viral eradication: the cure agenda

Washington D.C., USA, 22-27 July 2012www.aids2012.org

Viral Eradication: The Cure Agenda

AIDS Research Institute (IrsiCaixa)Autonomous University of Barcelona (UAB)

Catalan Institution for Research and Advanced Studies (ICREA)

Javier Martinez-Picado


Outline Limitations to cure HIV Potential strategies to achieve a

cure Current clinical trials aimed at cure Towards an HIV cure pipeline


HIV

RN

A (c

ps/m

L)

50

Years on cART0 1

1

Chun, Nature 1997; Chun, J Infect Dis 1997; Lewin, J Virol 1999; Palmer, PNAS 2008; Yukl J Infect Dis 2010

Cell associated HIV RNA

Plasma single copy assay

Cell associated HIV DNA

Infectious virus (IUPM)

Blood TissueCell associated HIV DNA

Cell associated HIV RNA

After 25-years improving therapies HIV cure is not feasible yet


Why do we need to cure HIV? Life expectancy remains reduced on cART Ongoing morbidity on cART Prevent HIV transmission Substantial stigma and discrimination Lifelong cART:

adherence toxicity long term-cost

Lohse, Ann Int Med 2007; Hogg. Lancet 2008; Deeks & Phillips, BMJ 2009; May, BMJ 2011

Estimated 2015 AIDS investment for universal

prevention, treatment, care and support

22 billion USD


Barriers to cure HIV infectionWhere is the virus and how is it

maintained in the face of suppressive therapy?

Residual replicatio

n

Latent infection

inflammationimmune activation


Residual viral replication

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

Differential drugpenetration in tissues

Biological markers Sensitivity Interpretation

Stable RNA or DNA following cART intens

ARTintensification

RNA

or D

NA

Greater HIV burden in

tissues

www.neurosolutionsnow.net

No genetic evolution(absence of DRM)

<50 c/mL

Cell-to-cell transmission


How latency is established and maintained in T-cells

Eckstein, Immunity 2001; Swiggard, J Virol 2005; Saleh, Blood 2007; Marini, J Immunol 2008; Bosque, Blood 2009; Cameron, PNAS 2010; Lassen, PLoS One 2012

Activated CD4+ T cell

Resting CD4+ T cell

cART

Negativeregulators

Survival(long-half life)

Homeostatic proliferation


Potential strategies to achieve a cure


HIV cure: 2-models


Strategies to cure HIVTreatmentoptimization& intensification

(eliminateall replication)

Reversal of HIV latency

(increase viral production)

Immune-basedtherapies

(reverse pro-latency signaling)

Therapeuticvaccination

(to enhance host-control)

Genetherapy


Clinical trials:treatment

intensification


Treatment intensification studies inpatients successfully treated with HAART

Study n Weeks CD4T-cells SCA Cell-associated

DNA or RNAImmune

activationBuzon et al. Nat Med ‘10Llibre et al. Antiv Ther ‘12

69 48RAL >500 No

Yes: 2LTRsNo: total/integrated HIV DNA

Yes:%CD38+ of CD8+RO+

Gandhi et al. PLoS Med ‘10 49

12 (+12)RAL >500 No – No

Hatano et al. JID ‘11 30 24

RAL<350 No – No

MacMahon et al CID ‘10 10 4

RAL 474 No – –

Dinoso et al. PNAS ‘09 9 12

EFV,LPVr,ATVr 564 No – –

Yulk et al. AIDS ‘10 7 12

RAL473 No

Yes: unspliced RNA/106 CD4+ T cells in the ileumNo: total HIV DNA

Trend

+ Gut

+ Gut


Current clinical trials: activating latency


Activating latent HIV: in vitroCytokines

IL-71,2

IL-153

IFNa 2bHistone deacetylase

(HDAC) inhibitors4,5

Anti-alcohol agent Disulfiram6

Methylation inhibitors 5-aza-dC7

Immune modulation Anti PD1

NF-kB activators Prostratin, PMA, TNF4

Akt/HEXIM-1 modulators HMBA8

Histone Methyltransferase inhibitors (HMTI)9

Chaetocin, BIX-01294Other

Quinolines10

Combination enhances potency4,9,11

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


ERAMUNE: treatment intensification, activation and

enhance immunity Primary endpoint – HIV DNA in PBM

C

DNA prime

Arm A

Arm B

HIV rAd5

ERAM

UNE

02 U

S/Ca

nada

n=28

8 28 560week 32

IL-7

Arm AArm B

ERAM

UNE

01 E

UROP

E cART + (Raltegravir + Maraviroc)

cART + (Raltegravir + Maraviroc)

n=29

NCT01019551 & NCT00976404



Gag,Pol,Nef,EnvClades A,B,C

Gag-Pol, EnvClades A,B,C


Interferon-alpha intensification in individuals on ART

NCT01295515

No effect on plasma viremia or total cell-associated HIV DNA Reversible increase in immune activation (CD8+CD38+) cells

IFNalpha approved to treat hepatitis C infection Reduces the level of HIV in non-treated individuals

0 4 48–4week

IFNa-2bPre-IFN Post-IFN

n=4; NIAID/CCMD Clinic, Univ of Pittsburgh cART>1 year; HIV RNA<50 & >0.6; CD4>300 cells/µl


HDACi turn HIV genes “on”

TF

OFF

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

HDACi

DNA nucleosomes


Potent HDACi licensed for cutaneous T-cell lymphoma

Endpoint is US viral RNA: in resting CD4+ T cells in total CD4+ T cells in blood & rectum

NCT01365065 & NCT01319383

Vorinostat (SAHA)

**cART Vorinostat 400 mg/day

0 7 14 21 841

rectal biopsies

day 283AUSTRALIA

n=20

leukapharesis*cART

200mg 400mg

2 43

*

visit

*

1 5PKUSA

n=8400mg

Stable cART >6 months; HIV RNA<50 c/ml; CD4>300 cells/µl


•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

Vorinostat induces HIV transcription in vivo


Disulfiram

Xing. JVirol 2011; NCT01286259; Spivak, 19th CROI, Seattle 2012, #369

FDA approved drug to treat alcoholism Reactivates HIV gene expression in an in vitro model of latency

Transient increase of low-level viremia after the 1st dose No decrease of the latent reservoir (IUPM)

cART Disulfiram 500 mg/day

0 7 14 843Day 10

IUPM IUPM

n=14; JHH & UCSF cART>18 months; HIV RNA<40 c/ml; CD4>200 cells/µl


Current clinical trials:making cells resistant to HIV


scBMT(X2)

Donor

Hütter. NEJM. 2009; Allers. Blood. 2010

HIV-1+AML

CCR5+

CCR5–

HIV-1– ?

CCR5–

off ARTno viral rebound

Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation

Chemotherapy (x4)Total-body irradiation (x2)


Nucleases chop up DNA: eliminate CCR5 expression or eliminate HIV

Holt , Nat Biotechnol 2010; Naldini , Nat Gen 2011; Lalezari , CROI’11

CCR5

Gene disruption


Gene therapy to eliminate CCR5

NCT01252641 & NCT00842634; Lalezari , CROI’11

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

SB728-902


What else … ?


The Global Scientific Strategy

“Towards an HIV Cure” was launched on 19 July 2012!

“Towards an HIV Cure”

www.iasociety.orgwww.iasociety.org


Int’l scientific collaborations

Interaction betweenBasic + Clinical

Science

Data exchange platforms

between pilot studies

New concepts,new generation Cross-talk with other

scientific disciplines

Cooperation public + privatessectors

Community

engagement

Funding

An Integrated Strategy


Stakeholders’ Advisory Board


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

Scientific and technical challenges ahead


Community engagement Expectations, acceptability of cure strategies

Ethical & Regulatory issues Risks and toxicities

Cost-effectiveness 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

Other critical considerations


AcknowledgementsSharon Lewin (Monash University, Melbourne, Australia)Steve Deeks (Univ. California San Francisco, USA)Françoise Barré-Sinoussi (Institut Pasteur, Paris, France)

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 GroupMarie-Capucine PenicaudRosanne Lamplough


… its complexity should not prevent the attempt

HIV-1 cure research …

… meanwhile, continuous investment to secure universal access to prevention,

treatment, care and support must remain a TOP PRIORITY

viral eradication: the cure agenda

Documents

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