The Quest for a Cure
Matt Sharp Project Inform/ATAC
Tim Horn aidsmeds.com/ATAC
Overview







Treatment vs. Cure
Sterilizing Cure
Functional Cure
Preventive Vaccines
Treatment as Prevention
Funding
Advocacy
2
Treatment vs. Cure
3
Why A Cure?


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
4


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
5

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
6


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
7

The ultimate goal for research on any
disease is a cure but…
– HIV cure research continues to face many
challenges and complexities
8

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

Would also allow some of the one
million people living with HIV in the US
to return to work and paying taxes
9
Different Possible “Cures”




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
10
Sterilizing Cure
11
The Hope

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

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)
12
The Reality

1997: Three teams discover third
compartment
– Resting, latently infected CD4 memory Tcells potentially lasting a lifetime
13

Ongoing viral replication
– Intensifying treatment further reduces VL
– Chronic inflammation

What’s causing this?
– Incomplete viral suppression?
– Intermittent production by stable cells?
– Anatomical reservoirs (brain, gut, etc.)
14
Treatment Intensification
Older Approaches
 Ziagen (abacavir)
 Protease inhibitor
 NNRTI
Newer Approaches
 Maraviroc
 Selzentry
15
Purging the Reservoir
Older Approaches
 IL-2
 IL-2 and interferon-g
 OKT3 and IL-2
Newer Approaches
 IL-7
 HDAC inhibition
– Valproic acid


Prostratin
HMBA
16
17
D. D. Richman et al., Science 323, 1304 -1307 (2009)
Therapeutic Vaccines

Activate transcription of proviral DNA in the
presence of ARV treatment
18
Gene Therapy







Berlin bone marrow transplant case
Anti-HIV ribozymes
Antisense
siRNA
Zinc-finger nucleases
TRIM5a
Note: Myleoablative conditioning
likely required
19
Is HIV eradication practical?


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?
20
Functional Cure
21
Learning from LTNPs

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
22
Early HIV Treatment

ARV therapy started during acute and
early HIV infection
– Can it protect immune function?
– Does it result in lower viral load “set
point?”
23
Therapeutic Vaccines

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
24
Older Approaches
 Whole inactive virus
Newer Approaches
 Prime-boost (GeoVax)
– Remune



Virus-derived gp160
Cell-derived gp160
Canarypox-based
– HIV DNA primer
– MVA (smallpox) booster

Vacc-4x (Bionor Immuno)
– ALVAC 1452
25
STIs

Encouraging initial results
– Berlin Patient
– Small studies

Discouraging follow-up results
– Danger in MDR HIV
– No proven benefit
– SMART study
26

Future of STIs
– In combination with immune-based
therapies?
– Will these be allowed by FDA?
27
Preventive Vaccines
28
The Big Picture






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
29
Treatment as Prevention
30


Can universal testing and treatment
snuff out HIV?
TLC+ framework
31
Funding
32

National Institutes for Health is the
largest funder of AIDS research in the
world yet is underfunded
33

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
34


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).
35


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
36
Advocacy
37

Cure Mobilization
– education
– misinformation
– complex information
– new


Bogus cures
More research dollars
38




IBT Strategy Group
Michael Palm Basic Science, Vaccines
& Prevention Project Weblog
Project Inform
www.projectinform.org
HIV Policy Project
www.aidspolicyproject.org
39