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Immune Activation / Inflammation
as Predictors of
Morbidity / Mortality
during HAART
Peter W. Hunt, MD
Associate Professor of Medicine in Residence
UCSF/SFGH HIV/AIDS Division
Life Expectancy Improving but a Gap Persists
By pre-ART CD4 count
• Life expectancy of patients on or
starting ART in North America
• ~23,000 person-years FU
• 1,622 deaths
• Majority of HIV+ around the world
still starting ART <350.
• May overestimate life expectancy
• Excludes those out of care
• “Survivorship bias” for older
patients who survived 80s
and 90s.
*For 20-year old initiating ART
Samji for NA-ACCORD, PLoS One, 2013
Age-associated Morbidities Increased
in Treated HIV Infection
• Cardiovascular disease [1-3]
• Cancer (non-AIDS) [4]
• Bone fractures / osteoporosis [5,6]
• Liver disease [7]
• Kidney disease [8]
• COPD [11]
• T2DM [12]
• Cognitive decline [9]
• Frailty [10]
1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2; Hsue P, et al. Circulation. 2004;109:316-319. 3. Grinspoon SK,
et al. Circulation. 2008;118:198-210. 4. Patel P, et al. Ann Int Med, 2008;148:728-736. 5. Triant V, et al. J Clin Endocrinol Metab.
2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8.
Choi A, et al. AIDS, 2009;23(16):2143-49. 9. McCutchan JA, et a. AIDS. 2007 ;21:1109-1117. 10. Desquilbet L, et al. J Gerontol A
Biol Sci Med Sci. 2007;62:1279-1286; 11Attia, Chest,2014; 12 Samaras, Diabetes Care, 2007.
NEJM, 2012
Why do HIV+ patients have
a higher risk of premature
mortality and ageassociated morbidities?
Inflammation May Independently Contribute
to Morbidity and Mortality in Treated HIV
ART
Toxicity
Ageassociated
Morbidity
Persistent
Lifestyle
Inflammation
Deeks and Phillips, BMJ, 2009
T Cell Activation Remains High During
ART-mediated Viral Suppresion
Hunt et al, JID, 2003; PLoS One, 2011
Inflammatory markers are higher in treated HIV
disease compared with HIV seronegatives,
adjusted for demographics and CV risk factors
Participants 45-76 years of age
Neuhaus J, et al. JID, 2010. (also see: French, JID, 2009)
Chronic Immune Activation May Also
Cause Lymphoid Tissue Fibrosis
• Associated with low %naïve T cells and poor CD4+ T cell recovery
• May impair functional immune responses
Estes, JID, 2008; Schacker, JCI, 2002; Zeng, JCI, 2011
What are the clinical
consequences of persistent
immune activation and
inflammation during ART?
A single measurement of IL-6 or Ddimers predicts morbidity or mortality
over next decade
Grund, CROI, 2013, #60
Increased Arterial Inflammation in HIV
HIV-
Aortic Inflammation
associated with
↑sCD163 levels
(monocyte
activation)
Subramanian/Grinspoon, JAMA, 2012
HIV+
Inflammation Predicts Disease
in Treated HIV Infection
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•
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Mortality (Kuller, PLoS Med, 2008; Tien, JAIDS, 2010; Justice, CID 2012)
Cardiovascular Disease (Duprez, Atherosclerosis, 2009)
Cancer (Breen, Cancer Epi Bio Prev, 2010; Borges, AIDS, 2013)
Venous Thromboembolism (Musselwhite, AIDS, 2011)
Type II Diabetes (Brown, Diabetes Care, 2010)
COPD (Attia, Chest, 2014)
Bacterial Pneumonia (Bjerk, PLoS One, 2014)
Cognitive Dysfunction (Burdo, AIDS, 2013; Letendre CROI 2012)
Depression (Martinez, JAIDS, 2014)
Frailty (Erlandson, JID, 2013)
What immunologic pathways
should we target?
Gut Barrier Dysfunction and Innate Immune
Activation Predict Mortality during Suppressive ART
SOCA cohort
Gut Epithelial
Barrier Dysfunction
IDO-1 Induction
Monocyte
Activation
Inflammation /
Coagulation
Hunt, JID, 2014 (see also : Sandler, JID, 2011; Tenorio, JID 2014)
Strength of Biomarker Association May
Depend on Proximity to End-Organ Disease
Macrophage
LN / hepatic activation
clearance
Neutrophil
function
Th17/Th22 levels
Gut microbiome
Gut barrier defect
(I-FABP)
Atherosclerosis
Plaque rupture
Tissue Factor
expression
Coagulation
(D-dimer)
Myocardial
Infarction
Adaptive Immune Defects More
Important in Resource-limited Settings?
Ranking of mortality predictors
(1=strongest, 5=weakest)
US-based cohorts
1.IL-6
2.D-dimer
3.sCD14
4.IDO-1 / KT ratio
5.T cell activation
Uganda (UARTO)
1.IDO-1 / KT ratio
2.T cell activation
3.IL-6
4.sCD14
5.D-dimer
Hunt, JID, 2014
Tenorio, JID, 2014
Lee, CROI 2015, #317
Balagopol, PLoS One, 2015
Non-infectious causes
Infectious causes
HIV-Mediated Immune Activation and Aging
HIV-1 Infection
Immunodeficiency
TLR 7,8
Nef, gp120
Microbial
Translocation
Viral Reactivation
(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover
and Lymphoid Fibrosis
Immune Exhaustion
Increased TF Expression
and clotting
CAD/Stroke, Thrombosis
Malignancy, Infections
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
Cytokine Secretion
(eg, IL-6, TNFL)
“Inflam-Aging”
(eg, atherosclerosis,
osteoporosis)
Summary
• Despite optimal ART, HIV increases mortality and
age-associated morbidities.
• Immune activation / inflammation persist despite
ART and may predict morbidity over long-term.
– “Immune Activation Set-point”
• Adaptive immune defects may be more important in
RLS, where infectious complications prevalent
• Biomarkers that predicts disease most strongly are
not necessarily best interventional targets.
• Need to integrate biomarker studies with a
“pathway” approach to inform interventional targets.
Acknowledgements
SCOPE/OPTIONS/UCSF
Steve Deeks
Jeff Martin
Hiroyu Hatano
Vivek Jain
Rick Hecht
Chris Pilcher
Ma Somsouk
Sulggi Lee
Melicent Peck
Leslie Cockerham
Rebecca Hoh
SCOPE and OPTIONS Teams
UCSF Drug Studies Unit
Yong Huang
CWRU
Michael Lederman
Nick Funderburg
Grace McComsey
Core Immunology Lab/DEM
Elizabeth Sinclair
Lorrie Epling
Jeff Milush
Mike McCune
SFGH Cardiology
Priscilla Hsue
UARTO
Helen Byakwaga
Priscilla Martinez
Alex Tsai
Sheri Weiser
David Bangsberg
NIAID/VRC
Jason Brenchley
Danny Douek
R01AI110271, R56AI100765,
1R21AI087035, 1R21AI07877, DDCF
CSDA, CHRP IDEA Award; Roche, Inc.