In people with chronic HIV, then, we have only
achieved cures in a few people where high-risk, complex measures are ethically
possible. This year, however, a number of cases of apparent cure or long-term
remission from HIV turned up in people subject to a more benign technique – antiretroviral
In the first report, the talk of the Conference on
Retroviruses and Opportunistic Infections (CROI) in Atlanta in March 2013, US
researchers identified a case of a functional cure in a baby girl infected with
HIV (the ‘Mississippi baby’), who began ART within two days of birth.3
The child has now been off treatment for 18 months, and although HIV DNA
(genetic material) has been detected at very low levels in her cells, she has
no detectable viral RNA in her blood and her virus is not reproducing – the
definition of a functional cure.
The apparent suppression of the girl’s HIV to levels
below which it could start replicating – either because there was no fully functional
HIV DNA left, or because her own immune system was controlling any remnants –
was initially greeted with some scepticism. Was the HIV truly an infection, or residual
maternal virus? Would HIV eventually reappear? There was nervousness about the
claim of researcher Deborah Persaud that “This is our Timothy Brown moment”. Even
if this was not an isolated case and could be repeated, few people get the
chance to start ART within days of infection.
However, a study published soon after CROI confirmed
not only that long-term off-treatment remission of HIV was possible, it might
even be quite common – and that ART did not necessarily have to be started
within the first day or two. French researchers4 found 14 (now 26) adult patients from a group called the VISCONTI cohort
who also started ART soon after infection, subsequently stopped it, and had not
had to re-start because they had largely – and in eight cases completely –
maintained undetectable viral loads for four to ten years after stopping
Furthermore, the researchers suggested that the only
reason such cases are not more common is simply because, once having started
ART, few people stop. They claimed that 15% (later revised downwards to 5 to 10%)
of people with HIV, if ART was started within six months of HIV infection and
maintained for at least a year, could subsequently become so-called ’post-treatment
Their estimate is a stark contrast to findings from studies conducted between 1996 and 2000, soon after the introduction of highly active ART, which found no
evidence that people who began treatment in primary infection soon after
acquiring HIV could control HIV after stopping treatment. The key difference is
that earlier studies looked at HIV control in people who had only received
treatment for 12 to 18 months. The French patients had been on treatment for an
average of three years before stopping, and all started treatment within ten
weeks of infection, compared to within six months in previous studies.
A further study, presented at the IAS conference, came
up with another patient – a 67-year-old German man - who had started ART within
—three months of infection and stayed on it for five years, but who stopped his
HIV therapy in 2004 and, apart from a small initial viral ‘rebound’, has not
had a detectable viral load result since.5
This patient’s CD4 and CD8 cells had strong anti-HIV
responses, meaning his immune system was actively preventing viral replication.
This is also characteristic of ‘elite controllers’, people who maintain
undetectable viral loads without therapy and, essentially, generate their own
long-term remission from active HIV.
Being an elite controller might not be good for you.
Another presentation at the IAS cure symposium found that HIV responses in
elite controllers were characterised by increased activation of virus-fighting
proteins such as interferon alpha which, as anyone who has taken it as hepatitis
C treatment knows, creates symptoms of its own.6 Another found high
levels of a second immunomodulator with known harmful effects called galectin
9.7 Elite controllers don’t just experience physical malaise: it had
already been shown that they have higher levels of cardiovascular disease than
average, similar to other people with HIV not on ART.8
The VISCONTI researchers found that the viral control
seen in their patients (and the Mississippi
baby) had almost an opposite explanation from that seen in the majority of
elite controllers, whose immune cells tended to be rather unresponsive to HIV.
Infection spread slowly through the body, which allowed the immune system time
to recognise HIV and mount a vigilant response to it.
In contrast, the VISCONTI patients’ immune cells were
unusually sensitive to HIV infection
and their acute HIV infection period was characterised by high viral load. HIV
invaded so fast, it gave their immune systems no time to react. Normally, this
would result in the body being ‘seeded’ with a large reservoir of HIV-infected
CD4 cells that would start pumping out virus as soon as viral suppression with
ART was removed.
The theory goes that, if ART is started quickly enough
and maintained for long enough, the viral reservoir remains small. In normal
HIV infection, even in people on ART, residual HIV - burning away like a pilot
light - remains; as soon as ART is removed it ‘lights the fire’ again,
stimulating cells into producing a new burst of HIV.
In the VISCONTI patients, on the other hand, there was
so little HIV around that, when ART was taken away, the immune system – which,
remember, had never been given time to ‘recognise’ HIV – simply acted as if it
was not there at all.
At the IAS cure symposium, Persaud mentioned
unpublished data showing that a number of the other children she has studied
might be in the same position as the Mississippi
baby – but after a decade on ART, rather than 18 months. In some cases, HIV DNA
that was still detectable when the children were six or seven years old could
no longer be found at twice that age.
This presents an ethical dilemma. The Mississippi baby case
was only identified because the girl’s mother stopped coming for appointments
when her daughter was 18 months old, reappearing six months later. Similarly,
the VISCONTI patients had taken themselves off ART voluntarily, often in
structured treatment-interruption studies. Other people who have come off
therapy in the past, however, have experienced disastrous crashes in their CD4
counts; at the very least, a viral ‘rebound’ upon stopping treatment will
replenish the reservoir of persistently infected cells.
So how do we decide who to take off therapy? What is
the threshold for judging that a person is a potential viral controller? Are
HIV DNA counts the best guide? Or is the disappearance of HIV antibodies, as happened
for Timothy Brown and the Mississippi
baby but not for all the VISCONTI patients, a better guide?