immune activation: impact on outcomes peter w. hunt,...
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Immune Activation: Impact on Outcomes
Peter W. Hunt, MD Associate Professor of Medicine
University of California San Francisco
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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
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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
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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
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Potential Role of Inflammation in Driving Morbidity in Older HIV+ Individuals
Lifestyle
ART Toxicity
Persistent Inflammation
Age- associated Morbidity
Deeks and Phillips, BMJ, 2009
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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
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T Cell Activation Remains Abnormally High During ART-mediated Viral Suppression
Hunt et al, JID, 2003; PLoS One, 2011
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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
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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
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What are the clinical consequences of persistent
immune activation and inflammation during ART?
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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
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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)
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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
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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
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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
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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
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Immune activation setpoint may be lower if ART is started very early.
Does morbidity and mortality also decline?
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Danel et al, Temprano trial, NEJM , 2015
Reduced but Persistently High Risk of TB with Early ART: Temprano Trial
CD4>500
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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
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Risk of infections decreases with very early ART, but remains
abnormally high.
What about non-infectious morbidities?
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No Difference in Cognitive Improvement with Early vs. Delayed ART
Wright, EACS 2015, #PS10/6
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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)
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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
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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
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What are the potential drivers of persistent immune
activation during suppressive ART?
And which ones are
established early vs. late?
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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
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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).
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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
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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
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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.
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What can we do to reverse immune activation during
suppressive ART?
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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!
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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
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• 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
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• 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
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