Immune Activation: Impact on Outcomes

Peter W. Hunt, MD Associate Professor of Medicine

University of California San Francisco

Legarth/Obel, JAIDS, 2016 (see also Samji, PLoS One, 2013)

10y Decreased Life Expectancy in Older HIV+ Adults in Modern ART Era

HIV- Controls 1996-2014

HIV+ 2006-2014 2000-2005

1996-2000

~9y shorter life expectancy even among those with no comorbidity

Many age-associated morbidities also increased in treated HIV

• Cardiovascular disease [1-3]

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

• COPD [12]

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

• Cognitive decline [9]

• Non-AIDS infections [10]

• Frailty [11]

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. Sogaard, CID, 2008; 47(10): 1345-53. 11. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286; 12 Attia, Chest,2014

Schouten, CID, 2014

Increased Multi-morbidity in Older HIV+ Individuals (AGEhIV)

Morbidities: • CAD / MI • HTN • PAD • CVD / Stroke • COPD • T2DM • Renal Dz • Non-AIDS CA • Osteoporosis

Potential Role of Inflammation in Driving Morbidity in Older HIV+ Individuals

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 Remains Abnormally High During ART-mediated Viral Suppression

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-dimer predicts morbidity/mortality over next 10y

Grund, CROI, 2013, #60; see also: Ledwama, PLoS One, 2012

Inflammation Predicts Disease in Treated HIV Infection

• Mortality (Kuller, PLoS Med, ‘08; Tien, JAIDS, ‘10; Justice, CID ‘12; Hunt, JID ‘14)

• 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)

• Renal Disease (Gupta, HIV Med, 2015)

• Bacterial Pneumonia (Bjerk, PLoS One, 2014)

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

• Depression (Martinez, JAIDS, 2014)

• Frailty (Erlandson, JID, 2013)

Hunt, JID, 2014 (see also :

Sandler, JID, 2011; Tenorio,

JID 2014)

Gut Barrier Dysfunction & Innate Immune Activation Predict Mortality during Suppressive ART

SOCA cohort

Gut Epithelial Barrier Dysfunction

Inflammation / Coagulation

IDO-1 InductionMonocyte Activation

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, JAIDS, 2015

Non-infectious causes Infectious causes

Does systemic inflammation necessarily reflect the degree of inflammation in all tissues (and risk for all morbidities)?

I don’t think so…

Impact of eary ART provides clues

Lower But Persistently Abnormal Immune Activation with Very Early ART (RV254)

• Thai study of HIV+ individuals dx very early during acute HIV infection

• Compared to high-risk HIV- controls and ART-suppressed HIV+ who initiated during chronic HIV infection

Chronic HIV on ART

HIV-uninfected

Utay, CROI 2015, #47

: 12 days : 16 days : 18 days

Estimated Duration of HIV Infection

Immune activation setpoint may be lower if ART is started very early.

Does morbidity and mortality also decline?

Danel et al, Temprano trial, NEJM , 2015

Reduced but Persistently High Risk of TB with Early ART: Temprano Trial

CD4>500

START trial, NEJM, 2015

Reduced but Persistently High Risk of Infections and Cancer with Early ART:

START Trial AIDS Events Non-AIDS Events

Outcome HR TB 0.29 Bacterial Infection 0.38 KS 0.09 Lymphoma 0.30 Non-AIDS Cancer 0.50

~1% of Immediate ART arm had an AIDS

Event by Year 5

Risk of infections decreases with very early ART, but remains

abnormally high.

What about non-infectious morbidities?

No Difference in Cognitive Improvement with Early vs. Delayed ART

Wright, EACS 2015, #PS10/6

START: No Difference in Cardiovascular Outcomes with Early vs. Delayed ART

START, NEJM, 2015 and Baker, CROI 2016, #41

Cardiovascular Events

(Early vs. Delayed):

HR 0.84 (0.4-1.8) P=0.65

Small Artery Elasticity (higher better)

Also no difference in pulmonary fn. decline (Base FEV1 96% pred)

(Kunisaki, EACS, 2015)

In Contrast, Interrupting ART Strongly Increased CAD, Renal, Liver Disease

SMART Trial

El-Sadr, SMART Trial, NEJM, 2007

HR for Drug Conservation vs. VL Suppression: 1.7 (1.1 – 2.5), P=0.009

Why Didn’t Non-infectious Morbidities Decrease in START Trial?

• START trial participants may have been too young – But only 7y younger than SMART, and no interaction by age

• The disease process was already established – Hard to reconcile with SMART trial result, CD4 nadir data

• May take time for morbidities to manifest – Plausible, but this was not the case in SMART

• The disease process hasn’t started yet – i.e., these are “low CD4 nadir” diseases

– Might suggest causes / immunologic pathways that are distinct from those causing infectious complications

What are the potential drivers of persistent immune

activation during suppressive ART?

And which ones are

established early vs. late?

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

HIV Reservoirs Established in First Week of Infection and Continue to Release Virus on ART

Mostly reflects release of virus from infected cells

without ongoing replication

Reservoirs in T cells established in first week

Reservoirs in myeloid cells (in fat, liver, brain, etc)

established late, ↓CD4 count

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).

CMV Sero-status Predicts Non-AIDS Events (and less so AIDS…): ICONA Cohort

Lichtner et al, JID, 2015 (see also Hsue, AIDS, 2006)

Strongest effect for CAD (HR 2.3)

CMV replicates in vascular endothelium and

contributes to transplant vasculopathy

Likely plays a greater role in individuals with

lower CD4 nadir

Microbial Translocation Persists on ART Particularly in Those with Low CD4 Nadirs

and Poor CD4 Recovery

Somsouk, AIDS, 2014 (also Marchetti, AIDS, 2008; Jiang et al, JID, 2009 )

HIV- HIV+ ART+ CD4>500

HIV+ ART+ CD4<350

Persistent neutrophil infiltration in rectal mucosa during treated HIV infection in response to mucosal barrier breach

Theoretical Model for Drivers of Immune Activation during Suppressive ART

CD4 Nadir

500

350

100 200

Adaptive Immune Defects

HIV in

Myeloid Cells

CNS, Liver, Metabolic Dz Vascular Dz

CMV

HIV Reservoir

in Lymphoid Tissues

Multiple Morbidities

Microbial Transl.

What can we do to reverse immune activation during

suppressive ART?

Statins Decrease Immune Activation and Aortic Plaque in Treated HIV Infection

sCD14 Declines with Rosuvastatin

Plaque Regression with Atorvastatin

Funderburg/McComsey, JAIDS, 2015 Lo/Grinspoon, Lancet HIV, 2015

REPRIEVE Trial of Pitavastatin (n=6500) Now Enrolling!

O’Brien, CROI 2016, Abstract 44LB

Aspirin Fails to Reduce Immune Activation or Improve Vascular Function

(A5331)

Serum thromboxane (cyclooxygenase inhibition)

sCD14

Placebo 100mg ASA 300mg ASA

• Smoking increases monocyte activation (Valiathan, PLoS One, 2014)

• Hazardous EtOH associated with ↑ sCD14 / microbial translocation (Carrico, Alc Clin Exp Res, 2015)

• Methamphetamine use increases immune activation and suppresses T cell function (Massanella, Sci Reports, 2015)

• Obesity associated with increased inflammation (Koethe, ARHR, 2013)

• Moderate exercise decreases inflammation in pilot trials (Longo, CROI 2014, #763)

Lifestyle Factors Contribute to Immune Activation in Treated HIV

• Despite optimal ART, HIV shortens life expectancy and ↑ age-associated morbidities. – But some may be “Low CD4 Nadir” diseases

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

• Very early ART may prevent many morbidities though adaptive immune defects may persist

• Statins – but not aspirin – show promise in decreasing immune activation – Await clinical endpoint trials (REPRIEVE)

• Lifestyle factors major contributors to immune activation (smoking, EtOH, meth, obesity)

Summary