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Evidence for the link between markers of inflammation, coagulation and immune
activation and end organ disease
Session: Immune Activation/Inflammation and HIV DiseaseIAS Conference, Rome, July 2011
Jens Lundgren, MD
Chair – INSIGHT’s scientific steering committeeProfessor – Univ. of Copenhagen
Chief physician – Copenhagen University HospitalDirector – Copenhagen HIV Programme
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Linking markers to organ disease:prognostic and surrogate biomarkers
• Prognostic marker– Predicts the risk of disease
• Causal: marker of process involved in pathogenesis• Epiphenomenon: not linked causally (e.g. subclinical stages
of disease itself raises levels)• Surrogate marker
– Change in level reflects the extent of benefit of an clinically beneficial intervention• Occurs sooner after intervention is initiated than the disease
– Surrogates are usually prognostic markers, but the opposite is seldom true
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Validation of surrogate biomarkers
Associated with Clinical
Events
[Case-control or Cohort Studies]
Modify with
Treatment
[Biomarker Studies (Phase II/Pilot/
Vanguard Studies)]
Markers that can be reliably measuredStored specimensProspectively identified and adjudicated eventsExcellent follow-upStudy is large enough to do nested case-controlled studies
[Clinical Trials with Clinical Outcomes]
Rx Effect on Biomarkers Predicts
Rx Effect on Clinical Events
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Median CD4+ During Follow-up
0 0.33
0.670000000000001
1 1.33
1.67
2 2.33
2.67
3 3.33
3.67
4 4.33
4.67
5 5.33
5.67
6 6.33
6.67
70
100200300400500600700800
IL-2Control
Year
CD4+
cel
l cou
nt (/
µL)
Avg Difference:160 cells, p<.001
Time spent IL-2 Control< 300 cells 6% 9%> 600 cells 57% 36%
IL-2: 2071 1846 1829 1797 1757 1721 1410 878
Control: 2040 1928 1861 1803 1739 1648 1350 824
No. pts
ESPRIT/INSIGHT study group, NEJM 2009
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Primary EndpointOpportunistic Disease or Death
IL-2 ControlNo. Rate* No. Rate* HR (95% CI) p-value
158 1.13 165 1.21 0.93 (0.75, 1.16) 0.52
Predicted HR based on CD4+ difference = 0.74
* rate per 100 person years
ESPRIT/INSIGHT study group, NEJM 2009
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Soluble Biomarkers of Inflammation & Coagulation in HIV
Biological process: Name of marker: Marker of:
Activation of:
immune cells, endothelium, platelets, and coagulation
Interleukin-6 hs-CRPsCD14D-dimerP-selectinsCD40 ligand
LymphocyteAcute phase reactantMacrophage/monocytefibrinolysisplatelets + endotheliumplatelets + endothelium + lymphocytes
Organ dysfunction
hyalyronic acid, FIB-4 NT-proBNPADMAeGFR, protinuria
LiverHeartEndotheliumkidney
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ESPRIT and SMART Control Group: Deaths by D-dimer Quartile at Study Entry
ESPRIT SMARTD-dimer levels:>0.38 g/mL0.26-0.380.19-0.25<0.19
D-dimer levels:>0.37 g/mL0.22-0.370.13-0.21<0.13
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ESPRIT Control Group: Hazard Ratios (D-dimer Q4/Q1) for Death by 4-Year Intervals
1
10
100H
R (4
th/1
st Q
uarti
le)
p-value = 0.18 for change in HR over follow-up
1st 4 years follow-up > 4 years follow-up# deaths, quartile 4: 15 24# deaths, quartile 1: 4 4HR (95% CI): 3.48 (1.2-10.5) 5.59 (1.9-16.1)
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OR for Mortality Associated with Baseline Biomarker Levels for Early (0-2 years) and Late
(2 > years) Deaths in SMART
Odd
s Rati
o (4
th/1
st Q
uarti
le)
Paton et al, IAS 2009 (#MOPEA034)
hsCRP IL-6 D-dimerMedian Level (IQR) ≤ 2 yr > 2 yr ≤ 2 yr > 2 yr ≤ 2 yr > 2 yr
Deaths 3.13 (1.57-7.35)
3.69 (1.5-7.51)
3.58 (2.13-6.86)
3.72 (2.51-5.50)
0.45 (0.24-1.06)
0.31 (0.21-0.55)
Controls 2.08(0.83-4.83)
1.93 (0.84-5.11)
2.14(1.38-3.16)
2.33 (1.53-3.48)
0.24 (0.15-0.45)
0.24(0.15-0.38
# Deaths/Controls 95/188 71/137 92/184 67/133 94/188 69/128
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Association with risk of death is reduced the longer the time from measurement of
biomarker in persons with peripheral arterial disease
Vidula et al, Ann Intern Med 2008
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Trajectories in d-dimer Levels in ESPRIT Control Group at study entry, 12 and 36 Months
N=244
UpperLimit ofnormal
% above ULN(0.25 µg/mL)
39% 39% 42%
No significant change over time
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ESPRIT and SMART Control Group: Hazard Ratios for Quartiles (4th vs. 1st)
of D-dimer Levels at Study EntryESPRIT SMART
Event HR P-value HR P-valueDeath 4.5 <.0001 6.0 .0007AIDS 1.7 .23 5.3 .007CVD 2.0 .11 2.7 .009Non-AIDS malignancy 1.8 .14 1.3 .52Serious Non-AIDS (SNA) 2.4 .003 2.0 .009SNA or death from non-AIDS 2.3 .0007 2.6 .0002
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Change in D-Dimer* from Study Entry to 1 Month
0
0,1
0,2
0,3
≤ 400 401-10,000 10,000-50,000 >50,000Month 1 HIV RNA Level (copies/mL)
∆ D
-Dim
er (µ
g/m
L)
P=.0005 for trend
* DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL
Kuller et al, PLoSMed 2008
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D-dimer Levels After Starting ARTin SMART
-0.51
-0.30
0.00
-1
0
1
∆ D-
dim
er (l
oge
µg/m
L)
P=0.02 for trend
≤ 400(n=77)
401-10,000(n=25)
Month 6 HIV-RNA Level (copies/mL)
>10,000 (n=22)
All participants were off ART at baseline (n=254) Randomized comparison of immediate ART (VS; n=128) or
deferral (D
No difference in IL-6 and hsCRPBaker et al JAIDS 2011
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SMART: Comparison of Associations with Different Outcomes: Univariate ORs
(4th versus 1st quartile) – Case-Control Analyses
All cause mortality CVD AIDS
D-dimer 12.3 1.9 2.0
IL-6 11.7 3.7 1.7
Small HDL particles 0.13 0.50
sCD14 6.0 1.7 1.4
Total HDL particles 0.18 0.44
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Cellular markers of end organ disease in HIV
• Activation of CD4 and/or CD8 cells and markers of organ disease (cross-sectional studies)– Intima-media thickness (Hsu et al, AIDS 2006, Kaplan et al, JID 2011) and
arterial stiffness (Kaplan et al, Atherosclerosis 2011)• Linked to AIDS/death events
– In cross sectional analysis: • OR= 1.94 for risk of AIDS/death by 17% more %CD8+/HLA-
DR+/CD38+ (Kalayjian et al, JID 2010) • OR=6.5 for AIDS for 4th vs 1st quartile (Smurzynski et al, JAIDS 2010)
– In cohort studies• HR=1.61, P=0.042 (Hunt et al, CROI 2011)
• Still unclear– prognostic marker for organ disease– changes reflect surrogacy for benefit from interventions
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Use of markers in routine clinical practise
• Identify persons at increased risk of disease– Intriguing that D-dimer levels predict risk after multiple years– Unclear which interventions specifically benefits such patients over-
and-above benefits from common interventions used in internal medicine
– Will cause concern• Surrogates of interventions
– Remains to be established
Markers of inflammation and coagulationremains a research tool and
are not yet ready for routine use in HIV medicine
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Summary
• Many markers are prognostic but very few are surrogates of benefit for clinically useful interventions– Establishment of surrogacy is critical when assessing for
potentially useful anti-inflammatory interventions• This research requires large clinical endpoint driven RCT’s
• Soluble markers of inflammatory and coagulation• long-term risk of – particularly fatal - end-organ disease• D-dimer: potential for surrogacy of benefits from ART
– additional research required (e.g. START) • Data emerging on cellular markers of inflammation• Markers of inflammation and coagulation:
– useful tools to advance co-morbidity research agenda, – role in routine clinical practise remains to be determined.
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Acknowledgements
• INSIGHT network incl. executive, scientific and operational committee members + international coordinating centres and affiliated sites– Jim Neaton, Jason Baker, Jacquie Neuhaus, Debby Wentworth,
Andrew Phillips, Calvin Cohen and Steven Deeks• Peter Hunt, UCSF• Division of AIDS, NIAID
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UARTO: High CD8+ T Cell Activation at Month 6 of ART Predicts Subsequent Mortality in
Ugandans with VL<400
Hunt et al, CROI 2011 (306)
In Cox Proportional Hazards models, each 10% increase in the frequency of activated (%CD38+ HLA-DR+) CD8+ T cells was associated with an increased hazard of death even after adjustment for
baseline CD4 count (HR: 1.62, P=0.048) or month 6 CD4 count (HR: 1.61, P=0.042).