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AIDS CLINICAL ROUNDS

Immune Activation in Treated HIV Infection:

Beyond the Basics

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

UCSF/SFGH HIV/AIDS Division

Disclosures • Consultant

– Merck – BMS – Gilead – Tobira

• Honoraria – Gilead – Janssen

Life Expectancy* May Start to Approach General Population with Early ART

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

• May overestimate life expectancy

• Excludes those out of care

• “Survivorship bias” for older patients who survived 80s and 90s.

• Majority of HIV+ around the world still starting ART <350.

Non-AIDS Diseases Now Account for Majority of Deaths in HIV

(1996-2006) • 1,876 deaths among 39,727 patients • Non-AIDS related deaths accounted for 50.5%

Antiretroviral Therapy Cohort Collaboration (ART-CC). Clin Infect Dis. 2010;50:1387-1396.

Non-AIDS infection

16.3%

CVD 15.7%

Non-AIDS Malignancy

23.5%

Violence, Substance

abuse 15.4%

Liver-related 14.1%

Other 9.0% Respiratory

3.1%

Renal 3.0%

Many age-associated morbidities also increased in treated HIV

• Cardiovascular disease [1-3]

• Cancer (non-AIDS) [4] • Bone fractures / osteoporosis [5,6]

• Liver disease [7] • Kidney disease [8]

• Cognitive decline [9]

• Frailty [10]

1. Freiberg, M., et al. JAMA Int Med. 2013;173(8):614-22. 2; Tseng, Z, et al. JACC. 2012;59(21):1891-6. 3. Grinspoon SK, et al. Circulation. 2008;118:198-210. 4. Silverberg, M., et al. AIDS, 2009;23(17):2337-45. 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

Why do HIV+ patients have a higher risk of premature

mortality and age-associated morbidities?

Many Chronic Diseases of Aging May Be Driven By Lifestyle Factors and ART Toxicity

Lifestyle (smoking, etc.)

ART Toxicity Age-

associated Morbidity

Deeks and Phillips, BMJ, 2009

SMART Study: Interrupting ART Increases the Risk of Heart Disease

% w

ith a

Maj

or C

VD E

vent

DC VS

Death from CVD 7 4

Non-fatal clinical MI 12 12

Non-fatal silent MI 11 5

Non-fatal stroke 8 3

CAD requiring surgery for invasive procedure

22 14

All major CVD events 48 31

El-Sadr, NEJM, 2007

2752 1306 713 379 10 2720 1292 696 377 10

No. at Risk

0.5 1.5 2.5 3.5 0 1 2 3 4 0

Years from Randomization

5

10

2.5

7.5

Intermittent CD4-guided ART (DC) Continuous ART (VS)

Intermittent ART

Continuous ART

Many chronic diseases of aging are more common in HIV+’s, even after adjustment for

ART use and lifestyle factors

Lifestyle

ART Toxicity

Persistent Inflammation

Age- associated Morbidity

Deeks and Phillips, BMJ, 2009

Rhesus Macaque

•Infect with SIV

•High Levels of Viral Replication

•AIDS and death

Silvestri, Immunity, 2003

An Important Clue from Nature

•Minimal Immune Activation •Massive Immune Activation

Sooty Mangabey

•Infect with SIV

•High Levels of Viral Replication

•No AIDS, normal lifespan

T Cell Activation Declines with ART

Hunt et al, JID, 2003; PLoS One, 2011

But Remains Abnormally 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

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

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)

• Cognitive Dysfunction (Burdo, AIDS, 2013; Letendre CROI 2012, Abs#82)

• Frailty (Erlandson, JID, 2013)

ART is important!

Maybe even in “elite” controllers…

What can we do about the inflammatory state in HIV?

Hunt, JID, 2008; Hunt, PLoS One, 2011.

Negative Inflammatory Consequences in HIV Controllers

• Controllers also have: – ↑ Microbial Translocation

(Hunt, JID, 2008)

– ↑ Monocyte activation (Pereyra, AIDS, 2012)

– ↑ Atherosclerosis (Hsue, AIDS, 2009; Pereyra, AIDS, 2012)

– ↑ Lymphoid fibrosis (Sanchez, CROI 2013, #74)

• Treating controllers with ART decreases immune activation (Hatano, CROI 2013, #75LB)

P<0.001

P=0.017

P<0.001

Early ART initiation might also be beneficial.

Sx of Acute HIV or Recent

Seroconversion

HIV-

HIV+ <6mo

Early ART Initiate <6 mo of Infxn

Late ART Initiate >2 yr of Infxn

OPTIONS Cohort: Early vs. Late ART Initiation

Persistently Abnormal Immune Activation When ART Initiated during Chronic Infection

Jain et al, JID, 2013 See also: Burdo, JID, 2011; Vinikoor, CROI 2012, Abstract #554

Early ART Appears to Cause Greater Reduction in Residual T Cell Activation

Jain et al, JID, 2013 See also: Burdo, JID, 2011; Vinikoor, CROI 2012, Abstract #554

Are there other potential interventions for inflammation

beyond ART alone?

Rosuvastatin Decreases Both Monocyte and T Cell Activation during Suppressive ART

SATURN Trial (n=147)

Funderburg, CROI 2014, Abstract #335 (see also: Funderburg, Clin Infect Dis, 2014)

Week Week

sCD14 CD8 Activation

Aspirin Might Decrease Monocyte Activation in Treated HIV Infection

• Uncontrolled trial of ASA 81mg x 1 week – HIV+ (n=25)

– HIV- (n=44)

• Decrease in sCD14 (and T cell activation) in HIV arm.

• Needs to be confirmed in an RCT.

O’Brien, JAIDS, 2013, (see also Petterson, JV, 2011, 85 (13): 6557-66)

Plas

ma

sCD

14 L

evel

Moderate Exercise Decreases Inflammation in Sedentary ART-suppressed HIV+ Patients (n=49)

Longo, CROI 2014, Abstract #763

3 Days/Wk x 12 Wks

1hr brisk walking (n=29) +strength training (n=20)

71% completed 12 wks

Also improved:

Weight (-3 kg) BMI

Waist Circumference LDL

Strength studies ALT

What if statins, aspirin, and exercise are not enough?

What is causing inflammation during suppressive ART?

Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008.

Low-level Viremia <75 copies/ml is Common During Apparent Viral Suppression on HAART

N=130

80% Patients had detectable viremia

Median 3.1 copies/ml

Are there indirect mechanisms by which HIV might drive persistent immune activation during ART?

Brenchley et al,

Nat Med, 2006

Microbial Translocation (“Leaky Gut”) as a Cause of Immune Activation in HIV

Disrupted Gut Epithelial Barrier

-↑EC Apoptosis (Li, JID, 2008)

-↓Tight Junctions (Epple, Gut 2009)

Loss of Mucosal Immunity

↓CD4+ T cells ↓Th17 cells

Veazey, Science, 1998; Brenchley , J Exp Med,

2004; Guadalupe, J Virol, 2003; Mehandru, J Exp

Med, 2004

Microbial Translocation Decreases with HAART but Persists for Years

Jiang et al, JID, 2009 (also Marchetti, AIDS, 2008)

HIV- Controls

HIV+ ART-suppressed

HIV+ Untreated

Median

Microbial Translocation May Drive Tissue Factor Expression in HIV

Potential Mechanism for CAD Risk

• Tissue Factor expression induced by LPS in vitro

• In vivo, associated with: – sCD14 (marker of microbial

translocation) – % activated CD8+ T cells – D-Dimer levels

Funderburg, Blood, 2009

Hunt, JID, 2014 (see also : Tenorio, JID, 2014)

Microbial Translocation Predicts Mortality during ART-mediated Viral Suppression

SOCA cohort

Microbial translocation

Inflammation / Coagulation

Do chronic co-infections also contribute to immune activation

during ART?

Blocking Asymptomatic CMV Replication with Valganciclovir ↓ Immune Activation

in HIV+ Patients with CD4<350 despite ART

-4.4%

HIV- Median

Hunt et al, JID, 2011

Valacyclovir, which has strong anti-HSV1/2 but minimal anti-CMV activity, failed to decrease immune activation (Yi et al, CID, 2013).

Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

HIV-1 Infection

Immunodeficiency Microbial

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 7,8 Nef, gp120

Increased TF Expression and clotting

CAD/Stroke, Thrombosis

Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

HIV-1 Infection

Immunodeficiency Microbial

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 7,8 Nef, gp120

Increased TF Expression and clotting

CAD/Stroke, Thrombosis

IDO-1-induced Tryptophan Catabolism

• IFN-γ/IFN-α and LPS induce Indoleamine 2,3-dioxygenase-1 (IDO-1) production in DCs/MØ

• Causes tryptophan catabolism • Kynurenine and Picolinic Acid

may impair T cell proliferation – Maternal tolerance of fetal antigens

– Cancer evasion of immune response

• Catabolites may be neurotoxic – Neurodegenerative diseases, ADC

• 3-Hydroxyanthralinic Acid (HAA) causes Th17 depletion, ↑Tregs

Favre, Mold et al, Science TM, 2010 (see also: Munn, Science, 1998; Boasso, Blood, 2007)

IDO-1

Kynurenine Tryptophan

(K/T Ratio) = Marker of Tryptophan Catabolism

IDO-1 Pathway and HIV Pathogenesis (Indoleamine 2,3-dioxygenase-1)

Favre, Science Transl Med, 2010 (see also Boasso, Blood, 2007)

Higher Kynurenine Pathway Activity (K/T ratio) Predicts ↑ Mortality during ART

Each tertile increase in baseline K/T ratio associated with a 2.1-fold greater hazard of death after adjustment for pre-ART BMI and CD4 count (P=0.01).

Byakwaga, JID, 2014

Kynurenine Pathway (IDO-1) Activity Declines during Suppressive ART

Byakwaga, JID, 2014

KT Ratio Continues to Predict Mortality during Suppressive ART

(VL<400 at Month 6 of ART)

Each tertile increase in month 6 K/T ratio associated with a 2.9-fold increased hazard of death after adjusting for BMI, CD4 count, and %CD38+HLA-DR+ CD8+ T cells (P=0.042).

Byakwaga, JID, 2014

Could tryptophan catabolism via the kynurenine pathway

contribute to other morbidities in HIV infection like depression?

Tryptophan required for serotonin synthesis….

HIV-associated depression may be in part mediated by IDO-induced tryptophan catabolism

(and improved by ART)

Martinez, JAIDS, 2014

Depressive Symptoms Plasma Tryptophan Levels

KT ratio and depression association strongest in patients with a low protein diet.

Could alterations in the gut microbiome contribute to

kynurenine pathway activity?

Bacterial Species That Catabolize Tryptophan Are Enriched in HIV Infection

Vujkovic, Sci Transl Med, 2013

Pseudomonas Fluorescens catabolizes tryptophan in vitro

% Genera with 3-4 Tryptophan catabolism enzymes

Enriched in untreated

HIV

Not Enriched in untreated

HIV

Presence of Bacterial Species That Catabolize Tryptophan Associated with Plasma K/T Ratio

Vujkovic, Sci Transl Med, 2013

Are all consequences of the kynurenine pathway bad in

HIV infection?

Well, maybe not...

Risk of many - but not all - cancers is increased in patients with HIV/AIDS

Shiels, Annals Int Med, 2010 (see also: Silverberg, AIDS, 2009)

Strikingly similar pattern of cancer risk in RA and psoriasis… (Smitten, Arth Res, 2008)

Increased Risk of KS/NHL during Early ART Are KS/NHL IRIS Events?

Jaffe for CASCADE cohort, AIDS, 2011 (see also Lanoy, Blood, 2011; Gopal, CID, 2014)

Hypothesis:

The Kynurenine Pathway May Increase the Risk of KS

by Suppressing T Cell Function.

100% Wrong!

↑Plasma KT Ratio Associated with Decreased Kaposi’s Sarcoma Risk in HIV-Infected Ugandans

Adjusted for CD4, HIV RNA, age, sex

Ref: Quartile 1

Plus Hb, BMI, physical and mental health status, asset index

Unadjusted

• Might IDO-mediated suppression of lymphocyte (or spindle cell?) proliferation suppress KS lesion development?

• Some consequences of immune activation in HIV might actually suppress or mask certain cancers.

Odds Ratio0.1 1.0

Quartile 4

Quartile 3

Quartile 2

Quartile 4

Quartile 3

Quartile 2

Quartile 4

Quartile 3

Quartile 2

0.50

0.41

0.21

1.10

1.11

1.02

0.86

0.74

0.51

Byakwaga, CROI 2014, #714

• Despite optimal ART, HIV shortens life expectancy and increases several age-associated morbidities.

• Immune activation / inflammation persist despite ART and may predict these morbidities.

• Earlier initiation of ART may decrease the degree of persistent immune activation.

• Targeted interventions directed at the underlying causes of inflammation may hold promise (i.e., HIV reservoirs, co-infections/CMV, microbial translocation).

• Not all consequences of immune activation are bad…

Summary

Acknowledgements NIAID/VRC Jason Brenchley Danny Douek

Core Immunology Lab/DEM Elizabeth Sinclair Lorrie Epling Mike McCune

SFGH Cardiology Priscilla Hsue

UARTO David Bangsberg Annet Kembabazi Helen Byakwaga

SCOPE/OPTIONS/UCSF Steve Deeks Jeff Martin Hiroyu Hatano Vivek Jain Rebecca Hoh Rick Hecht Ma Somsouk Sulggi Lee Yong Huang

CWRU Wei Jiang Michael Lederman Nick Funderburg Brian Claggett Grace McComsey

R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA, CHRP IDEA Award; Pfizer, Inc.; Roche, Inc.