The 8th International AIDS Society Conference on HIV
Pathogenesis, Treatment and Prevention (IAS 2015)
heard today of a case where a young woman, who was infected with HIV at birth and received
very early antiretroviral therapy as a child, has stayed off therapy since
the age of six with a viral load well below the detectability limit of
standard tests. Such 'post-treatment controllers' are models for the 'functional cure' which is one of the goals of treatment research.
Dr Asier Sáez-Cirión of the Institut Pasteur in Paris, who
also presented the results to the HIV Cure Symposium the previous day, said
that this was the first case of really prolonged remission seen in a person infected around the time of birth and who remains undetectable off therapy. (One previous case, the
so-called “Mississippi
Baby”, developed a detectable viral load again after a period of two years
and three months off therapy) .
In 2014 the VISCONTI
study found 14 adults who had taken early treatment and had then maintained
undetectable viral loads (eight of them without a single ‘blip’) when they
subsequently came off therapy. At that point the maximum length of time seen of
prolonged virological remission was 9.5 years, so the current patient has been
off therapy and undetectable at least as long as any of the VISCONTI patients.
Dr Sáez-Cirión said the current case added to the evidence
that in certain cases very early treatment of HIV infection could lead to the
person developing a kind of immune response that was able to control HIV in the absence of treatment.
The French ANRS (Agence Nationale de Recherche sur le SIDA),
the national HIV research organisation, has a database of over 10,000 mothers
with HIV and from 1989 onwards has seen the birth of 579 children who acquired
HIV from their mothers. Of these, 200 started treatment early, when less than
six months of age, and of these, just 15 have stopped antiretroviral therapy while their viral
load was below 500 copies/ml, with an average length of time on therapy before
interruption of just under three years.
In all but 2 of these 15 cases, the viral load ‘rebounded’
within a year of treatment interruption. In one case, the child maintained an
undetectable viral load for over three years. In the other case, the child, who
is now a young woman aged 18.5 years, remains virally undetectable to this day.
As was remarked in the original Visconti study, the fact that
two post-treatment controllers were found in only 15 children born with HIV may
imply that post-treatment control is not uncommon – or would not be if more of
them stopped antiretroviral therapy.
The young woman was born in 1996 to a mother whose only
treatment was monotherapy with the now-unused HIV drug zalcitabine (ddC) since
13 weeks of gestation. At the time of delivery the mother had a very high viral
load of 4.63 million copies/ml and was severely immune-compromised with a CD4
count of only 81 cells/mm3 and a CD4/CD8 ratio of
only 0.16.
Because of the mother’s high viral load, the baby was given
prophylactic zidovudine (AZT) and there were no signs of infection two weeks
after birth, but four weeks after birth she tested positive for HIV RNA. The
AZT was stopped six weeks after birth and the baby also developed a high viral
load of 2.17 million copies/ml. Because of this she started antiretroviral therapy when aged
three months with a therapy regimen that would now be unconventional but which was
indicated for children at the time – zidovudine, didanosine, lamivudine (AZT,
ddI, 3TC) and full-dose ritonavir.
At the age of five years and eight months, the child went abroad with
her mother and they were lost to follow-up. When they returned a year later the
girl had an undetectable viral load despite having her treatment stopped a few
months earlier. They had at least one more short-term treatment interruption
during this time too.
Since that time she has had two detectable viral load
measurements. One, at the age of twelve, was to 510 copies/ml and was probably
a real ‘blip’ or transient burst of viral production. The other at the age of
14 was only to 48 copies/ml (the detectability limit of the standard viral load
test used with her was 20 copies/ml) and was probably a laboratory
false-positive. Her actual viral load as determined by ultrasensitive assays
was below four copies/ml in 2014 and below seven copies/ml in 2015.
Her integrated viral
load – the amount of HIV DNA she has integrated into the genome of her immune
system cells, is 2.1 to 2.5 copies per million T-cells, which is quite low but
not exceptionally so. The HIV, in short, has not disappeared from her system:
instead, her immune system must be controlling it in some way. This is the
situation cure researchers term a ‘functional cure’.
In children CD4
percentage is used as a more reliable guide to immune function than CD4
count. This went down to below 20%, indicative of immune deficiency, between
the ages of two and four but has since then risen and now stands at about 40%,
which is within the normal range for an HIV-negative person.
Her immune responses are still being investigated but so far
two things stand out. Firstly, her so-called haplotype – the genetic variation
that predicts how susceptible one’s immune cells are to HIV infection – is a
normal one and not one of the types that is linked to lower viral loads and
slower progression.
The other is that her CD8 cells are particularly unresponsive to HIV, generating much
lower levels of immune-messenger chemicals like interferon-gamma and IL-2 when
stimulated by HIV antigens. Similarly, when her CD4 cells were stimulated with
immune activators, although some are infected with HIV, very little was actually
produced.
This lack of reaction to HIV antigens and gene activators is a
characteristic seen in other post-treatment controllers and is the opposite
reaction to that seen in so-called elite controllers, who maintain an
undetectable viral load post-infection without ever having had treatment.
Elite controllers tend to have haplotypes associated with low
viral loads and slow progression, but combine them with CD8 cells that are
particularly alert to HIV and efficient at destroying HIV-infected cells. Their
HIV, when it is produced, is therefore wiped out by efficient immune
surveillance. This has its drawbacks: over time, elite controllers have high
rates of cardiovascular disease and other conditions characteristic of inflammatory
states.
Post-treatment controllers, on the other hand, tend to have haplotypes
that are associated with high viral loads and fast disease progression, and tend
to have had primary HIV infection characterised by high viral loads.
Post-treatment, however, their immune response is characterised by a lack
of CD8+ cell responses to HIV. This implies a lack of activated
T-cells – which means a lack of cells producing HIV.
This challenges standard models of how to control HIV but does
provide possible insights into approaches to a cure that aims to dampen down
anti-HIV activity and therefore stop re-activation of the ‘reservoir’ of
HIV-infected cells. But exactly what combination of events prompts people into
becoming post-treatment controllers remains a mystery.