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Jason Baker MD, MS University of Minnesota / HCMC 22 nd July 2012

The Importance of Inflammation & Coagulation for Risk of Serious Non-AIDS Events: Results of Biomarker Studies. Jason Baker MD, MS University of Minnesota / HCMC 22 nd July 2012. Projects Motivated by Initial ( PLoS Med) Findings.

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Jason Baker MD, MS University of Minnesota / HCMC 22 nd July 2012

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  1. The Importance of Inflammation & Coagulation for Risk of Serious Non-AIDS Events: Results of Biomarker Studies Jason Baker MD, MS University of Minnesota / HCMC 22nd July 2012

  2. Projects Motivated by Initial (PLoS Med) Findings • Additional studies of predictive biomarkers and the biology underlying non-AIDS risk • Funding for cohort analyses and to confirm findings in other datasets (ESPRIT and SILCAAT) • Leveraging the experimental intervention to study the influence of HIV replication and ART

  3. % Diff. from General Population (MESA) Biomarkers Remain Elevated with Treated HIV HR adjusted for age, sex, race/ethnicity (RHS only adjusted for age and sex) • Among those with undetectable viral load (<400 copies/mL), hsCRP was 40% higher, IL-6 was 60% higher, and D-dimer was 49% higher, compared with controls from MESA Neuhaus et al JID 2010; 201(12): 1788, Folsom et al Am J Hematol 2009; 84(6):349, Harris et al Am J Med 1999; 106:506, and unpublished data (SMART adjusted ORs in table)

  4. Cumulative Deaths Over Time by D-dimer QuartileSMART/ESPRIT control arms with HIV RNA <500 at entry (n=3227) # Deaths N=45 N=31 N=15 N=5

  5. Cumulative Deaths Over Time by IL-6 QuartileSMART/ESPRIT control arms with HIV RNA <500 at entry (n=3227) # Deaths N=79 N=41 N=16 N=10

  6. 0.69 0.32 0.002 0.54 0.01 0.43 < 0.001 0.005 0.02 < 0.001 0.21 0.02 hsCRP D-dimer IL-6 Biomarker Associations Across OutcomesSMART/ESPRIT control arms with HIV RNA <500 at entry (n=3227) HR for Biomarkers (4th/1st quartile) adjusted for age, gender, race P-value AIDS Non-AIDS Cancer CVD All-Cause Mortality

  7. Central Question Raised by IL-6/D-dimer Findings: Among people with HIV on suppressive ART, does adjunctive treatment that reduces levels of IL-6 and D-dimer ALSO reduce risk for serious non-AIDS and mortality?

  8. The Effects of HIV Replication and ART 3 Complimentary Comparisons to Study the Effects of HIV Replication ON ART with HIV RNA <400 A) Baseline Comparison of Untreated vs. Treated OFF ART Randomize Randomize Defer ART (DC) Continue ART (VS) Start ART (VS) Stop ART (DC) Follow-up Follow-up B) Study the Effect of Starting ART C) Study the Effect of Stopping ART Biomarkers Studied: D-dimer, IL-6, CRP, Cystatin-C, Lipoprotein Particles, Apolipoproteins, ADMA, >10 coagulation factors Baker et al JAIDS 2012, Baker & Tracy CROI 2011, Baker et al JAIDS 2011, Baker et al AIDS 2011, Mocroft et al AIDS 2009, Duprez et al Atherosclerosis 2009, Kuller et al PLoS Med 2008

  9. D-dimer Levels 1 Month after ART Interruption 0.28 ∆ D-Dimer (µg/mL) 0.11 0.04 0.0 P=.0005 for trend >50,000 (N=39) ≤ 400 (N=34) 401-10,000 (N=30) 10,000-50,000 (N=29) Month 1 HIV RNA Level (copies/mL) Kuller et al PLoS Med 2008;5(10):1496

  10. General Thrombosis Model e.g., age, gene mutations, or synthetic function e.g., immune activation from endotoxemia e.g., trauma, stress Blood Clot Slide adapted from M. Cushman & R. Tracy

  11. Computational Model of Thrombin Generation via ‘Extrinsic’ (Tissue Factor) Coagulation Pathway Study differences in thrombogenesis based on the plasma composition of: •  f-II (prothrombin) • -- f-V • f-VII •  f-VIII • -- f-IX •  f-X •  TFPI •  AT-III •  Protein C Untreated n=197 ART-treated n=475 Slide c/o K. Brummel-Ziedins(Methods: J Bio Chem 1994;269:23367, ThromHaem 2008;6:104)

  12. Summary • Ongoing Inflammation and coagulation abnormalities likely contribute to risk for long term non-AIDS complications • D-dimer findings specifically have motivated new research to understand the impact of HIV infection, and ART, on coagulation homeostasis and disease • Large outcome trials like SMART change practice, establish new research agendas, and inform the design of a new generation of trials

  13. Acknowledgements Participants in: SMART ESPRIT All INSIGHT site investigators and, in particular, the many who contributed to these biomarker data Specific content contributions and analyses from: Jim Neaton, Jens Lundgren, Lew Kuller, Jacquie Neuhaus, Debby Wentworth, Kathleen Brummel-Ziedins and Russ Tracy

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