immune activation / inflammation as predictors of morbidity / mortality during haart peter w. hunt,...
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Immune Activation / Inflammation as Predictors of
Morbidity / Mortalityduring HAART
Peter W. Hunt, MD
Associate Professor of Medicine in Residence
UCSF/SFGH HIV/AIDS Division
Life Expectancy Improving but a Gap PersistsLife Expectancy Improving but a Gap Persists
Samji for NA-ACCORD, PLoS One, 2013*For 20-year old initiating ART
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.
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 age-associated morbidities?
Inflammation May Independently Contribute to Morbidity and Mortality in Treated HIV
Lifestyle
ARTToxicity
PersistentInflammation
Age-associatedMorbidity
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
Neuhaus J, et al. JID, 2010. (also see: French, JID, 2009)
Participants 45-76 years of age
Chronic Immune Activation May Also Cause Lymphoid Tissue Fibrosis
Estes, JID, 2008; Schacker, JCI, 2002; Zeng, JCI, 2011
• Associated with low %naïve T cells and poor CD4+ T cell recovery• May impair functional immune responses
What are the clinical consequences of persistent
immune activation and inflammation during ART?
A single measurement of IL-6 or D-dimers predicts morbidity or mortality over next
decade
Grund, CROI, 2013, #60
Increased Arterial Inflammation in HIV
Subramanian/Grinspoon, JAMA, 2012
HIV- HIV+
Aortic Inflammation associated with ↑sCD163 levels
(monocyte activation)
Inflammation Predicts Disease in Treated HIV Infection
• 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
ARTSOCA cohort
Gut Epithelial Barrier Dysfunction
Inflammation / Coagulation
IDO-1 InductionMonocyte Activation
Hunt, JID, 2014 (see also : Sandler, JID, 2011; Tenorio, JID 2014)
Strength of Biomarker Association May Depend on Proximity to End-Organ Disease
Gut barrier defect(I-FABP)
Myocardial Infarction
Gut microbiome
Th17/Th22 levels
Neutrophil function
LN / hepatic clearance
Macrophage activation
Coagulation(D-dimer)
Tissue Factor expression
Plaque rupture
Atherosclerosis
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
Hunt, JID, 2014
Tenorio, JID, 2014
Uganda (UARTO)
1.IDO-1 / KT ratio
2.T cell activation
3.IL-6
4.sCD14
5.D-dimer
Lee, CROI 2015, #317
Balagopol, PLoS One, 2015
Non-infectious causes Infectious causes
Adapted from Appay V, et al. J Pathol. 2008;214:231-241.
HIV-1 Infection
ImmunodeficiencyMicrobial
Translocation Viral
Reactivation(eg, CMV)
Innate Immune Activation (MØ/DC)
Increased Cell Turnover and Lymphoid Fibrosis
Immune Exhaustion
Malignancy, Infections
Cytokine Secretion(eg, IL-6, TNFL)
“Inflam-Aging”(eg, atherosclerosis,
osteoporosis)
HIV-Mediated Immune Activation and Aging
TLR 7,8Nef, gp120
Increased TF Expression and clotting
CAD/Stroke, Thrombosis
• 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.
Summary
AcknowledgementsCore Immunology Lab/DEMElizabeth SinclairLorrie EplingJeff MilushMike McCune
SFGH CardiologyPriscilla Hsue
UARTOHelen ByakwagaPriscilla MartinezAlex TsaiSheri WeiserDavid Bangsberg
NIAID/VRCJason BrenchleyDanny Douek
SCOPE/OPTIONS/UCSFSteve DeeksJeff Martin Hiroyu HatanoVivek JainRick HechtChris PilcherMa SomsoukSulggi LeeMelicent PeckLeslie CockerhamRebecca HohSCOPE and OPTIONS Teams
UCSF Drug Studies UnitYong Huang
CWRUMichael LedermanNick FunderburgGrace McComsey
R01AI110271, R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA, CHRP IDEA Award; Roche, Inc.
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