Download Toward a Cure for HIV

Toward A Cure for HIV
Plenary Lunch
Keynote
Dr. Sharon Lewin
Head, Department
of Infectious Diseases
Alfred Hospital
and Monash University
Finding a cure for HIV: the
need for science, advocacy
and collaboration
Sharon R Lewin
Director, Infectious Disease Unit, Alfred Hospital
Professor, Department of Medicine, Monash University
Co-head, Centre for Virology, Burnet Institute,
Melbourne, Australia
US Conference on AIDS, Las Vegas, October 1st., 2012
The end of AIDS?
seek,
test and treat
prevention
cure
Why we need a cure for HIV
 Life expectancy remains reduced and
ongoing morbidity on cART
 For every 2 new patients who initiate
cART there are 5 new infections
 Globally, only 60% of patients who need
cART are being treated
 Funding lifelong cART for all who need it is
unlikely to be sustainable
Outline
 What are the major barriers to cure?
 What type of cure might be achieved?
 What is being tested in clinical trials?
 Current and future challenges in HIV cure
research
what are the major
barriers to cure?
Virus persists in all patients on
cART
Blood
Tissue
Cell associated HIV DNA
HIV RNA
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 et al., Nature 1997; 387: 183; Lewin et al., J Virol 1999; 73:6099; Palmer et al., Proc Natl Acad Sci U S A.
2008;105:3879; Chun et al., J Infect Dis 1997;195:1762; Yukl J Infect Dis 2010;
Barriers to cure
 Latently infected T-cells
 Residual viral replication
 Anatomical reservoirs
HIV latency and infection of resting
T-cells
cART
Activated CD4+ T-cell
Resting CD4+ T-cell
HIV latency
Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865; Saleh et al., Blood 2007;
110:416; Marini et al., J Immunol 2008; 181: 7713-20; Bosque and Planelle, Blood 2009; 113:58;
Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934
Latently infected T-cells
cART
Residual replication
cART
cART
Anatomical reservoirs
What type
of cure
might be achieved?
HIV eradication: cure or remission
Cure
Remission
Infectious Diseases model
Cancer model
Elimination of all HIVinfected cells
Long term health in absence
of cART
HIV RNA < 1 copy/ml
HIV RNA < 50 copies/ml
Sterilising cure
Functional cure
Sterilising cure: transplantation of
“HIV resistant” bone marrow
Chemotherapy (x4)
Total-body irradiation (x2)
CCR5–
(DD32)
scBMT
(X2)
off cART
no viral rebound
cART
CCR5+
(WT)
“CCR5–”
Donor
HIV+
Leukemia (AML)
“sterilising cure”
Sterilising cure: lessons learned
AML diagnosis
HIV-1 RNA (copy/mL)
cART
Bone marrow
transplantation
2nd bone marrow
transplantation
cART
107
GI tract biopsy
106
Brain biopsy
105
104
CSF
103
102
Plasma RNA +/GI tract DNA +/? significance
GI tract biopsy
2007
2008
2012
Hutter et al., N Engl J Med, 2009; 360:692; Allers et al., Blood. 2010 117(10):2791; Yukl et al., International
Workshop on HIV and Hepatitis Resistance, Sitges, June 2012
Could allogeneic transplantation be
enough?
Reduced intensity irradiation
(RISC)
cART
CCR5+
(WT)
Allogeneic
BMT
CCR5+
(heterozygous)
HIV DNA neg
HIV RNA neg
(2-4 yrs post Tx)
HIV+
Lymphoma
(n=2) Henrich et al., XIXth IAC, Washington DC, July 2012
Functional cure: elite controllers

Strong HIV-specific T-cell
responses

Enriched for “protective” HLA
types

Long term effects
Long term non-progressors
Elite
Controllers
VL<50c/ml
– Loss of CD4 (7%)
– Ongoing virus replication and
evolution
– Immune activation increased
Hunt et al., J Infect Dis 2008 ;197:126; Hatano et al., J Virol 2009; 83: 329; Pereyra et al., J Infect Dis
2009; 200:984; HIV Controller Study, Science. 2010;330(6010):1551-7 Soghoian DZ et al., Sci Transl Med
2012; 4(123):123ra25; Hersberger et al., Blood. 2011;117(14):3799-808
Functional cure: post cART controllers
VISCONTI cohort
n=14, France
treated in acute infection
median time on ART =37 months;
median times since stopping ART = 80 months
“Unique” immunological profile
<5.5%
CASCADE cohort; Europe and Aust; n=259 treated in acute infection and ceased cART
Hocqueloux et al., AIDS 2010; 2010;24(10):1598; Goujard et al., Antiviral Therapy 2012;17:1001;
Lodi et al., Arch Int Med 2012; 172(16):1252; Saez-Cirion et al., XIXth IAC, Washington DC, July 2012
What “cure” do PLWHA want?
No ART
Option 1
Option 2
Option 3
Option 4



potentially
Not
infectious
Never get
HIV again



potentially
Highly desirable
Somewhat desirable
95%
potentially
41%
27%
potentially
24%
potentially
5
32%
potentially
19%
32%
Survey of Dutch PLWHA; N=458 (46% of respondents)
Verdult, F, IAS HIV Cure Workshop, Washington DC, July 20-21, 2012
Strategies to achieve a cure
 Eliminate latently infected cells
 Eliminate residual virus replication
 Enhance HIV-specific immunity
 Make cells “resistant” to HIV
current clinical trials:
eliminating latently
infected cells
Eliminate latently infected T-cells:
activate latent HIV
cART
Activated CD4+ T-cell
Resting CD4+ T-cell
Activating latent HIV
The Economist, July 17, 2011
Activating latent HIV: in vitro





Histone deacetylase
(HDAC) inhibitors1, 2
Cytokines
– IL-73,4
– IL-155



Anti-alcohol agent
– Disulfuram6
Methylation inhibitors
– 5-aza-dC7
Immune modulation
– Anti PD1
1Contreras,


NF-kB activators
– Prostratin, PMA, TNF4
Akt/HEXIM-1 modulators
– HMBA8
Histone Methyltransferase
inhibitors (HMTI)9
– Chaetocin, BIX-01294
Other
– Quinolines10
Combination enhances
potency4,9,11
J Biol Chem. 2009;284(11):6782-9; 2Wightman., Immunol Cell Biol 2012; 3Wang, J Clin Invest 2005;
115:128; 4Saleh, Retrovirology 2011;8:80; 5Chomont, 6th IAS Rome 2011; 6Xing, J Virol; 2011;85(12):6060-4;
7Friedman, J Virol;2011 85:9078-8; 8Contreras PLoS Pathog. 2007 3(10):1459-69 ; 466-72; 9Bouchat, AIDS 2012;
10Xing et al., J Antimicrob Chemother. 2012;67(2):398-403; 11Reuse et al., PLos One 2009;4:e6093
Activating latent HIV: HDACi vorinostat
Australia; n=20
day 0
cART>3 years
HIV RNA<50 c/ml
CD4>500 cells/ml
cART
*
3
7
14
84
Vorinostat 400 mg/day
Rectal biopsy
US; n = up to 20
cART > 6 months
HIV RNA < 50 c/ml
CD4 > 300 cells/ml
In vitro response to
vorinostat
*
1
*
*
visit 1
cART
2
3
4
PK
*
200mg
400mg
5
*
400mg
Leukapharesis (post dose as per PK)
Archin et al., Nature 2012; 487: 482
Vorinostat turns HIV genes “on” in vivo
Relative HIV-1 gag copies
Baseline cART
Vorinostat 400 mg
800
600
400
200
100
60
40
20
0
Pt 1
Pt 2
Pt 3
Pt 4
Pt 5
Pt 6
Pt 7
Pt 8
Cell associated RNA quantified in resting CD4+ T-cells (mean of 20-30 replicates)
Archin et al., Nature 2012; 487: 482
Trials of other latency “activating”
agents
Agent
Design
PI (location)
Status
HDACi
Vorinostat
14 days
400 mg/day
Lewin (Australia)
Fully enrolled
Panobinostat
3 x /week x4
Ostergard (Denmark)
Enrolling
Rhomedepsin
Single dose
ACTG (US)
In discussion
3 doses
+intensification
Katlama (Europe)
Fully enrolled
14 days
500 mg/day
Deeks (US)
Ongoing
3 days
dose escalation
Deeks (US)
Elliot/Lewin (Australia)
Submitted
Single dose
ACTG (US)
In discussion
Cytokine
IL-7
Other
Disulfiram
Anti-PD-1
Will latently infected T-cells die
post activation?
cART
Activated CD4+ T-cell
?
Resting CD4+ T-cell
+
Immune clearance
Shan et al., Immunity 2012; 36:1-11
Latently infected cells are rare
current clinical trials:
eliminating virus
replication
Eliminating viral replication: no
effect of treatment intensification
HIV RNA
T20
LPV/r
ATV/r
Raltegravir (x5)
Maraviroc (x3)
HIV DNA
50
1
0
1
Years on cART
intensification
Dinoso et al., Proc Natl Acad Sci U S A, 2009. 106(23): 9403; McMahon et al., Clin Infect Dis, 2010. 50: 912;
Ghandi et al., J Infect Dis. 2010.201:293; Buzon et al., Nat Med, 2010 16: 460; Ghandi et al., Plos Med 2011;7
Yukl et al., AIDS 2010;16:2451; Hatano et al., J Infect Dis 2011; 203:960; Gutierrez, Plos One 2011:12:e27864
Eliminating viral replication:
the need to go beyond cART
 Reduce immune activation1
–
–
–
–
Mesalamine (UCSF)
Rifaximin (ACTG)
ACE inhibitors (lisinopril; UCSF/amfAR)
Methotrexate (ACTG)
 Enhance tissue/cell delivery
– Nanoparticles2
– Pro-drugs eg., GS-73403
 Target cells of the myeloid lineage
1Clinical
trials.gov; 2Kovochich et al., Plos One 2011; 6: e18270; 3 Ruane et al., 19th CROI Seattle #103
current clinical trials:
making cells
resistant to HIV
Nucleases chop up DNA: eliminate
CCR5 expression
CCR5
Naldini et al., Nature Genetics 2011; 12:301; Holt et al., Nature Biotechnol 2010;28(8):839-47; Lalezari et al.,
18th CROI, Boston, Feb 2011; Tebas et al., 18th CROI, Boston, Feb 2011 abstract 165
Gene therapy to eliminate CCR5
Inclusion criteria
n
NCT01044564
(PI Tang, Sangamo; 5 cohorts)
Dose escalation
3x3
cART failure
4
20*
CCR5D32 hetero
NCT00842634
(PI Tebas, Sangamo; 3 cohorts)
cART failure
6
Stable cART
6*
Poor CD4 recovery
6
NCT01252641
(PI Tang, Sangamo)
No cART
Lalezari et al., 18th
CROI, Boston, 2011
30
* Treatment interruption
current and future
challenges in HIV
cure research
Scientific challenges
 Multiple barriers to eradication means a
combination approach will be likely
 Standardised, non-invasive assays to quantify
viral reservoirs in vivo for multi-site clinical
trials
 Drug development to increase specificity for
latently infected cells, enhance tissue delivery
and reduce toxicities
 Better understanding of the immune system in
controlling low level viremia and latent infection
Ethical considerations
 What are acceptable risks and toxicities of
interventions in a population doing well on stable
cART?
 What marker(s) of viral persistence will justify
treatment interruption as a clinical endpoint in
subsequent clinical trials?
 Expectations of study participants in early
“proof of concept” studies. Community literacy
and engagement is critical
 Universal access to cART must remain a top
priority
science,
collaboration and
advocacy
Funding cure research
Towards an HIV Cure: a global
scientific strategy launched July 2012
An integrated strategy
Funding
Int’l scientific
collaborations
Community
engagement
Cooperation
public + privates
sectors
New concepts,
new generation
Data exchange
platforms between
pilot studies
Interaction between
Basic + Clinical
Science
Cross-talk with other
scientific disciplines
We need a cure that is scalable,
deliverable and cheap
http://www.afripol.org/africa-newspapers/3-africa/2-newshour-with-jim-lehrer-africa-coverage-pbs.html
Acknowledgements
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Department of Medicine,
Monash University
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Paul Cameron
Suha Saleh
Ajantha Solomon
Fiona Wightman
Miranda Smith
Pushparaj Velaydham
Gabriela Khoury
Vanessa Evans
Nitasha Kumar
Jenny Anderson
Hao Lu
The Alfred
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Julian Elliott
Jennifer Hoy
Janine Roney
James McMahon
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National Association of
People living With AIDS
– Jo Watson
– Bill Whittaker
Peter Macallum Institute
– Miles Prince
– Ricky Johnston
Others
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Steve Deeks
Christine Katlama
Brigitte Autran
Christine Rouzioux
Dan Kuritzes
Javier Picado Martinez
www.aids2014.org