Is a functional cure for HIV feasible within the foreseeable future or
is it a hopeless quest robbing resources from more practical approaches to
improve the lives of people living with HIV? This question was the crux of a
mock trial held yesterday on the opening day of the 14th European
AIDS Conference in Brussels.
The debate was part of a satellite session sponsored by Bristol-Myers
Squibb (BMS) to mark the launch of its
new Partnering for Cure initiative, which will support education and
research into novel treatment and cure
strategies for chronic viral diseases including HIV
and hepatitis B and C.
Christine Katlama of Pierre and Marie Curie University in Paris,
playing the 'judge', noted the recent increase in attention to the possibility
of an HIV cure at scientific meetings and in the popular media, spurred in part
by 'proof-of-concept' cases like that of Timothy Ray Brown (the 'Berlin patient') and that of the Mississippi baby.
Speaking in defence of the proposition that an HIV cure is possible,
Carlo Federico Perno of the University
of Rome gave the example
of hepatitis C as a virus that can be eradicated.
Whilst traditional interferon-based therapy relied on stimulating the
immune response, new direct-acting agents work by interfering with various
steps of the hepatitis C virus (HCV) lifecycle, much like combination
antiretroviral therapy (ART) for HIV. Two highly effective and well-tolerated
compounds – Janssen's simeprevir and Gilead Sciences' sofosbuvir – are
scheduled for US
approval by the end of the year (assuming the federal government shutdown does
not disrupt the work of the Food and Drug Administration).
The inclusion of this argument was no doubt intended as an opportunity
to educate about hepatitis C, which is increasingly making its way into HIV
conferences. Many people with HIV have hepatitis C co-infection, and HIV clinicians
are increasingly called upon to treat it. BMS has some promising
hepatitis C direct-acting agents in the pipeline including the NS5A
the HCV protease inhibitor asunaprevir and the non-nucleoside polymerase
But no one, including Perno, really thinks hepatitis is a good model for
an HIV cure.
HCV remains confined to a cell's cytoplasm, where it must either
"replicate or die", Perno explained. If it does not do so
immediately, HCV RNA is rapidly degraded; drugs that fully halt replication can
therefore offer a permanent cure. Perhaps the main scientific barrier to
hepatitis C treatment is that the virus is highly variable – much more so than
HIV – which means different drugs work best against different HCV genotypes
and combination therapy is needed to prevent resistance.
HIV, in contrast, enters host cell chromosomes where it may remain
latent for decades and perhaps even a lifetime. Speaking for the 'prosecution',
Alcamí of the European University of Madrid
said that viral latency, existence of viral reservoirs and destruction of the
immune system by the virus are the three main barriers to a cure.
in resting CD4 T-cells can awaken when these cells become activated as part of
an immune response, leading to renewed viral replication, he explained. For
this reason people with HIV must remain on ART – as far as we know for life –
to guard against viral rebound.
researchers are testing several different strategies to reverse latency and
flush the virus out of hiding. The so-called 'shock and kill' approach involves
using agents such as HDAC inhibitors to awaken latent virus coupled with
immune-boosting therapies to kill infected cells. But current anti-latency
drugs trigger only weak viral reactivation and target only a small proportion
of the viral reservoir.
addition to long-lived memory T-cells, the HIV reservoir also includes
anatomical sites such as the lymph nodes, gut lymphoid tissue and central
nervous system. HIV preferentially targets CD4 cells – the "brain of the
immune system" – and persistent immune activation caused by the virus leads
to immune senescence and eventual exhaustion of immune function, Alcamí said.
"I would like to give good news, but we face a virus we are not
able to cure with drugs we have available or even drugs we may have in the future,"
he concluded. "The
destruction of the immune system remains a barrier to a cure."
Returning to the 'defence', Giuseppe Pantaleo of Centre Hospitalier
Universitaire Vaudois in Lausanne
countered that we should not feel too depressed as "there is a lot to be
Pantaleo outlined the important proof-of-concept cases, previously
reported on aidsmap.com, that indicate that a cure is possible at least in
principle. These include the Berlin patient who was cured after a bone marrow stem cell transplant for leukaemia,
baby who shows no evidence of remaining virus after starting ART within a
day after birth; two
Boston stem cell transplant patients with sustained viral suppression after
antiretroviral interruption; and the French
VISCONTI cohort of individuals who appear HIV-free after ART
initiation during acute infection.
Pantaleo argued that continuing residual viral replication despite ART
is "probably responsible" for replenishment of latent reservoirs and
better antiretroviral drugs that fully suppress replication may offer hope for
a functional cure. Data on this point are mixed, however, and some researchers
think that at least current classes of antiretrovirals already provide maximum
Summing up, Pantaleo noted that only 25% of people with HIV in the US have
achieved undetectable viral load on ART and that even excellent current therapy
remains "very hard to take" especially over the long term.
A combination of strategies will be the secret of an HIV cure, he
concluded. "We're just at the beginning," he said. "A functional
cure is possible if there is the right investment in these new approaches."
Perno added that there is "clear evidence that persistent virus is
harmful." Even if 'undetectable', the virus is not absent in the body and
even a few copies may be detrimental, for example by maintaining a state of
persistent immune activation. "In the long term we will pay a price or
this," he cautioned.
But the effectiveness of modern antiretroviral treatment was the gist of
Georg Behrens argument against pursuing a cure. Behrens, of Hannover Medical
School, explained that
current ART is so good that attempts to cure HIV are not worth the risk. Donor
stem cell transplants, for example, can be fatal and are only appropriate for
people with life-threatening conditions such as leukaemia or lymphoma.
Furthermore, better antiretrovirals are in the works including agents
that target HIV attachment and maturation, the "very ends of the
replication cycle." Treatment dramatically extends survival of people with
HIV and the relatively small percentage who do not do well on current ART –
due to co-morbidities or adherence problems, for example – are "not the
best candidates" for risky cure approaches.
Behrens concluded that research should focus on improving ART for the
broad population of people with HIV, not on curing a few exceptional patients.
"We should ask not only is a cure possible, but what is the real benefit
for patients," he said. "We may be able to fly to the moon, but that doesn't solve our problems with
traffic here [on earth]."
After hearing the arguments on both sides the audience 'jury' rendered
its verdict. Among the more than 100 participants,
opinion was nearly evenly divided as to whether a cure for HIV is an achievable
and worthwhile goal.
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