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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, TNF4 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 Department of Medicine, Monash University – – – – – – – – – – – Paul Cameron Suha Saleh Ajantha Solomon Fiona Wightman Miranda Smith Pushparaj Velaydham Gabriela Khoury Vanessa Evans Nitasha Kumar Jenny Anderson Hao Lu The Alfred – – – – Julian Elliott Jennifer Hoy Janine Roney James McMahon National Association of People living With AIDS – Jo Watson – Bill Whittaker Peter Macallum Institute – Miles Prince – Ricky Johnston Others – – – – – – Steve Deeks Christine Katlama Brigitte Autran Christine Rouzioux Dan Kuritzes Javier Picado Martinez www.aids2014.org