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Immuno-virological discordance in treated suppressed patients

Immuno-virological discordance in treated suppressed patients

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Immuno-virological discordance in treated suppressed patients

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  1. Immuno-virological discordance in treated suppressed patients Julià Blanco IGTP/IrsiCaixa Badalona, Catalonia, Spain

  2. Description N = 92 N = 17 N = 17 CD4 CD4 CD4 VL VL VL Time (months) Adaptedfrom: Piketty et al AIDS 1998, 12:745–750 immunological response: increase in CD4 cells > 50 cell µL above baseline virological response: decrease in plasma pVL > 1 log10 below baseline or achievement of undetectable level

  3. Clinical Relevance • Incidence: • Ranging from 6 to 30% • Consequences: • Higher mortality risk • Higher clinical progression • AIDS related • non AIDS related Gazzola et al 2009, CID 48:328–37 Gutiérrez et al, 2008, Curr HIV Res 6:100-107 WELBB01 - Oral Abstract Riskofprogressionto AIDS ordeath in relationto CD4 celllevels in HIV-infectedadultswith a suppressed viral load undercART Heiner C. Bucher

  4. A definition of discordance • CD4 T celllevels < 350–500 cells/mLafter 4–7 yearsofeffective HAART • Guidelinesforthe use ofantiretroviralagents in HIV-1 infectedadultsandadolescents. DepartmentofHealthand Human Services. 2008. • …and many others • Based on: Defined by: • CD4 T cell increases (100/200) Short-term outcome • Absolute counts (350/500) Long-term outcome

  5. Short- or long-term CD4 T cellcount 20-30/month 200-250 >300-350 1-6 months 2 years >4 years Corbeau & Reynes 2011, BLOOD 117:5582-95590 Increase or absolute counts

  6. What immunology says Massanella et al, 2010 AIDS, 24:959-68 • Thymic output (CD4) • Sensitivity to cell death (CD4) • CD4 T cell activation • CD8 T cell activation • Nadir, best predictor. CD4 T cell death and activation associate with discordance in MV analysis.

  7. The life of a CD4 T cell Precursors (Bone Marrow / Thymus) Half life CD45RA+ CD27+ CCR7+ CD31+ Naive cells Antigen Experienced cells CD45RA+ CD27+ CCR7+ CD31- CD45RA- CD27+ CCR7+ CD45RA- CD27+ CCR7- CD57 PD-1 CD95 CD45RA+/- CD27- CCR7- Maturationof T cellsmodifiesthephenotypeandshortenslifespan AdaptedfromAppay et al 2009, Cytometry 73A: 975-983

  8. The life of CD4 T cells Thymus BONE MARROW Naive cells Regulatory cells Memory cells Activated cells IL-7 ANTIGEN Thenumberof CD4 T cellsiscontrolled by production (Thymus), proliferation (antígen o cytokines) anddestruction (Apoptosis). Additional control mechanisms: regulatorycellsand homeostasis. Adaptedfrom: Gazzola et al 2009, CID 48:328–37

  9. Less and older cells Thymus BONE MARROW Naive cells Regulatory cells Memory cells Activated cells Thymic Output IL-7 ANTÍGEN Naive cell expansion Activation Cell Death Low precursor andthymic output + increasedactivationaccumulationofcells in late stagesofmaturation, increasing global susceptibilitytocelldeath (for CD4 T cells)

  10. Immunosenescence • Affects CD4, CD8 andprobablyotherimmunecells • Oneofthecharacteristicsof AGING, andreponsibleforincreasedage-relateddiseases • T cellactivationisassociatedwith • CD4 T celldecay(Bofill et al, 1996, AIDS 10: 827-34) • Preclinicalcarotidarterydisease(Kaplan et al, 2011, JID 203:452-63)

  11. Soluble biomarkers • As for T cellactivation, Inflamatory, endothelialdisfunctionorcoagulationmarkers are notcompletelynormalized by HAART. • Pretherapyvaluesrelevant(Boulware et al 2011, JID 203: 1637-46) • CRP, IL-6 (inf), D dimer (coag) andHyaluronicacid (fib) • sCD14, • GALT disfunction, independentpredictorofmortality(Sandler et al 2011, JID 203:780-90)

  12. How to treat discordance?Identifying patients at risk Treat early and then whatto do? • We have accumulated lots of Post HAART data • Need pre HAART markers • Nadir? • Exposure to low CD4 cell count • Immunological/soluble markers • Evaluate short term responses,

  13. How to treat discordance?Identifying primary causes THYMUS 2- BACTERIAL TRANSLOCATION BONE MARROW Thymic output IL-7 ANTÍGEN Activation Naive cell expansion 1- TISSUE DAMAGE 5- RESIDUAL VIRAL REPLICATION Cell Death 3- COINFECTIONS 4- HAART

  14. Tissue damage LymphopoiesisandThymicfunction(Sauce et al 2011, BLOOD 117: 5142-51) Fibrosis in LymphNodes(Zeng et al, 2011, JCI 121: 998-1008) GALT andmicrobialtranslocation (higherlevelsof LPS, sCD14) Residual Viral replication Associatedwithhigher CD4 and CD8 T cellactivation (BuzonMassanella et al 2010, Nat Med 16:460–65)

  15. HAART Toxicity and efficacy NRTI toxicity(Negredo E, et al AIDS 2004; 18:459–463) IP vs NNRTI (Badley AD. CellDeathDiffer 2005; 12:924–931) Mostfrequentcombinations NNRTI vs IP o abacavir-lamivudina vs. tenofovir-emtricitabinaworksimilarly(Negredo et al 2010, CID 48:328–37) Newregimens (RAL, MRV) Coinfections HCV, unclear role (Negredo et al 2010, CID 48:328–37) CMV, immunosenescence /response to HAART (Appay et al 2011, AIDS In press)

  16. Therapeuticoptions Isreduction in CD8 T cellactivationsufficientto reduce risk??, shouldwealso reduce CD4 T cellactivation??

  17. Future actions. • Full characterization of Immunosenescence • B cells, NK cells. Expanding the concept immunoreconstitution. • Search for Pre-HAART markers? • New therapeutic approaches (Fibrosis inhibitors, antiinflamatory drugs, GH, IL-7) • Combined approaches, long-term trials

  18. Thanks!! • Marta Massanella • Mª José Buzón • Mª Carmen Puertas • Elisabet Garcia • Silvia Marfil • Rafi Ayen • Tania Gonzalez • Eulalia Grau • Javier Martínez-Picado • Bonaventura Clotet • Julià Blanco • Eugenia Negredo • Jordi Puig • NúriaPérez-Álvarez • RoserEscrig • Jessica Toro • José Moltó • Josep M Llibre