Post on 24-Feb-2016
description
transcript
www.ias2011.org
Immuno-virological discordance in treated suppressed patients
Julià Blanco
IGTP/IrsiCaixa
Badalona, Catalonia, Spain
www.ias2011.org
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 = 17V
L
VL
VL
CD
4
CD
4
CD
4
Time (months)
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Clinical Relevance Incidence:
Ranging from 6 to 30%
Consequences:
Higher mortality risk Higher clinical progression
o AIDS relatedo non AIDS related
Gutiérrez et al, 2008, Curr HIV Res 6:100-107
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
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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. 2008.
…and many othersBased on: Defined by:
CD4 T cell increases (100/200) Short-term outcomeAbsolute counts (350/500) Long-term outcome
A definition of discordance
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Short- or long-term
Corbeau & Reynes 2011, BLOOD 117:5582-95590
CD
4 T
cell
coun
t
1-6 months 2 years >4 years
20-30/month 200-250 >300-350
Increase or absolute counts
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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.
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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: 975-983
CD57PD-1CD95
Halflife
Maturation of T cells modifies the phenotype and shortens lifespan
Naive cells
AntigenExperienced
cells
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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 cellsRegulatory cellsMemory cellsActivated cells
ThymusBONE
MARROW
ANTIGENIL-7
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Less and older cells
ANTÍGEN
ThymicOutput
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 cellsRegulatory cellsMemory cellsActivated cells
ThymusBONE
MARROW
IL-7
Naive cell expansion
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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: 827-34)
Preclinical carotid artery disease (Kaplan et al, 2011, JID 203:452-63)
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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: 1637-46)
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)
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How to treat discordance?
Identifying patients at risk
We have accumulated lots of Post HAART data
Need pre HAART markersNadir?Exposure to low CD4 cell countImmunological/soluble markers
Evaluate short term responses,
Treat early
and then what to do?
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THYMUSBONE
MARROW
ANTÍGENIL-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
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Tissue damage
Residual Viral replication
Lymphopoiesis and Thymic function (Sauce et al 2011, BLOOD 117: 5142-51)
Fibrosis in Lymph Nodes (Zeng et al, 2011, JCI 121: 998-1008)
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)
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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)
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Therapeutic optionsCD8 T cellActivation
CD4 T cellActivation
CD4 T cellcounts
RALTEGRAVIR (48 w) Transient increase
MASSANELLA (Unpublished)
RALTEGRAVIR (24 w) HATANOJID 2011
MARAVIROC (24 w) STEPANYUKAIDS 2009
VALGANCICLOVIR (8 w) HUNTJID 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??
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Future actions.
Full characterization of ImmunosenescenceB 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
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Thanks!!
Marta MassanellaMª José BuzónMª Carmen PuertasElisabet GarciaSilvia MarfilRafi AyenTania GonzalezEulalia GrauJavier Martínez-PicadoBonaventura ClotetJulià Blanco
Eugenia NegredoJordi PuigNúria Pérez-ÁlvarezRoser EscrigJessica ToroJosé MoltóJosep M Llibre