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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