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Viral Eradication: The Cure Agenda

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). Outline. Limitations to cure HIV Potential strategies to achieve a cure

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Viral Eradication: The Cure Agenda

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  1. 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)

  2. Outline • Limitations to cure HIV • Potential strategies to achieve a cure • Current clinical trials aimed at cure • Towards an HIV cure pipeline

  3. After 25-years improving therapies Tissue Cell associated HIV DNA Cell associated HIV RNA Cell associated HIV DNA Cell associated HIV RNA Infectious virus (IUPM) Plasma single copy assay 1 HIV cure is not feasible yet Blood HIV RNA (cps/mL) 50 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

  4. Why do we need to cure HIV? Estimated 2015 AIDS investment for universal prevention, treatment, care and support 22 billion USD Lohse, Ann IntMed 2007; Hogg. Lancet 2008; Deeks & Phillips, BMJ 2009; May, BMJ 2011 • Life expectancy remains reduced on cART • Ongoing morbidity on cART • Prevent HIV transmission • Substantial stigma and discrimination • Lifelong cART: • adherence • toxicity • long term-cost

  5. Barriers to cure HIV infection Where is the virus and how is it maintained in the face of suppressive therapy? Residual replication Latent infection inflammation immune activation

  6. Residual viral replication <50 c/mL Differential drug penetration in tissues No genetic evolution (absence of DRM) Greater HIV burden in tissues Cell-to-cell transmission Stable RNA or DNA following cARTintens ART intensification • Biological markers • Sensitivity • Interpretation RNA or DNA www.neurosolutionsnow.net Hermankova, JAMA 2001; Persaud, J Virol2004; Sedgahat, PLoSPathog 2007; Chun, J InfectDis 2008; Buzon. Nat Med 2010; Brennan, J Virol2009; Dinoso, PNAS 2009; Yulk, J InfectDis 2010;Yulk, AIDS 2010; Sigal, Nature 2011; Llibre, AntivTher 2012; Fletcher. CROI’12; Joseffson. CROI’12

  7. How latency is established and maintained in T-cells cART Activated CD4+ T cell Negative regulators Resting CD4+ T cell Survival (long-halflife) Homeostaticproliferation Eckstein, Immunity 2001; Swiggard, J Virol2005; Saleh, Blood 2007; Marini, J Immunol 2008; Bosque, Blood 2009; Cameron, PNAS 2010; Lassen, PLoS One 2012

  8. Potential strategies to achieve a cure

  9. HIV cure: 2-models

  10. Strategies to cure HIV Treatment optimization & intensification Gene therapy (eliminate all replication) Therapeutic vaccination Reversal of HIV latency (to enhance host-control) (increase viral production) Immune-based therapies (reverse pro-latency signaling)

  11. Clinical trials:treatment intensification

  12. Treatment intensification studies inpatients successfully treated with HAART + Gut + Gut

  13. Current clinical trials: activating latency

  14. Cytokines IL-71,2 IL-153 IFNa 2b Histonedeacetylase (HDAC) inhibitors4,5 Anti-alcohol agent Disulfiram6 Methylation inhibitors 5-aza-dC7 Immune modulation Anti PD1 NF-kB activators Prostratin, PMA, TNF4 Akt/HEXIM-1 modulators HMBA8 HistoneMethyltransferase inhibitors (HMTI)9 Chaetocin, BIX-01294 Other Quinolines10 Combination enhances potency4,9,11 Activating latent HIV: in vitro     1Wang, J Clin Invest 2005; 2Saleh,Retrovirol 2011; 3Chomont, 6th IAS Rome 2011; 4Contreras, J BiolChem 2009; 5Wightman, Immunol Cell Biol 2012; 6Xing, J Virol 2011; 7Friedman, J Virol 2011; 8Contreras PLoSPathog 2007; 9Bouchat, AIDS 2012; 10Xing, J AntimicrobChemother 2012; 11Reuse, PLoS One 2009

  15. ERAMUNE: treatment intensification, activation and enhance immunity week 0 8 28 32 56 n=29 cART+ (Raltegravir + Maraviroc) Arm A Arm B cART+ (Raltegravir + Maraviroc) ERAMUNE 01 EUROPE Primary endpoint – HIV DNA in PBMC IL-7 n=28 Arm A cART+ (Raltegravir + Maraviroc) cART+ (Raltegravir + Maraviroc) Arm B ERAMUNE 02 US/Canada DNA prime HIV rAd5 Gag,Pol,Nef,Env CladesA,B,C Gag-Pol, Env CladesA,B,C NCT01019551 & NCT00976404

  16. Interferon-alpha intensification in individuals on ART week –4 0 4 48 • IFNalpha approved to treat hepatitis C infection • Reduces the level of HIV in non-treated individuals Pre-IFN IFNa-2b Post-IFN • n=4; NIAID/CCMD Clinic, Univof Pittsburgh • cART>1 year; HIV RNA<50 & >0.6; CD4>300 cells/µl • No effect on plasma viremia or total cell-associated HIV DNA • Reversible increase in immune activation (CD8+CD38+) cells NCT01295515

  17. HDACi turn HIV genes “on” HDACi TF OFF nucleosomes DNA Bolden, Nat Rev Drug Disc 2006; Prince. ClinCanc Res 2009; Contreras, J BiolChem2009; ArchinAIDS Res Hum Retrovir 2009; Reuse, PLoS One 2009; Burnett , J Virol 2010

  18. Vorinostat (SAHA) • Potent HDACi licensed for cutaneous T-cell lymphoma • Stable cART >6 months; HIV RNA<50 c/ml; CD4>300 cells/µl 0 1 7 14 21 28 84 3 day AUSTRALIA n=20 cART Vorinostat 400 mg/day * * rectal biopsies 1 2 3 4 5 visit * USA n=8 leukapharesis PK cART * * 400mg 200mg 400mg • Endpoint is US viral RNA: • in resting CD4+ T cells • in total CD4+ T cells in blood & rectum NCT01365065 & NCT01319383

  19. Vorinostat induces HIV transcription in vivo • Up to 48x 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 Archinet al. CROI 2012; Full cohort (n=8) Archin et al. Nature in press

  20. Disulfiram • FDA approved drug to treat alcoholism • Reactivates HIV gene expression in an in vitro model of latency 0 3 7 14 84 10 Day cART Disulfiram 500 mg/day • n=14; JHH & UCSF • cART>18 months; HIV RNA<40 c/ml; CD4>200 cells/µl 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

  21. Current clinical trials:making cells resistant to HIV

  22. Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation Chemotherapy (x4) Total-body irradiation (x2) off ART no viral rebound CCR5– scBMT (X2) CCR5+ CCR5– Donor HIV-1+ AML HIV-1– ? Hütter. NEJM. 2009; Allers. Blood. 2010

  23. Nucleases chop up DNA: eliminate CCR5 expression or eliminate HIV CCR5 Gene disruption Holt , Nat Biotechnol 2010; Naldini , Nat Gen 2011; Lalezari , CROI’11

  24. Gene therapy to eliminate CCR5 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

  25. What else … ?

  26. “Towards an HIVCure” The Global ScientificStrategy “Towards an HIVCure” waslaunched on 19 July 2012! www.iasociety.org www.iasociety.org

  27. 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

  28. Stakeholders’ AdvisoryBoard

  29. Scientific and technical challenges ahead • Reviewbasic science to understand the cellular, viral and immunological mechanisms that control HIVpersistence • Develop new assays and experimental models to tackle viral reservoirs(tissues and cellular sources) in long term ART-treated individuals • Investigate new therapeutic agents and immunological strategies to achieve viral remission in absence of cART

  30. Other critical considerations • Community engagement • Expectations, acceptability of cure strategies • Ethical& Regulatoryissues • 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 prioritiestowards a world free of AIDS

  31. Sharon Lewin(MonashUniversity, 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 Group Marie-CapucinePenicaud RosanneLamplough Acknowledgements

  32. 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

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