Peter W. Hunt, MD Associate Professor of Medicine in Residence

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Presentation transcript:

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 age-associated morbidities?

Inflammation May Independently Contribute to Morbidity and Mortality in Treated HIV ART Toxicity Age- associated Morbidity Lifestyle Persistent 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) 8

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 D-dimers predicts morbidity or mortality over next decade Grund, CROI, 2013, #60

Increased Arterial Inflammation in HIV Aortic Inflammation associated with ↑sCD163 levels (monocyte activation) Subramanian/Grinspoon, JAMA, 2012

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 ART SOCA cohort Hunt, JID, 2014 (see also : Sandler, JID, 2011; Tenorio, JID 2014)

Myocardial Infarction Strength of Biomarker Association May Depend on Proximity to End-Organ Disease Macrophage activation LN / hepatic clearance Atherosclerosis Neutrophil function Plaque rupture Tissue Factor expression Th17/Th22 levels Gut microbiome Coagulation (D-dimer) Gut barrier defect (I-FABP) Myocardial Infarction

Non-infectious causes Adaptive Immune Defects More Important in Resource-limited Settings? Ranking of mortality predictors (1=strongest, 5=weakest) US-based cohorts IL-6 D-dimer sCD14 IDO-1 / KT ratio T cell activation Hunt, JID, 2014 Tenorio, JID, 2014 Uganda (UARTO) IDO-1 / KT ratio T cell activation IL-6 sCD14 D-dimer Lee, CROI 2015, #317 Balagopol, PLoS One, 2015 Non-infectious causes Infectious causes

HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency Microbial Translocation TLR 7,8 Nef, gp120 Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Increased TF Expression and clotting CAD/Stroke, Thrombosis Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Immune Exhaustion “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241. 18

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.