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State of the ART: HIV Cure – where are we now and where are we going?

State of the ART: HIV Cure – where are we now and where are we going?. Jintanat Ananworanich, MD, PhD Associate Director for Therapeutics Research US Military HIV Research Program (MHRP) Maryland, USA Deputy Director of SEARCH The Thai Red Cross AIDS Research Center

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State of the ART: HIV Cure – where are we now and where are we going?

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  1. State of the ART: HIV Cure – where are we now and where are we going? Jintanat Ananworanich, MD, PhD Associate Director for Therapeutics Research US Military HIV Research Program (MHRP) Maryland, USA Deputy Director of SEARCH The Thai Red Cross AIDS Research Center Bangkok, Thailand

  2. Outline • Is HIV cure possible? • HIV persistence • Cure Strategies • Ethical and social considerations Short video on patients’ perspectives on cure

  3. A Case of Cure Hutter G, NEJM 2009; Allers K, Blood 2011; Yukl SA, Plos Pathogens 2013;

  4. Transient but Encouraging HIV Remission 1Henrich T, JID 2013; 2Annals Internal Medicine (in press); 3Persaud D, NEJM 2014

  5. HIV Persistence cell death resting state

  6. Measuring the HIV Reservoir Integrated HIV DNA Total HIV DNA Replication competent virus HIV DNA (100%) Replication competent (0.1%) Intact, inducible (10%) Ho, Cell, 2013; Cillo, PNAS 2014

  7. Reservoir and Immunity immunity latent virus Boston patients Mississippi child

  8. Strategies to Eliminate HIV Persistence “Shock and Kill” Eliminate Infected Cells Vaccine ART BeforeHIV Infection AcuteHIV Infection ChronicHIV Infection Viral LoadSuppressed • Possible interventions: • Latency reversing agents • Broadly neutralizing antibody • Gene-editing therapy HIV RNA

  9. Novel vaccine given before exposuremay aid in viral control: SIV/macaque model No protection but Virus eradicated in 50% Controllers (n=9) Hansen SG and Picker LJ, Nature 2013

  10. VISCONTI Cohort of Post-Treatment Controllers • 14 people • ART in first • 3 months • Control VL • after • stopping ART Why are these patients able to control HIV without ART? HIV reservoir amount and location? • Low HIV DNA • In shorter-lived CD4 cells Saez-Cirion A, Plos Pathogens 2013

  11. Early ART limits persistence of HIV reservoir in Long-lived CD4+ T cell subsets (RV254/SEARCH010) 0% 63% Duration of HIV at ART initiation 100% Long-lived central memory CD4+ T cells Nicolas Chomont (VGTI-Florida) Updated from Ananworanich J, 2013 CROI

  12. Early ART in Infants Visconti post treatment controllers N=15 Ananworanich J, AIDS 2014 Three US teenagers treated from infancy have no replication competent HIV Luzuriaga K, JID 2014

  13. Shocked but not KilledHDACiPanobinostat n=16 Fold increase in CA-US RNA days ANOVA p<0.0001 Replication competent virus did not decline Rasmussen et al, 2014 CROI

  14. Broadly Neutralizing Antibody 6 Viral load suppression in macaques (n=3) 5 4 3 Cell death 2 Viral clearance 60 100 0 40 20 80 PGT121 • > 30 antibodies identified • Human studies • VRC01: RV397/398 in acute HIV • 3BNC117, 10-1074, PGT121 VL log Days after infusion Barouch DH, Nature 2013

  15. Gene therapy to eliminate CCR5 Leukapharesis CD4+ T-cell isolation CCR5- CCR5+ ZFN cut CCR5 gene Re-infuse Tebas P, NEJM 2014

  16. Examples of strategies currently in human studies MINIMIZE RESERVOIR Limit reservoir with early treatment Antiretroviral therapy Broadly neutralizing antibodies Combination Cure SHOCK Reactivating latently- infected cells Inhibit histone deacetylase Inhibit bromodomainextraterminal Activate toll-like receptors Activate protein kinase C KILL Viral clearance by the immune system Broadly neutralizing antibodies Therapeutic HIV vaccines Anti programmed cell death (PD)1Anti PD ligand 1 HIV RESISTANT CELLS Transfusing cells without CCR5 gene Gene-editing therapy Bone marrow or cord blood transplantation

  17. HIV Cure and Cure Research:Social and Ethical Considerations

  18. Societal and Individual Expectation • Eradicated = normal or free of disease or healed • Long-term adverse consequences of HIV • New normal • Long-term monitoring of viral load • Stigma and discrimination • When to call someone “cured”?1 • Best measure of reservoir is not known • HIV remission • VSLLDOTtime = Viral Suppression Off ART 1Forum Cure Project (V. Miller)

  19. Australian Participants’ Priorities on Outcomes of Cure Research 20 participants with chronic HIV infection in vorinostat (HDACi) trial 0 McMahon J, Elliott J and Lewin S, 2013 IAS

  20. Ethics of HIV cure • Ideal candidates are persons who are well with viral suppression • Potentially toxic interventions • ART interruption • Cost and accessibility Shah SK, Lancet ID 2014; Lo B and Grady C, CurrOpin HIV AIDS 2013

  21. What might the future look like?

  22. Acknowledgements Study Volunteers and Research Teams RV254/SEARCH010 acute HIV and HIV-NAT 194/pediatric reservoir Monash University Sharon Lewin Thai Red Cross AIDS Research Center PraphanPhanuphak NittayaPhanuphak SuteerapornPinyakorn Northwestern University Ellen Chadwick Johns Hopkins University Robert Siliciano Deborah Persaud Alison HIll NIAID, NIH Anthony Fauci NICHD, NIH Lynne Mofenson University of Pennsylvania Pablo Tebas US Military HIV Research Program Nelson Michael Jerome Kim Merlin Robb Lisa Reilly Aarhus University Lars Ostergaard Oregon Health Science University Louis Picker Vaccine and Gene Therapy Institute-Florida Nicolas Chomont University of Pittsburg John Mellors UCSF Steve Deeks Harvard University Dan Barouch Purple Haze TarandeepAnand ChattiyaNitpolprasert Institut Pasteur AsierSaez-Cirion Funding for Acute Infection Study RV254 provided by U.S NIH, U.S. DoD and amfAR

  23. “What does HIV cure mean to me?”

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