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Why is inflammation elevated in treated HIV infection and why does it matter?

Why is inflammation elevated in treated HIV infection and why does it matter?. Steven G. Deeks Professor of Medicine University of California, San Francisco. Many Age-associated Diseases Are More Common in Treated HIV Disease Than In Age-matched Uninfected Persons. Cardiovascular disease

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Why is inflammation elevated in treated HIV infection and why does it matter?

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  1. Why is inflammation elevated in treated HIV infection and why does it matter? Steven G. DeeksProfessor of MedicineUniversity of California, San Francisco

  2. Many Age-associated Diseases Are More Common in Treated HIV Disease Than In Age-matched Uninfected Persons Cardiovascular disease Cancer (non-AIDS) Bone fractures/osteopenia Left ventricular dysfunction Liver failure Kidney failure Cognitive decline Frailty Immune system Multiple factors likely explain this increased risk, including co-morbid conditions and antiretroviral drug toxicity

  3. Co-morbid conditions common in HIV-infected adults HIV-infected adults age 50-55 similar to uninfected adults > 65 Schouten J AIDS 2012

  4. Inflammatory Biomarkers Predict Risk for All-Cause Mortality among Treated Adults T cells Microbes Fibrosis Coagulation Innate

  5. Chronic inflammation is also harmful in non-HIV-infected adults “Over the past decade, it has become widely accepted that inflammation is a driving force behind chronic diseases that will kill nearly all of us . . .” Science , 2010 Courtesy of Peter Reiss

  6. Is there something unique about inflammation in HIV disease?

  7. T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal” HIV + Untreated (n=82) HIV + ART (n=65) HIV – (n=132) Hunt et al JID 2003, PLoS ONE 2011 and unpublished

  8. % Diff. from General Population (MESA) Many common plasma biomarkers of inflammation are also higher in treated HIV disease than “normal” • 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

  9. Among treated adults, D-dimers (and perhaps other biomarkers) are stable over years Courtesy of Jens Lundgren

  10. Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE) Hunt et al CROI 12

  11. A single measurement of D-dimers predicts mortality through 8 years of observation, whereas effect wanes in 2-3 years in general population (SMART/ESPRIT; n=3227) There were only 5 deaths over 8 years among those in the lowest quartile (as compared to 45 deaths in highest quartile) Lane et al; CROI 2011

  12. Are all of the biomarkers describing the same mechanistic pathway?

  13. Biomarkers covering apparently unique pathways (inflammation and coagulation) provided independent prognostic capacity in FRAM Associations for CRP and Fibrinogen persist when CD4 >500 Tien et. al. JAIDS 2010;55(3):316-322

  14. Among adults with durable viral suppression, a low CD4+ T cell count is associated with significant T cell abnormalities P = 0.0001 P < 0.0001 P = 0.05 P < 0.0001 Hatano CROI 2011

  15. After controlling for CD4+ T cell count, inflammatory biomarkers have stronger prognostic effect that T cell activationtreated infection Hunt et al CROI 12

  16. Early ART Also Appears to Reduce Residual T Cell Activation during ART Jain et al, CROI 2011

  17. What causes HIV-associated inflammation?

  18. HIV-associated fat Metabolic syndrome CMV Excess pathogens HIV production HIV replication Inflammation ↑ Endothelium adhesion ↑ Monocyte activation Dyslipidemia Hypercoagulation/ thrombotic events Endothelial dysfunction HIV-mediated loss of regulatory cells (Tregs) Microbial translocation

  19. Conclusions Inflammation during treated HIV disease is unique Higher than expected Stable over time Stronger prognostic significance Multiple mechanisms cause activation Residual HIV production (or replication) Microbial translocation CMV and other co-pathogens Loss of immunoregulatory responses Lymphoid fibrosis Metabolic syndrome, abdominal obesity Treatment toxicity (e.g., telomerase inhibition)

  20. Acknowledgements INSIGHT Jason Baker Cliff Lane Andrew Phillips Jim Neaton Jens Lundgren Elsewhere Netanya Sandler Danny Douek Mike Lederman (CLIC) Peter Reiss Rafick Sekaly Tim Schacker UCSF Peter Hunt Hiroyu Hatano Priscilla Hsue Jeff Martin Becky Hoh Ma Somsouk Vivek Jain Elizabeth Sinclair Mike Busch Steve Yukl Joe Wong Mike McCune

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