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HIV and Aging: A Paradigm Shift in the Management of HIV Disease
Slide 1.
HIV and Aging: A Paradigm Shift in the Management of HIV Disease
Slide 1.
Outline
Slide 2.
HAART: "The First Decade"
Slide 3.
Dramatically Improved Life Expectancy in Early HAART Era
Slide 4.
HAART: Major limitations of 1st Decade
Slide 5.
Early HAART regimens were no fun...
Slide 6.
Modern HAART
Slide 7.
HAART: Major limitations of 1st Decade
Slide 8.
Facial Lipoatrophy
Slide 9.
HAART: Major limitations of 1st Decade
Slide 10.
<50% Patients Achieved Complete Viral Suppression on Early PI-based Regimens
Slide 11.
Incidence of Failure of ≥ 2 ART Regimens Has Declined Dramatically in North America
Slide 12.
Why is the risk of drug resistance declining over time?
Slide 13.
New HAART Era
Slide 14.
Salvage Regimens with 3 New "Active" Agents Can Have High VL Success Rates
Slide 15.
Challenges of the "2nd Decade"
Slide 16.
Does HAART restore normal health?
Slide 17.
CNICS: ˜ 40% of patients with a nadir CD4 < 200 fail to achieve a normal CD4+ cell count, even after 10 years of viral suppression (n=300)
Slide 18.
CD4 count at HAART Initiation, 2003-5
Slide 19.
Improved Survival in Early HAART Era
Slide 20.
Late HAART Era Extended Life Expectency Even Further
Slide 21.
Late HAART Era Patients Still Have a 10y Shorter Life Expectancy than HIV- Controls
Slide 22.
ART-CC: Treated patients do not have a normal life span, particularly if therapy is started late
Slide 	23.
Almost 2/3 of All Deaths in Late HAART Era Are Non-AIDS-associated-ANRS E19
Slide 24.
Do HIV+ Patients Have ↑ Risk for non-AIDS Events than General Population?
Slide 25.
Cardiovascular Disease
Slide 26.
Increased Cardiovascular Disease Event Rates in HIV-infected Patients
Slide 27.
Risk of MI: HIV + Compared to HIV (-)
Slide 28.
Carotid Artery Intima-Media Thickness (IMT) A marker of Atherosclerosis and CV Risk
Slide 29.
Untreated HIV+ Patients Have Abnormal Levels of Atherosclerosis Independent of Traditional RFs
Slide 30.
Elite Controllers Also Have Abnormal Atherosclerosis Independent of Traditional RFs
Slide 31.
Is the increased risk of CAD in HIV due to ARVs?
Slide 32.
Increasing Exposure to PIs Increases Risk of Cardiac Events, Independent of Other Factors (DAD cohort)
Slide 33.
NRTIs and MI Risk in D:A:D
Slide 34.
Is the increased risk of CAD in HIV due to the virus itself?
Slide 35.
SMART Study: Risk of CVD with ART Interruptions
Slide 36.
Higher Risk of Serious non-AIDS events and Death with Deferring ART to CD4 <350 in SMART
Slide 37.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 38.
Non-AIDS-associated Cancer
Slide 39.
AIDS-associated Cancer Risk Declining
Slide 40.
Persistent / Increasing Non-AIDS Cancer Risk
Slide 41.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 42.
Neurocognitive Dysfunction
Slide 43.
Neurocognitive Dysfunction Common in HIV
Slide 44.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 45.
Osteoporosis
Slide 46.
HIV+ Adults Have High Prevalence of Osteoporosis
Slide 47.
MGH/BMW: HIV+ Adults with Higher Risk of Fractures than HIV-'s.
Slide 48.
Might ARVs Increase Risk of Osteoporosis?
Slide 49.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 50.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 51.
Independent Effect of HIV on Non-AIDS Morbidity?
Slide 52.
Persistently High Hospitalization Rates For Pneumonia in Modern HAART Era
Slide 53.
HIV+ Adults with High Risk of Frailty (MACS)
Slide 54.
Why are HIV-infected Patients at Increased Risk for Diseases Associated with Aging?
Slide 55.
Non-AIDS Events May Be Partially Driven By Lifestyle Factors and HAART Toxicity
Slide 56.
Non-AIDS events are more common in HIV disease, even after adjustment for age, HAART exposure and traditional risk factors
Slide 57.
An Important Clue from Nature
Slide 58.
T Cell Activation Declines with Lower Viral Load in Untreated HIV
Slide 59.
T Cell Activation Declines Further During ART-mediated VL Suppression
Slide 60.
...but ART-suppressed Patients Have Persistently Abnormal T Cell Activation
Slide 61.
High T Cell Activation Associated with Blunted CD4 Recovery
Slide 62.
Inflammatory markers are higher in treated HIV disease compared with HIV seronegatives, adjusted for demographics and CV risk factors
Slide 63.
SMART: Inflammatory Markers Strongly Associated with Mortality and CVD Events
Slide 64.
Inflammation persists during suppressive HAART, which may blunt CD4 recovery and increase risk of AIDS- and non-AIDS-associated morbidities.
Slide 65.
Low-level Viremia <75 copies/ml is Common During Apparent Viral Suppression on HAART N=130
Slide 66.
HIV RNA Is Also Readily Detectable in Rectal Tissue During "Suppressive" HAART
Slide 67.
Is this residual low-level virus in plasma and tissues the result of productive viral replication or just release from latent reservoir?
Slide 68.
Most recent HAART intensification trials have NOT reduced low-level viremia
Slide 69.
HIV itself a cause of persistent immune activation during suppressive ART?
Slide 70.
Are there indirect mechanisms by which HIV might drive persistent immune activation during ART?
Slide 71.
HIV Causes Depletion of Gut-associated CD4+ T Cells and Disruption of Mucosal Barrier
Slide 72.
Mucosal Translocation of Bacterial Products
Slide 73.
Microbial Translocation Decreases with HAART but Persists for Years
Slide 74.
Microbial Translocation May Drive Tissue Factor Expression in HIV
Slide 75.
Interventions to decrease microbial translocation?
Slide 76.
Altering bowel flora and/or reducing microbial translocation (BITE)
Slide 77.
Do chronic co-infections also contribute to immune activation during ART?
Slide 78.
HCV Associated with Blunted CD4 Gains During HAART
Slide 79.
CMV elicits massive immune responses even in asymptomatic HIV- individuals
Slide 80.
CMV-specific T Cell Responses are Higher in HIV-infected Patients
Slide 81.
Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation
Slide 82.
Does longstanding HIV-associated inflammation prior to HAART result in irreversible damage to the immune system?
Slide 83.
Immunosenescence Phenotypes Associated with Aging in HIV-
Slide 84.
ART-suppressed Patients Have Abnormally Low % Naïve CD8+ T Cells
Slide 85.
ART-suppressed Patients Have Expansion of CD8s lacking co-stimulatory CD28
Slide 86.
Immunosenescence in HIV: Unanswered Questions
Slide 87.
Summary
Slide 88.
Acknowledgements
Slide 89.

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