“We are at the earliest dawn of a new stage of HIV therapy”
said Carl Dieffenbach, director of the Division of AIDS at the US National Institute of Allergy and Infectious
Disease (NIAID), speaking at the Towards an HIV Cure workshop on the opening
day of the 7th International AIDS
Society conference (IAS 2013) in Kuala Lumpur, Malaysia.
HIV researchers need to start thinking about research into a
potential cure for HIV infection as the next stage in the refinement of
antiretroviral therapy, he said, and to recognise that research efforts are now
in the early stages of identifying the most suitable targets for multi-target
combination therapy to eradicate HIV – or at least to control it for life
without medication.
“The reservoir of latently infected cells is the first
target [to be identified], in the same way that reverse transcriptase was the
first target for antiretroviral therapy drug development,” said Dieffenbach.
But he stressed that whereas HIV drug development had
proceeded against a series of unique viral processes that had no overlap with
human cellular processes, the task of HIV eradication necessarily requires much
greater knowledge of the complex cellular processes that maintain HIV latency
in cells – and a better understanding of the knock-on effects of intervening in
these processes to wake up the virus and kick it out of cells.
“The Mississippi baby case shows just how fast this field
can evolve." Carl Dieffenbach
Dieffenbach encouraged researchers to think about other
processes involved in the maintenance of HIV persistence and replication in the
body as parallel targets that may need to be attacked in combination. These
include activation of the resting CD4 cells that contain latently integrated
HIV DNA, so that the cells can be identified by the immune system and killed.
Cure research will also require the development of even more efficient forms of
antiretroviral therapy, in order to control HIV in all cellular compartments
after activation, as well as therapies to control HIV replication and perturb
latency that can penetrate into protected anatomical sites such as the brain.
He also reminded the
audience that new discoveries relating to HIV cure and remission could make
demands on the entire HIV field for rapid adjustment in the standard of care,
citing the
example of an HIV-infected infant in the United States treated within 30 hours
of delivery who was declared to be functionally cured earlier this year
after stopping treatment without viral rebound at the age of 18 months.
“The Mississippi baby case shows just how fast this field
can evolve – it’s now about getting those infants onto treatment, not within 6
weeks [as currently recommended] but within 30 hours,” he said. Earlier
identification of HIV-infected infants through rapid HIV DNA testing within
hours of delivery could create the potential for functional cure, or 'remission', in many more infants if health systems can adjust to the speed of
diagnosis and treatment initiation that is likely to be needed to deliver this
result in much larger numbers of infants worldwide.
HIV cure research will also demand new thinking from
pharmaceutical companies and regulators. For example, advice from the US Food
and Drug Administration (FDA) for companies planning trials of multiple promising
agents in combination only refers to pharmaceutical agents. The incorporation
of biologics such as therapeutic vaccines are not covered in these
recommendations, said Guenter Kraus of Tibotec/Janssen, and needs to be
addressed if promising combinations are to be moved forward rapidly in the
future.
Pharmaceutical companies may need to work together from the
very early stages in order to identify promising combinations of compounds and
to share data for independent analysis, he said. “We may need new business
models and research platforms to reach this very complex goal,” Kraus concluded,
citing the example of the Drugs for Neglected Diseases Initiative (DNDI) as an
example of the form of collaborative venture that may be appropriate for HIV
cure research.
Research efforts must not rush ahead of the need to prove
that interventions are safe however. “We shouldn’t get too far ahead of
ourselves here. We’re talking about people who can control HIV on one pill once
a day and one disaster in phase 1 could set this field back 20 years. The
priority is proving that it’s safe and not harming people,” said Lynda Dee of
AIDS Action Baltimore.
Discussions at the meeting also revealed unease from some in
the HIV community sector over the dangers of describing lifelong control of HIV
without viral eradication as a cure. Gus Cairns, editor of NAM’s HIV treatment update newsletter, urged researchers at the workshop to encourage more
realistic expectations by describing cases of post-treatment HIV control in the
terminology used in cancer treatment – 'remission' – or in hepatitis C treatment
– sustained virologic response – if eradication of HIV cannot be confirmed.