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

Adapted from: Piketty et al AIDS 1998, 12:745–750 Description 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 N = 92 N = 17 N = 17 VL CD4 Time (months)

Clinical Relevance  Incidence:  Ranging from 6 to 30%  Consequences:  Higher mortality risk  Higher clinical progression o AIDS related o non AIDS related Gutiérrez et al, 2008, Curr HIV Res 6: Gazzola et al 2009, CID 48:328–37  WELBB01 - Oral Abstract  Risk of progression to AIDS or death in relation to CD4 cell levels in HIV-infected adults with a suppressed viral load under cART  Heiner C. Bucher

 CD4 T cell levels < 350–500 cells/mL after 4–7 years of effective HAART  Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services  …and many others  Based on:Defined by:  CD4 T cell increases (100/200)Short-term outcome  Absolute counts (350/500)Long-term outcome A definition of discordance

Short- or long-term Corbeau & Reynes 2011, BLOOD 117: CD4 T cell count 1-6 months 2 years >4 years 20-30/month > Increase or absolute counts

What immunology says Massanella et al, 2010 AIDS, 24:  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.

Precursors (Bone Marrow / Thymus) The life of a CD4 T cell CD45RA+ CD27+ CCR7+ CD31+ CD45RA+ CD27+ CCR7+ CD31- CD45RA- CD27+ CCR7+ CD45RA- CD27+ CCR7- CD45RA+/- CD27- CCR7- Adapted from Appay et al 2009, Cytometry 73A: CD57 PD-1 CD95 Half life Maturation of T cells modifies the phenotype and shortens lifespan Naive cells Antigen Experienced cells

The life of CD4 T cells Adapted from: Gazzola et al 2009, CID 48:328–37 The number of CD4 T cells is controlled by production (Thymus), proliferation (antígen o cytokines) and destruction (Apoptosis). Additional control mechanisms: regulatory cells and homeostasis. Naive cells Regulatory cells Memory cells Activated cells Thymus BONE MARROW ANTIGENANTIGEN IL-7

Less and older cells ANTÍGEN Thymic Output Cell Death Activation Low precursor and thymic output + increased activation accumulation of cells in late stages of maturation, increasing global susceptibility to cell death (for CD4 T cells) Naive cells Regulatory cells Memory cells Activated cells Thymus BONE MARROW IL-7 Naive cell expansion

Immunosenescence  Affects CD4, CD8 and probably other immune cells  One of the characteristics of AGING, and reponsible for increased age-related diseases  T cell activation is associated with  CD4 T cell decay (Bofill et al, 1996, AIDS 10: )  Preclinical carotid artery disease (Kaplan et al, 2011, JID 203:452-63)

Soluble biomarkers  As for T cell activation, Inflamatory, endothelial disfunction or coagulation markers are not completely normalized by HAART.  Pretherapy values relevant (Boulware et al 2011, JID 203: )  CRP, IL-6 (inf), D dimer (coag) and Hyaluronic acid (fib)  sCD14,  GALT disfunction, independent predictor of mortality (Sandler et al 2011, JID 203:780-90)

How to treat discordance? Identifying patients at risk  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, Treat early and then what to do?

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

Tissue damage Residual Viral replication Lymphopoiesis and Thymic function (Sauce et al 2011, BLOOD 117: ) Fibrosis in Lymph Nodes (Zeng et al, 2011, JCI 121: ) GALT and microbial translocation (higher levels of LPS, sCD14) Associated with higher CD4 and CD8 T cell activation (Buzon Massanella et al 2010, Nat Med 16:460–65)

HAART Toxicity and efficacy Coinfections NRTI toxicity (Negredo E, et al AIDS 2004; 18:459–463) IP vs NNRTI (Badley AD. Cell Death Differ 2005; 12:924–931) Most frequent combinations NNRTI vs IP o abacavir-lamivudina vs. tenofovir-emtricitabina work similarly (Negredo et al 2010, CID 48:328–37) New regimens (RAL, MRV) HCV, unclear role (Negredo et al 2010, CID 48:328–37) CMV, immunosenescence /response to HAART (Appay et al 2011, AIDS In press)

Therapeutic options CD8 T cell Activation CD4 T cell Activation CD4 T cell counts RALTEGRAVIR (48 w) Transient increase MASSANELLA (Unpublished) RALTEGRAVIR (24 w) HATANO JID 2011 MARAVIROC (24 w) STEPANYUK AIDS 2009 VALGANCICLOVIR (8 w) HUNT JID 2011 HYDROXICLOROQUINE In %PICONI BLOOD 2011 IL-2 Is reduction in CD8 T cell activation sufficient to reduce risk??, should we also reduce CD4 T cell activation??

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

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 Núria Pérez-Álvarez Roser Escrig Jessica Toro José Moltó Josep M Llibre