Transcript Powerpoint - Aids 2012

Viral Eradication: The Cure Agenda
Javier Martinez-Picado
AIDS Research Institute (IrsiCaixa)
Autonomous University of Barcelona (UAB)
Catalan Institution for Research and Advanced Studies (ICREA)
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Outline
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Limitations to cure HIV
Potential strategies to achieve a cure
Current clinical trials aimed at cure
Towards an HIV cure pipeline
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
After 25-years improving therapies
HIV cure is not feasible yet
HIV RNA (cps/mL)
Blood
Tissue
Cell associated HIV DNA
Cell associated HIV RNA
Cell associated HIV DNA
Cell associated HIV RNA
Infectious virus (IUPM)
50
Plasma single copy assay
1
0
1
Years on cART
Chun, Nature 1997; Chun, J Infect Dis 1997; Lewin, J Virol 1999; Palmer, PNAS 2008; Yukl J Infect Dis 2010
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Why do we need to cure HIV?
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Life expectancy remains reduced on cART
Ongoing morbidity on cART
Prevent HIV transmission
Substantial stigma and discrimination
Lifelong cART:
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adherence
toxicity
long term-cost
Estimated 2015 AIDS investment for
universal prevention, treatment, care
and support
22 billion USD
Lohse, Ann Int Med 2007; Hogg. Lancet 2008; Deeks & Phillips, BMJ 2009; May, BMJ 2011
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Barriers to cure HIV infection
Where is the virus and how is it maintained in
the face of suppressive therapy?
Residual
replication
inflammation
immune activation
www.aids2012.org
Latent
infection
Washington D.C., USA, 22-27 July 2012
Residual viral replication
<50 c/mL
Differential drug
penetration in tissues
Greater HIV
burden in tissues
No genetic evolution
(absence of DRM)
Cell-to-cell transmission
Biological markers
 Sensitivity
 Interpretation
www.neurosolutionsnow.net
RNA or DNA
Stable RNA or DNA
following cART intens
ART
intensification
Hermankova, JAMA 2001; Persaud, J Virol 2004; Sedgahat, PLoS Pathog 2007; Chun, J Infect Dis 2008;
Buzon. Nat Med 2010; Brennan, J Virol 2009; Dinoso, PNAS 2009; Yulk, J Infect Dis 2010;Yulk, AIDS 2010; Sigal,
Nature 2011; Llibre, Antiv Ther 2012; Fletcher. CROI’12; Joseffson. CROI’12
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Washington D.C., USA, 22-27 July 2012
How latency is established and
maintained in T-cells
cART
Activated CD4+ T cell
Negative
regulators
Resting CD4+ T cell
Survival
(long-half life)
Homeostatic
proliferation
Eckstein, Immunity 2001; Swiggard, J Virol 2005; Saleh, Blood 2007; Marini, J Immunol 2008;
Bosque, Blood 2009; Cameron, PNAS 2010; Lassen, PLoS One 2012
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Potential strategies to
achieve a cure
www.aids2012.org
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HIV cure: 2-models
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Strategies to cure HIV
Gene
therapy
Treatment
optimization
& intensification
(eliminate
all replication)
Therapeutic
vaccination
Reversal of
HIV latency
(to enhance
host-control)
(increase viral
production)
Immune-based
therapies
(reverse pro-latency signaling)
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Clinical trials:
treatment intensification
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Treatment intensification studies in
patients successfully treated with HAART
Study
Buzon et al.
Nat Med ‘10
Llibre et al.
Antiv Ther ‘12
n
Weeks
69
48
SCA
49
Hatano et al.
JID ‘11
30
MacMahon et al
CID ‘10
10
Dinoso et al.
PNAS ‘09
9
7
Cell-associated
DNA or RNA
Yes: 2LTRs
No: total/integrated
HIV DNA
Immune
activation
Yes:
%CD38+ of
CD8+RO+
>500
No
RAL
>500
No
–
No
24
<350
+ Gut
No
–
No
474
No
–
–
564
No
–
–
RAL
12 (+12)
Gandhi et al.
PLoS Med ‘10
Yulk et al.
AIDS ‘10
CD4
T-cells
RAL
4
RAL
12
EFV,LPVr,ATVr
12
RAL
473
+ Gut
www.aids2012.org
No
Yes: unspliced
RNA/106 CD4+ T
cells in the ileum
No: total HIV DNA
Trend
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Current clinical trials:
activating latency
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Activating latent HIV: in vitro
 Cytokines
 IL-71,2
 IL-153
 IFNa 2b
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 NF-kB activators
 Prostratin, PMA, TNF4
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 Akt/HEXIM-1 modulators
 HMBA8
 Histone deacetylase (HDAC)
inhibitors4,5
 Anti-alcohol agent
 Disulfiram6
 Methylation inhibitors
 5-aza-dC7
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 Histone Methyltransferase
inhibitors (HMTI)9
 Chaetocin, BIX-01294
 Other
 Quinolines10
 Combination enhances
potency4,9,11
 Immune modulation
 Anti PD1
1Wang,
J Clin Invest 2005; 2Saleh, Retrovirol 2011; 3Chomont, 6th IAS Rome 2011; 4Contreras, J Biol Chem 2009;
5Wightman, Immunol Cell Biol 2012; 6Xing, J Virol 2011; 7Friedman, J Virol 2011; 8Contreras PLoS Pathog 2007;
9Bouchat, AIDS 2012; 10Xing, J Antimicrob Chemother 2012; 11Reuse, PLoS One 2009
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ERAMUNE: treatment intensification,
activation and enhance immunity
week 0
8
28
32
ERAMUNE 01
EUROPE
Arm A
cART + (Raltegravir + Maraviroc)
Arm B
cART + (Raltegravir + Maraviroc)
IL-7
ERAMUNE 02
US/Canada
n=28
Arm A
cART + (Raltegravir + Maraviroc)
Arm B
cART + (Raltegravir + Maraviroc)
DNA prime
HIV rAd5
Gag,Pol,Nef,Env
Clades A,B,C
Gag-Pol, Env
Clades A,B,C
Primary endpoint – HIV DNA in PBMC
n=29
56
NCT01019551 & NCT00976404
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Interferon-alpha intensification in
individuals on ART
 IFNalpha approved to treat hepatitis C infection
 Reduces the level of HIV in non-treated individuals
 n=4; NIAID/CCMD Clinic, Univ of Pittsburgh
 cART>1 year; HIV RNA<50 & >0.6; CD4>300 cells/µl
week –4
Pre-IFN
0
4
IFNa-2b
48
Post-IFN
 No effect on plasma viremia or total cell-associated HIV DNA
 Reversible increase in immune activation (CD8+CD38+) cells
NCT01295515
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HDACi turn HIV genes “on”
HDACi
nucleosomes
DNA
OFF
TF
Bolden, Nat Rev Drug Disc 2006; Prince. Clin Canc Res 2009; Contreras, J Biol Chem 2009;
Archin AIDS Res Hum Retrovir 2009; Reuse, PLoS One 2009; Burnett , J Virol 2010
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Vorinostat (SAHA)
 Potent HDACi licensed for cutaneous T-cell lymphoma
 Stable cART >6 months; HIV RNA<50 c/ml; CD4>300 cells/µl
visit 1
USA
n=8
3
4
5
PK
cART
*
day
AUSTRALIA
n=20
2
200mg
0
cART
1
3
400mg
7
*
400mg
14
leukapharesis
*21
28
84
Vorinostat 400 mg/day
* rectal biopsies
*
 Endpoint is US viral RNA:
 in resting CD4+ T cells
 in total CD4+ T cells in blood & rectum
NCT01365065 & NCT01319383
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Vorinostat induces HIV transcription in
vivo
• Up to 48 x 1 million resting
cells assayed
• Mean 4.8-fold induction
(range 1.5- to 10-fold)
• All increases significant
(p<0.01)
• No AE due to VOR
Archin et al. CROI 2012;
Full cohort (n=8) Archin et al. Nature in press
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Disulfiram
 FDA approved drug to treat alcoholism
 Reactivates HIV gene expression in an in vitro model of latency
 n=14; JHH & UCSF
 cART>18 months; HIV RNA<40 c/ml; CD4>200 cells/µl
0
Day
cART
3
7
10
14
84
Disulfiram 500 mg/day
IUPM
IUPM
 Transient increase of low-level viremia after the 1st dose
 No decrease of the latent reservoir (IUPM)
Xing. JVirol 2011; NCT01286259; Spivak, 19th CROI, Seattle 2012, #369
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Current clinical trials:
making cells resistant to HIV
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Long-term control of HIV by CCR5
Δ32/Δ32 stem cell transplantation
Chemotherapy (x4)
Total-body irradiation (x2)
CCR5–
off ART
no viral rebound
scBMT
(X2)
CCR5+
CCR5–
HIV-1+
AML
HIV-1– ?
Donor
Hütter. NEJM. 2009; Allers. Blood. 2010
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Washington D.C., USA, 22-27 July 2012
Nucleases chop up DNA: eliminate
CCR5 expression or eliminate HIV
CCR5
Gene disruption
Holt , Nat Biotechnol 2010; Naldini , Nat Gen 2011; Lalezari , CROI’11
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Gene therapy to eliminate CCR5
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SB728-902
CCR5-disrupted T cells
engraft, proliferate,
and persist in peripheral
blood and rectal mucosa
Increase CD4 T-cell
counts and
normalization of
CD4:CD8 ratio after
single infusion
The treatment is well
tolerated
NCT01252641 & NCT00842634; Lalezari , CROI’11
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What else … ?
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“Towards an HIV Cure”
The
Global Scientific Strategy
“Towards an HIV Cure”
was launched on 19 July 2012!
www.iasociety.org
www.iasociety.org
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
An Integrated Strategy
Funding
Int’l scientific
collaborations
Community
engagement
Data exchange
platforms between
pilot studies
Cooperation
public + privates
sectors
Interaction between
Basic + Clinical
Science
New concepts,
new generation
Cross-talk with other
scientific disciplines
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Stakeholders’ Advisory Board
www.aids2012.org
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Scientific and technical challenges
ahead
1.
Review basic science to understand the cellular,
viral and immunological mechanisms that control HIV
persistence
2.
Develop new
assays and experimental models to
tackle viral reservoirs (tissues and cellular sources) in long
term ART-treated individuals
3.
Investigate new
therapeutic agents and
immunological strategies to achieve viral
remission in absence of cART
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Other critical considerations
 Community engagement
 Expectations, acceptability of cure strategies
 Ethical & Regulatory issues
 Risks and toxicities
 Cost-effectiveness
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Safe, affordable and scalable cure strategies
Ensure its availability to all patients wherever they live
 Cure & Vaccine research are two inseparable
priorities towards a world free of AIDS
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Acknowledgements
 Sharon Lewin (Monash University, Melbourne, Australia)
 Steve Deeks (Univ. California San Francisco, USA)
 Françoise Barré-Sinoussi (Institut Pasteur, Paris, France)
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Ventura Clotet and colleagues (IrsiCaixa, Badalona, Spain)
Christine Katlama (Univ Pierre et Marie Curie & Orvacs, Paris, France)
Frank Maldarelli (NCI, Bethesda, USA)
David Margolis (Univ North Carolina-Chapel Hill, NC, USA)
Pablo Tebas (Univ. of Pennsylvania, USA)
 IAS “Towards the HIV cure” Working Group
 Marie-Capucine Penicaud
 Rosanne Lamplough
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
HIV-1 cure research …
… its complexity should not prevent the
attempt
… meanwhile, continuous investment to secure
universal access to prevention, treatment, care
and support must remain a TOP PRIORITY
www.aids2012.org
Washington D.C., USA, 22-27 July 2012