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J Sierra-Madero, I.Sanne,L.Azzoni, L Montaner, S Ellenberg, I Sereti, M Lederman

CCR5 antagonists to prevent IRIS: Rationale, design and update of a blinded multicenter study in progress (CADIRIS) . J Sierra-Madero, I.Sanne,L.Azzoni, L Montaner, S Ellenberg, I Sereti, M Lederman Alicia Piñeirua Menendez . Rationale for CCR5 antagonists for IRIS.

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J Sierra-Madero, I.Sanne,L.Azzoni, L Montaner, S Ellenberg, I Sereti, M Lederman

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  1. CCR5 antagonists to prevent IRIS: Rationale, design and update of a blinded multicenter study in progress (CADIRIS) J Sierra-Madero, I.Sanne,L.Azzoni, L Montaner, S Ellenberg, I Sereti, M Lederman Alicia Piñeirua Menendez

  2. Rationale for CCR5 antagonists for IRIS IRIS: in pathogen-specificinflammatory responses Peripheraltissue Lymphoidtissue Celltrafficking MARAVIROC Blockade of cellulartrafficking and activation ? Reduction in Ocurrence/Severity of IRIS CD4+ CCR5+ T cells increased in TB-IRIS patients when compared with TB-non IRIS patients (Landay, et al 2012) Lederman et al, JAMA 2006; 296 (7) : 815-26 Westby et al, AntivirChemChemother 2005; 16:339-354 Funderbug et al, PLoSone 2010; 5 (10): e 13188 Landay et al, 19th Conferenceonretroviruses and oportunisticinfections (CROI) 2012 abstract # P-154 Poster #940

  3. CADIRIS Study design Multicenter, double –blinded, placebo-controlledstudy Mexico: 5 sites. South Africa :1 site • Secondaryendpoints: • IRIS event/death WK 48 • Proportion of severe IRIS • Virologic/immunologic response • AIDS defining/relatedevents • Non-AIDS relatedevents Primaryendpoint: Time toany IRIS eventduring 1st 24 WK of cART TVD+EFV+ PLACEBO Screening and OI assesment HIV + ARV naive CD4 < 100 cells/mm3 (n=276) Randomization TVD+EFV + MVC 600 BID Assuming IRIS incidence 30% 125 subjects/arm 80% power 50% IRIS reduction in thefirst 24 WK *IRIS: Definedby ACTG criteria Each case evaluatedby a studyendpointcommittee ( 4 experts)

  4. CADIRIS Substudies Substudy A: ImmunologySubstudy Case Western Reserve (Lederman) Frequency of CCR5+ CD4+/CD8+ circulatingcellsreactingtodifferentpathogens (n=40) Substudy B: ImmunologySubstudy WistarInstitute (Montaner) P53 gene and apoptosis network gene expression in isolatedmonocytes and CD4 T cells (n=60) Substudy C: Biomarkers NIH/NIAID (Sereti) Predictors of venousthromboticdisease (n=276) Substudy D: Neurologic Mexico (Sierra) Neuropsychological, imaging and CSF markersassesment (n=14)

  5. Basal characteristics and studyoutcomes at WK 24 (Blinded) Primaryanalysis: August 2012 11.07.12 Lastenrolledsubjectreached WK 24 Unblinding : Jan 2013

  6. Participants/Acknowledgements MEXICO INCMNSZ Pablo F. Belaunzarán Z Brenda Crabtree R Maria Eugenia Zghaib Alondra Lopez Alicia Piñeirúa Rosa Brena Audelia Alanís Hospital Central Ignacio Morones Prieto Martín Magaña Hospital General de León Juan Luis Mosqueda Hospital Civil de Guadalajara Jaime Andrade Hospital General de México Cesar Rivera UNITED STATES The Wistar Institute Maria Picone University of Cape Town GraemeMeintjes Case Western Reserve Institute BenignoRodríguez University of the Witwatersrand /ThembaLethu Clinic Tracey Webster Mohammed SiddiqueRassool Nicola Baines University of Pennsylvania School of Medicine Amy H. Praestgaard, M.S Ann Tierney, M.S.

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