Immune Activation / Inflammation as Predictors of Morbidity / Mortality during HAART Peter W. Hunt, MD Associate Professor of Medicine in Residence UCSF/SFGH.

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.