Inflammation biomarkers in HIV infection Laurence WEISS
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Predictive biomarkers in HIV infection 1.Reflect The extent of
immune deficiency The level of HIV replication and of HIV reservoir
The level of chronic immune activation/inflammation The strength
and quality of HIV-specific immune responses 2.Type of biomarkers
Virologic, immunologic, activation/inflammatory and genetic
biomarkers (HLA, CCR5, KIR) Predictive biomarkers for HIV
progression in untreated and/or treated patients Predictive
biomarkers for the occurrence of co morbidities in patients with
ART-mediated viral suppression
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Predictive biomarkers in HIV infection 1.Reflect The extent of
immune deficiency The level of HIV replication and of HIV reservoir
The level of chronic immune activation/inflammation The strength
and quality of HIV-specific immune responses 2.Type of biomarkers
Virologic, immunologic, activation/inflammatory and genetic
biomarkers (HLA, CCR5, KIR) Surrogate markers for HIV progression
in untreated and/or treated patients Surrogate markers for the
occurrence of co morbidities in patients with ART-mediated viral
suppression
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- Membrane expression of the activation markers HLA-DR (MHC
class II), CD38, CD25, CD70 - Intranuclear expression of Ki-67
(cell cycle) T-cell activation markers in the chronic phase of HIV
infection Giorgi, JID 99 Leng et al, J.AIDS 2001 Hazenberg et al,
AIDS 2003 HLA-DR CD38 CD4 CD8 Healthy donorSurvival > 18
MSurvival < 6 M T-cell activation is associated with
mortality
Soluble activation biomarkers 2- microglobulin, neopterin
hsCRP: acute phase protein IL-6, IL-1RA, sTNFR: Cytokines and CR of
innate immunity D dimer: marker of procoagulant activity sCD14:
acute phase protein, monocyte activation sCD163: secreted by
activated monocytes/macrophages ICAM, VCAM: endothelial
activation/dysfunction IP-10: chimiokine produced in response to
IFN Fahey, NEJM 1990, Kuller, PloS Med 2008, Sandler, JID 2011,
Burdo, JID 2011
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Predictive biomarkers in primary HIV infection
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Deeks, Blood 2004 Immune activation set point during early HIV
infection: predictive of subsequent CD4 T-cell changes
independently of viral load CD38-MFI on CD8 T cells Time (weeks)
proportion with CD4 > 350 Time to a CD4 T-cell count less than
350 cells/mm 3 68 recently HIV-infected adults before ART CD8
T-cell activation set point
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The early level of double negative CD4 - CD8 - T cells predicts
the level of T-cell activation at set point R= -0.76 p= 0.004 R=
-0.60 p= 0.035 Petitjean, Chevalier et al, AIDS 2012 DN T cells
might play a role in the control of the harmful systemic immune
activation DN T cells produce anti-inflammatory cytokines
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BaselineM6 plasma IL-1RA (log pg/mL) IL-1RA An innate immune
setpoint ? plasma sCD14 at baseline (ng/mL) plasma IL-1RA at
baseline (log pg/mL) % CD38 + HLA-DR + CD8 T cells at M6 % CD38 +
HLA-DR + CD8 T cells at M6 % CD38 + HLA-DR + CD8 T cells at M6 log
Th17/Treg ratio at baseline Acute HIV baseline Acute HIV M6 Chronic
HIV (untreated) Sepsis (S. aureus) n=27 n=25n=20n=10 plasma 16S
rDNA (copies/L) Chevalier, Plos Path 2013 Innate immune activation
set point plasma sCD14 (ng/mL) BaselineM6 sCD14
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Predictive biomarkers in untreated chronic infection
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T-cell activation, predictive marker of AIDS progression
independent of VL Proportion of CD70+CD4+ T cells > median ()
< median (- - -) Giorgi, JAIDS 1998 Hatzenberg, AIDS 2003
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Relationship between T-cell activation and HIV reservoir The
proportion of HLA-DR+ CD38+/ CD8+ T cells before TI predicts the
increase in total HIV- DNA levels between baseline and M12 of TI
(ANRS 116 SALTO) (r= 0.552; p = 0.004) Weiss, PlosOne 2010 Positive
relationship between total HIV-DNA and CD8 and CD4 T-cell
activation at 12 months of TI See poster Weiss et al MOPDA0106
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Predictive values of soluble biomarkers in cohort studies C
Reactive Protein Level: associated with AIDS - free survival
Multivariate model VariableRelative Time (95% CI) P Value CRP, mg/L
2.3 1.0 0.86 (0.68-1.09) 0.63 (0.51-0.79) 0.21
Fibrinogen and CRP, independent predictors of mortality in the
FRAM study Tien, JAIDS 2010 922 HIV-infected participants > 85%
on cART (past or present) 70% with history of AIDS 50% HIV-RNA BLD
20% HCV+ 5-year mortality risk
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Biomarker levels associated with progression in RCT All-cause
mortality: higher for patients with CD4> 350 randomly assigned
to CD4- guided interruption of ART (DC) than continuous ART (VS)
Most common causes of death: non AIDS-malignancy, CVD Case control
study (85 cases and 170 matched controls) ; a study to compare DC
and VS participants for biomarker changes (249 DC and 250 VS)
Baseline IL-6, hsCRP and D-dimer associated with all cause
mortality Higher BL IL-6, D-dimer and hsCRP: related to CVD IL-6
and D-dimer at 1 mo in the DC group. Increases related to HIV-RNA
levels BL or latest IL-6 or hsCRP: predictive of OI Elevated
pre-ART levels of hsCRP, IL-6 and D-dimer: strongly associated with
early mortality after ART initiation Ledwaba, PlosOne 2012 Other
markers associated with disease progression (case control ACTG 384
and 5015) : sTNFR-1, sCD27 and sCD40L Kalayjian, JID 2010 Kuller
Plos Medicine 2008 Rodger JID 2008 Duprez PlosOne 2012 SMART
PHIDISA (South Africa trial)
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IP10 and sCD163 levels predict subsequent CD4 counts Predictive
inflammatory biomarkers in HIV controllers Lambotte, IAS 2014,
MoAA0102
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Predictive biomarkers in patients with chronic infection and
ART-mediated viral suppression Residual immune activation and
inflammation under ART
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Hunt, JID, 2003 Hunt, JID 2008 Persistence of residual chronic
T-cell activation in ART- treated patients n = 30 HIV+ with CV <
75 c/mL
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Despite long-term viral suppression, soluble inflammatory
biomarkers remain higher in patients compared to the general
population % Diff. from General Population (MESA) Neuhaus JID
2010
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Inflammation with ongoing viral replication Inflammation with
ongoing viral replication Inflammation under ART Inflammation under
ART Inflammation HIV- controls Inflammation HIV- controls
MonocytespDCs Innate Immunity NK Adaptative immunity
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Nested case-control study in SMART 74 deaths + 120 CV events +
100 AIDS events (20 NA) / N= 5472 2 controls/case Most patients
under ART with VL < 400 cp/mL Baseline plasma sCD14, IFABP, LPS,
EndoCAB SCD14: marker of monocyte activation (acute phase protein)
not necessarily indicative of microbial translocation Sandler, JID
2011 Plasma levels of sCD14: independent predictor of mortality in
the SMART study
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Can we improve prediction of mortality by adding inflammatory
biomarkers? Veterans Aging Cohort Study: 1 302 veterans under ART;
70% with VL
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Cardio- Vascular Diseases Cognitive disorders Inflammation
CANCER CHRONIC VIRAL INFECTIONS (HIV) Osteoporosis
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Cardiovascular comorbidities In HIV infection : Alteration in
biomarkers known or potentially associated with CVD in non-HIV
infected individuals HDL cholesterol depletion Chronic inflammation
( CRP, IL-6, sCD14) Endothelial activation/dysfunction ( VCAM,
ICAM) Activation of coagulation ( D-dimer) Only partially
normalized during sucessfull ART Atherosclerotic plaque
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Association of soluble CD163 with arterial inflammation
Hypothesis: Arterial inflammation -> HIV + pts compared with
non-HIV FRS-matched controls -Correlated to mono/M activation
(CD163) 81 participants. 27 HIV pts under ART (CD4 nadir 100)
FDG-PET (activated M : high metabolic rate) VariablesHIV+ (N= 27)
FRS-matched HIV- (N= 27) HIV- atheroscl (N= 27) P value Mean FDG
uptake (95% CI) 2.23 (2.07-2.40)1.89 (1.80-1.97)2.13
(2.03-2.23)