Why is inflammation elevated in treated HIV infection and why does it matter?
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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
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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
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Schouten J AIDS 2012
Co-morbid conditions common in HIV-infected adultsHIV-infected adults age 50-55 similar to uninfected adults > 65
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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
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“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
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Is there something unique about
inflammation in HIV disease?
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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Hunt et al JID 2003, PLoS ONE 2011 and unpublished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
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+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)
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0
25
50
75
100
125
150
175
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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
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(M
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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”
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Among treated adults, D-dimers (and perhaps other biomarkers) are stable over years
Courtesy of Jens Lundgren
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Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE)
Hunt et al CROI 12
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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
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Are all of the biomarkers describing the same mechanistic
pathway?
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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
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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
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After controlling for CD4+ T cell count, inflammatory biomarkers have stronger prognostic effect that T cell
activationtreated infection
Hunt et al CROI 12
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Early ART Also Appears to Reduce Residual T Cell Activation during ART
Jain et al, CROI 2011
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What causes HIV-associated
inflammation?
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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)
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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)
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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