Transcript The Quest for a Cure - HIV Research Catalyst Forum

The Quest for a Cure
Matt Sharp Project Inform/ATAC
Tim Horn aidsmeds.com/ATAC
Overview
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Treatment vs. Cure
Sterilizing Cure
Functional Cure
Preventive Vaccines
Treatment as Prevention
Funding
Advocacy
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Treatment vs. Cure
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Why A Cure?
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Chronic and manageable disease?
HIV drugs, though essential for life in
the absence of a cure, take a
potentially lethal toll on the bodies of
people with HIV, precipitating
problems ranging from liver cancer to
heart attacks
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More and more people will be taking
antiretroviral medications as treatment
guidelines shift and treatment-forprevention programs begin rolling out
Treatment fatigue will become a
growing concern as well as cumulative
toxicities
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Antiretroviral drugs work well for most
people but…
– Some have discordant or inadequate
responses for a variety of known and
unknown reasons
– There are some people who have run out
of treatment options despite the number
of approved medications
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Antiretrovirals are only available to
40% of people who need them around
the world
Providing antiretroviral therapy for
every person with HIV/AIDS, for the
rest of their lives, is financially and
logistically problematic
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The ultimate goal for research on any
disease is a cure but…
– HIV cure research continues to face many
challenges and complexities
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A cure would save federal dollars
– The US currently spends $11 billion
annually on caring for people with AIDS
in the US, and in 2008 spent $6 billion on
its successful US global AIDS program
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Would also allow some of the one
million people living with HIV in the US
to return to work and paying taxes
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Different Possible “Cures”
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Sterilizing cure: eliminating all HIV from the
body
Functional cure: permanent viral
suppression without therapy
Preventive vaccines
Treatment as prevention: universal,
widespread use of treatment to radically
reduce risk of HIV transmission
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Sterilizing Cure
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The Hope
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1995: David Ho and others suggest HIV
eradication with early use of drug
combinations, much like approach used to
cure diseases like TB and leukemia
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One and a half to three years of treatment
necessary to kill off two HIV compartments:
– Free HIV and actively infected CD4s
– chronically infected cells (macrophages and dendritic
cells)
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The Reality
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1997: Three teams discover third
compartment
– Resting, latently infected CD4 memory Tcells potentially lasting a lifetime
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Ongoing viral replication
– Intensifying treatment further reduces VL
– Chronic inflammation
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What’s causing this?
– Incomplete viral suppression?
– Intermittent production by stable cells?
– Anatomical reservoirs (brain, gut, etc.)
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Treatment Intensification
Older Approaches
 Ziagen (abacavir)
 Protease inhibitor
 NNRTI
Newer Approaches
 Maraviroc
 Selzentry
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Purging the Reservoir
Older Approaches
 IL-2
 IL-2 and interferon-g
 OKT3 and IL-2
Newer Approaches
 IL-7
 HDAC inhibition
– Valproic acid
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Prostratin
HMBA
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D. D. Richman et al., Science 323, 1304 -1307 (2009)
Therapeutic Vaccines
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Activate transcription of proviral DNA in the
presence of ARV treatment
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Gene Therapy
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Berlin bone marrow transplant case
Anti-HIV ribozymes
Antisense
siRNA
Zinc-finger nucleases
TRIM5a
Note: Myleoablative conditioning
likely required
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Is HIV eradication practical?
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With advances in HIV therapy, is
striving for HIV eradication in more
than a few specific cases worth the
drastic interventions likely to be
required to accomplish this?
Are there simpler approaches?
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Functional Cure
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Learning from LTNPs
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Lessons from long-term
nonprogressors and elite controllers
– Elite controllers: <1% of PLWHIV
– 50% have strong HIV-specific CD8 cells
– Other possibilities: NK cells, low CCR5
expression, skewed HLA-C expression,
low immunoregulatory response
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Early HIV Treatment
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ARV therapy started during acute and
early HIV infection
– Can it protect immune function?
– Does it result in lower viral load “set
point?”
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Therapeutic Vaccines
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Training the immune system to better
respond to HIV in the absence of ARV
treatment
– An effective preventive vaccine could
potentially work as a therapeutic vaccine,
and vice versa
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Older Approaches
 Whole inactive virus
Newer Approaches
 Prime-boost (GeoVax)
– Remune
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Virus-derived gp160
Cell-derived gp160
Canarypox-based
– HIV DNA primer
– MVA (smallpox) booster
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Vacc-4x (Bionor Immuno)
– ALVAC 1452
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STIs
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Encouraging initial results
– Berlin Patient
– Small studies
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Discouraging follow-up results
– Danger in MDR HIV
– No proven benefit
– SMART study
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Future of STIs
– In combination with immune-based
therapies?
– Will these be allowed by FDA?
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Preventive Vaccines
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The Big Picture
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By inoculating populations HIV would be
stopped
Humoral vs cellular responses
Several vaccine candidates have failed
STEP Merck trial interrupted and discontinued
RV 144 adenoviral candidate showed 31%
efficacy-trials are ongoing
Huge, expensive trials with large cohorts and
complicated science
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Treatment as Prevention
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Can universal testing and treatment
snuff out HIV?
TLC+ framework
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Funding
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National Institutes for Health is the
largest funder of AIDS research in the
world yet is underfunded
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Budget of the NIH has essentially been
flat funded since 2003, and in constant
dollars lost 13.4% of its annual
spending power by 2009 due to
biomedical inflation
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President Obama’s 2011 proposed budget
would add only 3% to the overall NIH
budget, a continued decline in spending
power
Due to the current economic crisis,
President Obama dedicated $10 billion in
Stimulus Package funds to NIH research,
and about 1/10 of this was designated to
NIAID (National Institute of Allergy and
Infectious Diseases).
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NIAID announced that a portion of
these funds would be used for basic
research into viral persistence—HIV
eradication
Fauci has put cure research as one of
the top of the NIAID research agenda
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Advocacy
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Cure Mobilization
– education
– misinformation
– complex information
– new
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Bogus cures
More research dollars
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IBT Strategy Group
Michael Palm Basic Science, Vaccines
& Prevention Project Weblog
Project Inform
www.projectinform.org
HIV Policy Project
www.aidspolicyproject.org
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