute <100 (≥ 5 yrs)
|
Return of CD4 count to ≤ baseline value (≥5 yrs at
baseline) |
Essentially, immunological failure and virological failure seem even
less likely to correspond in children than adults. It is important to point out
however, as Dr Davies noted, that her study was merely an algorithm applied
retrospectively to the data set, which had no clinical data on the
participants. So it wasn’t possible to exclude the possibility that low CD4
cell counts may have been due to a clinical cause such as tuberculosis.
Nevertheless, the researchers concluded that better access is needed to viral
load monitoring in order to accurately diagnose treatment failure in children —
otherwise, virological failure may simply go unnoticed.
Unfortunately, this would present some of the same challenges as it does
in adults, where studies have shown that routine viral loads do not appear to
improve patient management and are not cost-effective — at least not during the
first few years when treatment works well in most people.
In the Kheth’Impilo study, the proportion of children achieving
virological suppression after six months was fairly high, at 83% (95% CI:
80-85.1) and 79.7% (95% CI 76.6-82.6%) after twelve months on ART. The study
did note however, that children aged over two years when they went onto
treatment had significantly better virological suppression 81.8% (95% CI:
80.2-83.3%) compared to 72% (95% CI 67.4-77.7%, p<0.0005) in children aged
under two years of age at any time-point on treatment. However, other cohorts
in similar settings, perhaps where children and their caregivers receive less
support, have described higher rates of virological failure. For instance, one
recent report described 38% of children on ART for more than a year experienced
virological failure, and the authors’ remarked that the “correlation
between virologic failure and immunologic decline was nearly absent.”6
Treatment failure could reflect the inadequacy of antiretroviral
formulations for infants and small children — and/or the difficulty young
mothers may have making sure that their infants get the doses they need (see
more on adherence below). But it also means that a significant proportion of
the children will need to switch to second-line therapy at a fairly young age.
Over time the number of children failing first and then second-line treatment
can only be expected to increase.
But the available treatment options for switching are even more limited
in children than adults in most resource-limited settings. Consequently,
there
are questions about how best to manage treatment failure. One approach could be
to keep them on virologically failing failing treatment regimens as long as their CD4
cell count and/or clinical response is good. The danger, of course, is that
over time on a failing regimen, they will develop drug-resistant virus that
will be less likely to respond to subsequent ART regimens as they become
available. Children who became infected in utero or despite PPTCT may already
be at a disadvantage due to exposure to antiretrovirals that could have led to
resistance.
Drug resistance
increasing in children
Indeed, drug resistance is emerging in children on ART in South Africa.
One study described a large number of resistance mutations found in
thirteen children at Kalafong Hospital in Pretoria, who were started on a
protease inhibitor-based regimen when they were younger than 36 months of age
(mean age 22.4 months), some of whom had already been switched to a second line
NNRTI regimen.7 The
mean duration of treatment at testing was 45.9 months. “All these children were
deemed to be at high risk as they suffered co-morbid conditions and had
documented poor adherence,” according to the poster’s authors. Three of the
children had WHO Stage 3 disease, and ten had WHO stage 4 disease; while 62% of
their caregivers reported poor adherence, and 54% had a history of missed
clinic appointments. Only one had ever achieved an undetectable viral load.
Resistance testing found that all of these children had virus resistant
to nucleoside analogues (the 3TC-related M184V mutation being the most common),
five had major protease inhibitor resistance mutations, and nine had resistance to mutations to
non-nucleoside analogue reverse transcriptase inhibitors (NNRTI, i.e. efavirenz
or nevirapine) — only one of these had been exposed to nevirapine as PPTCT.
A second poster presentation found drug resistance was more common in paediatric
than adult patients experiencing virological failure on their second line
protease inhibitor-based regimen at Tshwane
Academic Hospital
(Pretoria).8
All patients had been started on d4T/3TC with either nevirapine or efavirenz,
and they were all switched to either AZT/ddI/ or a variation (AZT/abacavir)
with ritonavir-boosted lopinavir (Kaletra
/ Aluvia).
About half of the failing adult patients showed no evidence of
resistance at all, suggesting that they simply were not taking their treatment,
but the virus from 91% of the children (30 out of 33) of the paediatric
patients failing treatment had resistance mutations. In these children, virus
in seven out of 33 (21%) had major PI mutations, five had more than three PI
mutations, and 27.3% still showed evidence of the K103 mutation conferring
resistance to NNRTIs (note, the mutation would probably have been detected in
more children if they were still taking nevirapine or efavirenz). Finally,
75.8% of the children had virus that was resistant to 3TC, and 18.2 % had
multiple thymidine analogue mutations (TAMs) that significantly decrease the
chances of responding to subsequent nucleoside analogues.
Notably, some of these children had only moderate levels of viral load
which — in the presence of less than universal resistance to the PIs —
suggested that they may have been taking their treatment, but that adherence was
suboptimal.
Nevertheless, the authors concluded that children exhibited increased
levels of resistance to all three drug classes, perhaps because of higher
levels of viral replication that typically occur in children or perhaps
because some of them had previous exposure to unboosted PI therapy (ritonavir
monotherapy).
Dr Theresa Rossouw of the University
of Pretoria, who was the
lead author of the latter poster, also gave an oral presentation describing
findings from the Southern African Treatment and Resistance Network (SATuRN),
which is monitoring emerging patterns of drug resistance in the region.9
She described higher rates of resistance among 49 children in SATuRN (though it
is not clear to what extent these patients overlap) with PI resistance being
documented in almost one third of the patients and three or more PI resistance
mutations in 20.4%. NNRTI Resistance was seen in 21/49 (42.86%). Resistance to
the nucleoside analogues was detected in 41/49 (83.67%), with eleven out of 49
(22.45%) with TAMS, and eight out of 49 (16.28%) with three or more TAMs. She noted several other South African cohorts
have also documented high levels of resistance among children failing
treatment.10, 11, 12, 13
Resistance, and limited treatment options will make it more difficult
for these children to live with HIV into adolescence, when other challenges to
treatment success seem to emerge.