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Immune Activation in Treated HIV Infection: A New Paradigm
Slide 1.
Immune Activation in Treated HIV Infection: A New Paradigm
Slide 1.
10y Decreased Life Expectancy in Older HIV+ Adults in Modern ART Era
Slide 2.
Life Expectancy Further Reduced By Low CD4 Nadir
Slide 3.
Many age-associated morbidities also increased in treated HIV
Slide 4.
Increased Multi-morbidity in Older HIV+ Individuals (AGEhIV)
Slide 5.
Does HIV accelerate aging?
Slide 6.
HIV Primarily Increases Risk of Infection- and Smoking-Related Cancers
Slide 7.
Potential Role of Inflammation in Driving Morbidity in Older HIV+ Individuals
Slide 8.
An Important Clue from Nature
Slide 9.
T Cell Activation Remains Abnormally High During ART-mediated Viral Suppression
Slide 10.
Inflammatory markers are higher in treated HIV disease compared with HIV seronegatives, adjusted for demographics and CV risk factors
Slide 11.
Chronic Immune Activation May Also Cause Lymphoid Tissue Fibrosis
Slide 12.
What are the clinical consequences of persistent immune activation and inflammation during ART?
Slide 13.
A single measurement of IL-6 or D-dimer predicts morbidity/mortality over next 10y
Slide 14.
Inflammation Predicts Disease in Treated HIV Infection
Slide 15.
What can we do to reverse immune activation during suppressive ART now?
Slide 16.
Pick the Low-lying Fruit First
Slide 17.
Lifestyle Factors Contribute to Immune Activation in Treated HIV
Slide 18.
Statins Decrease Immune Activation and Aortic Plaque in Treated HIV Infection
Slide 19.
Aspirin Fails to Reduce Immune Activation or Improve Vascular Function (A5331)
Slide 20.
What if statins and lifestyle interventions are not enough?
Slide 21.
HIV Reservoirs Established in First Week of Infection and Continue to Release Virus on ART
Slide 22.
HIV RNA is Preferentially Expressed in Lymphoid Tissues and Gut
Slide 	23.
Blocking Asymptomatic CMV Replication with Valganciclovir Immune Activation
Slide 24.
CMV Sero-status Predicts Non-AIDS Events (and less so AIDS...): ICONA Cohort
Slide 25.
Microbial Translocation ("Leaky Gut") as a Cause of Immune Activation in HIV
Slide 26.
Microbial Translocation Persists on ART Particularly in Those with Low CD4 Nadirs and Poor CD4 Recovery
Slide 27.
Which inflammatory pathways most strongly predict morbidity and mortality?
Slide 28.
Gut Barrier Dysfunction and Innate Immune Activation Predict Mortality during Suppressive ART SOCA cohort
Slide 29.
Adaptive Immune Defects More Important in Resource-limited Settings?
Slide 30.
Unlike Aging, Classical Markers of T Cell Senescence Fail to Predict Mortality during Suppressive ART SOCA cohort
Slide 31.
CD8+ T Cell Proliferation & Maturation with CMV and Aging
Slide 32.
Maturational/Proliferative CD8+ T Cell Defect in HIV
Slide 33.
Low (Not High) CD57 on CD28- CD8+ T Cells Predicts Mortality in Treated HIV
Slide 34.
HIV-Mediated Immune Activation and Aging Current Paradigm
Slide 35.
Does systemic inflammation necessarily reflect the degree of inflammation in all tissues (and risk for all morbidities)?
Slide 36.
Lower But Persistently Abnormal Immune Activation with Very Early ART (RV254)
Slide 37.
Immune activation setpoint may be lower if ART is started very early.
Slide 38.
Reduced but Persistently High Risk of TB with Early ART: Temprano Trial
Slide 39.
Reduced but Persistently High Risk of Infections and Cancer with Early ART: START Trial
Slide 40.
Persistent Risk of TB Even with Early ART: Temprano Trial
Slide 41.
Risk of infections decreases with very early ART, but remains abnormally high
Slide 42.
No Difference in Cognitive Improvement with Early vs. Delayed ART
Slide 43.
START: No Difference in Cardiovascular Outcomes with Early vs. Delayed ART
Slide 44.
In Contrast, Interrupting ART Strongly Increased CAD, Renal, Liver Disease SMART Trial
Slide 45.
Why Didn't Non-infectious Morbidities Decrease in START Trial?
Slide 46.
Cardiovascular Complications Much Lower in START than SMART Role of CD4 nadir
Slide 47.
Theoretical Model for Drivers of Immune Activation during Suppressive ART
Slide 48.
Can we find the tree trunk?
Slide 49.
Summary
Slide 50.
Acknowledgements
Slide 51.