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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 - PowerPoint PPT Presentation
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Why is inflammation elevated in treated HIV infection and
why does it matter?
Steven G. DeeksProfessor 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• 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
Schouten J AIDS 2012
Co-morbid conditions common in HIV-infected adultsHIV-infected adults age 50-55 similar to uninfected adults > 65
Inflammatory Biomarkers Predict Risk for All-Cause Mortality among Treated Adults
Cohort Design T cell acti-
vation
CRP IL-6 K/T IDO
Cysta-atin C
sCD-14
D-dimer
Fibrin-ogen
Hyalu-ronic Acid
SMARTESPRIT
Case-control ✔ ✔ ✔ ✔ ✔
FRAM Cohort ✔ ✔ ✔SOCA/SCOPE Cohort ✔ ✔ ✔ ✔ ✔ ✔
UARTO Cohort ✔ ✔VACS Cohort ✔ ✔FIRST (Pre-ART)
Case-control ✔ ✔ ✔ ✔
Pfidisas(Pre-ART)
Case-control ✔ ✔ ✔
T cells
Innate
Microbes
Coagulation
Fibrosis
“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
Chronic inflammation is also harmful in non-HIV-infected adults
Courtesy of Peter Reiss
Is there something unique about
inflammation in HIV disease?
T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal”
Hunt et al JID 2003, PLoS ONE 2011 and unpublished
% C
D38
+HLA
DR
+C
D8+
T C
ells
0
20
40
60
80
HIVNegative(n=82)
Non-Controller
(n=65)
HAART(n=132)
P < 0.001
P < 0.001
HIV –(n=132)
HIV +ART
(n=65)
HIV +Untreated
(n=82)
0
25
50
75
100
125
150
175
200
IL-6 D-dimer Cystatin-C
UnadjustedAdjusted for age, gender, raceFully adjusted
UnadjustedAdjusted for age, gender, raceFully adjusted
hsCRP
% D
iff.
from
Gen
eral
Pop
ula
tion
(M
ESA
)
Neuhaus et al JID 2010
• 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
Many common plasma biomarkers of inflammation are also higher in treated HIV disease than “normal”
Among treated adults, D-dimers (and perhaps other biomarkers) are stable over years
Courtesy of Jens Lundgren
Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE)
Hunt et al CROI 12
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
Are all of the biomarkers describing the same mechanistic
pathway?
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
Among adults with durable viral suppression, a low CD4+ T cell count is associated with significant T cell abnormalities
Hatano CROI 2011
P = 0.0001 P < 0.0001
P < 0.0001 P = 0.05
After controlling for CD4+ T cell count, inflammatory biomarkers have stronger prognostic effect that T cell
activationtreated infection
Hunt et al CROI 12
Early ART Also Appears to Reduce Residual T Cell Activation during ART
Jain et al, CROI 2011
What causes HIV-associated
inflammation?
Inflammation↑ Endothelium adhesion↑ Monocyte activation
DyslipidemiaHypercoagulation/thrombotic events
Endothelial dysfunction
Microbial translocation
HIV-associated fatMetabolic syndrome
HIV productionHIV replication
CMVExcess pathogens
HIV-mediated loss of regulatory cells (Tregs)
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)
AcknowledgementsUCSFPeter HuntHiroyu HatanoPriscilla HsueJeff MartinBecky HohMa SomsoukVivek JainElizabeth SinclairMike BuschSteve YuklJoe WongMike McCune
INSIGHTJason BakerCliff LaneAndrew PhillipsJim NeatonJens Lundgren
ElsewhereNetanya SandlerDanny DouekMike Lederman (CLIC)Peter ReissRafick SekalyTim Schacker
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