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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 Disease IAS Conference, Rome, July 2011 Jens Lundgren, MD Chair – INSIGHT’s scientific steering committee
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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 Disease IAS Conference, Rome, July 2011 Jens Lundgren, MD Chair – INSIGHT’s scientific steering committee Professor – Univ. of Copenhagen Chief physician – Copenhagen University Hospital Director – Copenhagen HIV Programme
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
Validation of surrogate biomarkers [Clinical Trials with Clinical Outcomes] [Biomarker Studies (Phase II/Pilot/ Vanguard Studies)] [Case-control or Cohort Studies] Rx Effect on Biomarkers Predicts Rx Effect on Clinical Events Associated with Clinical Events Modify with Treatment • Markers that can be reliably measured • Stored specimens • Prospectively identified and adjudicated events • Excellent follow-up • Study is large enough to do nested case-controlled studies
Median CD4+ During Follow-up Avg Difference: 160 cells, p<.001 No. pts ESPRIT/INSIGHT study group, NEJM 2009
Primary EndpointOpportunistic Disease or Death ESPRIT/INSIGHT study group, NEJM 2009
ESPRIT and SMART Control Group: Deaths by D-dimer Quartile at Study Entry ESPRIT SMART D-dimer levels: >0.37 g/mL 0.22-0.37 0.13-0.21 <0.13 D-dimer levels: >0.38 g/mL 0.26-0.38 0.19-0.25 <0.19
ESPRIT Control Group: Hazard Ratios (D-dimer Q4/Q1) for Death by 4-Year Intervals HR (4th/1st Quartile) p-value = 0.18 for change in HR over follow-up
OR for Mortality Associated with Baseline Biomarker Levels for Early (0-2 years) and Late (2 > years) Deaths in SMART Odds Ratio (4th/1st Quartile) Paton et al, IAS 2009 (#MOPEA034)
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
Trajectories in d-dimer Levels in ESPRIT Control Group at study entry, 12 and 36 Months Upper Limit of normal No significant change over time N=244 % above ULN (0.25 µg/mL) 39% 39% 42%
ESPRIT and SMART Control Group: Hazard Ratios for Quartiles (4th vs. 1st) of D-dimer Levels at Study Entry
Change in D-Dimer* from Study Entry to 1 Month ∆ D-Dimer (µg/mL) P=.0005 for trend ≤ 400 401-10,000 10,000-50,000 >50,000 Month 1 HIV RNA Level (copies/mL) * DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL Kuller et al, PLoSMed 2008
D-dimer Levels After Starting ARTin SMART • 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 hsCRP Baker et al JAIDS 2011
SMART: Comparison of Associations with Different Outcomes: Univariate ORs (4th versus 1st quartile) – Case-Control Analyses
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
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 coagulation remains a research tool and are not yet ready for routine use in HIV medicine
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.
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
UARTO: High CD8+ T Cell Activation at Month 6 of ART Predicts Subsequent Mortality in Ugandans with VL<400 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). Hunt et al, CROI 2011 (306)