Determining which of the evolving
technologies to detect exposure and diagnose HIV infection in infants has been complicated
by changes in the prevention and treatment of HIV in infants, however, Dr
Some of these complications could be a
matter of life and death.
need for an earlier early-infant
The profound reduction in infant mortality seen
in the CHER study may have largely been due to when ART was initiated — at
around seven weeks of age in the immediate treatment arms of that study. Dr
Sherman pointed out that judging from the death records in South Africa, there
is a peak of early infant mortality at around 8 to 12 weeks of age.
“If we test at 6 weeks of age, in general
children get results by 10 weeks of age and are hardly ever initiated on ART
before 12 weeks of age — a little bit
late” she said.
But it may be possible to do better.
Although a meta-analysis performed in 1995 found that if infants were tested at
birth, only 38% of early infections (in-utero and intra-partum infections)
would be detected, and if tested 28 days after birth, 96% of all infections could
be detected —these data were drawn from studies using early PCR technology and came
from a time when most women weren’t even receiving any ARVs to prevent HIV
transmission to the infant. Now there are new more sensitive PCR assays, and
prophylaxis consists of multiple ARVs for much longer periods of time.
There are few published data on how the
newer EID assays perform before six weeks of age – but Dr Sherman shared some
of NHLS’s unpublished data showing how the CAP/CTM and Aptima assay performed on samples from birth and later.
838 mother-infant pairs were enrolled into
a programme at a Johannesburg delivery unit. Of those, an HIV status was
established in 710 (667 were HIV-negative). 43 infants were infected (five were
only detected late after six months of age), but there were 29 in-utero
infections, defined by a positive PCR at birth, and nine intra-partum
infections, as defined by a negative PCR at birth and a positive PCR by six
weeks of age. Later however, when this routine programme tested infants at six
weeks of age, it only managed to detect 26
infected infants. So even though testing at birth would have missed the
intra-partum infections, it would have detected more infections.
“This means, with the new assays – and this
is true for both of these assays that are more sensitive – we could detect 76%
of ALL early infections at birth,” she said. “We also need to consider that
these in-utero infected infants may well be those that are the rapid progressors,
and need to initiate ART earlier. Added to that, if we had identified them at
birth, we could have spared them the daily dose nevirapine which would have
almost certainly made them resistant!”
need to prevent nevirapine resistance in HIV-infected children
Indeed, this is a potential downside of the
current WHO guidelines to prevent HIV-transmission to infants exposed by
breastfeeding — while daily nevirapine for the duration of breastfeeding protects
exposed uninfected infants, it poses a serious risk of resistance for any
HIV-infected child taking it. Although studies seem to suggest that exposure to
sdNVP may not totally eliminate the benefit of a subsequent nevirapine-based
regimen, daily dosing of nevirapine monotherapy almost certainly would lead to
significant drug resistance in children who are already infected — and leave ART
programmes with little option to use more expensive Kaletra-based regimens (which also requires cold storage).
potential reduction in EID accuracy associated with new regimens to prevent
Exclusive breastfeeding is now the
preferred infant feeding option, so programmes also need to ensure that
algorithms can identify any children that are infected post-natally and that
testing continues until there is no further risk of post-natal transmission. What
is less appreciated however is that prophylactic regimens, such as daily dosed
nevirapine, may also affect the accuracy
of tests used for EID.
“There is evidence emerging now that
multi-drug infant and maternal prophylaxis does delay a diagnosis, and
certainly reduces viral loads — but what about infant daily dose nevirapine? No
data,” said Dr Sherman.
In the Johannesburg cohort, Dr Sherman described
above, the infants and mothers had taken maternal AZT and sdNVP, and as already
noted, 29 were infected at birth using the sensitive CAP CTM and Aptima assays. However, when Sherman and her colleagues
tested 18 infants with blood samples available at two weeks, four infants had
become negative… and then became positive again at 4 weeks.
“This was probably number one, a nevirapine
effect, and probably because we detected their viral loads at very low levels
at birth because we were using very sensitive assays, but if this is what a
single dose of nevirapine at birth does, it’s highly possible – or probable –
that daily-dose nevirapine is going to extend the time that it takes to detect
intra-partum infection. In other words, it will delay detecting that infection beyond
six weeks of age.
More data needs to be collected to
determine the best revision of a testing algorithm, but Dr Sherman believes
that it may be better to perform testing at birth — possibly with point-of-care
tests — which would give healthcare workers a better chance of retaining
HIV-infected infants in care. For intra-partum infection and post-partum
infections, screening should perhaps come a bit later.
This may sound alarming to some programme
“Whenever I say this to our Department of Health,
they see two PCR tests now – not one,” said Dr Sherman. “So to try and reduce
the number of PCR tests that we would require… we could possibly use rapid
tests to try and show seroreversion in some children and reduce the number of
PCR tests that would be required. The rapid tests would have to be evaluated on
infants in the field to know which rapid tests to use when looking for exposure,
and which to use for seroreversion and minimize the number of infected infants
that we miss.”
Finally, she concluded that the
implementation of the whole PMCTC programme – including EID – needs to be
improved “and to that end, the laboratory information system data is going to
be very useful.”