Download How HIV Causes AIDS: Is HIV an Inflammatory Disease?

Immune Activation:
Impact on Outcomes
Peter W. Hunt, MD
Associate Professor of Medicine
University of California San Francisco
10y Decreased Life Expectancy in
Older HIV+ Adults in Modern ART Era
~9y shorter life expectancy even
among those with no comorbidity
HIV- Controls
1996-2014
HIV+
2006-2014
2000-2005
1996-2000
Legarth/Obel, JAIDS, 2016 (see also Samji, PLoS One, 2013)
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): 134553. 11. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286; 12 Attia, Chest,2014
Increased Multi-morbidity in
Older HIV+ Individuals (AGEhIV)
Morbidities:
• CAD / MI
• HTN
• PAD
• CVD / Stroke
• COPD
• T2DM
• Renal Dz
• Non-AIDS CA
• Osteoporosis
Schouten, CID, 2014
Potential Role of Inflammation in Driving
Morbidity in Older HIV+ Individuals
ART
Toxicity
Ageassociated
Morbidity
Persistent
Lifestyle
Inflammation
Deeks and Phillips, BMJ, 2009
An Important Clue from Nature
Sooty Mangabey
Rhesus Macaque
•Infect with SIV
•Infect with SIV
•High Levels of Viral Replication
•High Levels of Viral Replication
•No AIDS, normal lifespan
•AIDS and death
•Minimal Immune Activation
•Massive Immune Activation
Silvestri, Immunity, 2003
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
Participants 45-76 years of age
Neuhaus J, et al. JID, 2010. (also see: French, JID, 2009)
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-dimer
predicts morbidity/mortality over next 10y
Grund, CROI, 2013, #60; see also: Ledwama, PLoS One, 2012
Inflammation Predicts Disease
in Treated HIV Infection
•
•
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•
•
•
•
•
•
•
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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)
Gut Barrier Dysfunction & Innate Immune
Activation Predict Mortality during Suppressive ART
SOCA cohort
Gut Epithelial
Barrier Dysfunction
IDO-1 Induction
Monocyte
Activation
Inflammation /
Coagulation
Hunt, JID, 2014
(see also :
Sandler, JID,
2011; Tenorio,
JID 2014)
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
Uganda (UARTO)
1.IDO-1 / KT ratio
2.T cell activation
3.IL-6
4.sCD14
5.D-dimer
Hunt, JID, 2014
Tenorio, JID, 2014
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)
Estimated Duration
of HIV Infection
: 12 days
: 16 days
: 18 days
Chronic HIV on ART
HIV-uninfected
• 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
Utay, CROI 2015, #47
Immune activation setpoint may be
lower if ART is started very early.
Does morbidity and mortality
also decline?
Reduced but Persistently High Risk of
TB with Early ART: Temprano Trial
CD4>500
Danel et al, Temprano trial, NEJM , 2015
Reduced but Persistently High Risk of
Infections and Cancer with Early ART:
START Trial
Non-AIDS Events
AIDS Events
~1% of Immediate
ART arm had an AIDS
Event by Year 5
Outcome
TB
Bacterial Infection
KS
Lymphoma
Non-AIDS Cancer
HR
0.29
0.38
0.09
0.30
0.50
START trial, NEJM, 2015
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
Small Artery Elasticity
(higher better)
Cardiovascular
Events
(Early vs. Delayed):
HR 0.84 (0.4-1.8)
P=0.65
Also no difference in
pulmonary fn. decline
(Base FEV1 96% pred)
(Kunisaki, EACS, 2015)
START, NEJM, 2015 and Baker, CROI 2016, #41
In Contrast, Interrupting ART Strongly
Increased CAD, Renal, Liver Disease
SMART Trial
HR for Drug Conservation vs. VL Suppression:
1.7 (1.1 – 2.5), P=0.009
El-Sadr, SMART Trial, NEJM, 2007
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?
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
Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008.
Blocking Asymptomatic CMV Replication
with Valganciclovir ↓ Immune Activation
in HIV+ Patients with CD4<350 despite ART
-4.4%
HIVMedian
Valacyclovir, which has strong anti-HSV1/2 but minimal anti-CMV
activity, failed to decrease immune activation (Yi et al, CID, 2013).
Hunt et al, JID, 2011
CMV Sero-status Predicts Non-AIDS Events
(and less so AIDS…): ICONA Cohort
CMV replicates in vascular
endothelium and
contributes to transplant
vasculopathy
Strongest effect
for CAD (HR 2.3)
Likely plays a greater
role in individuals with
lower CD4 nadir
Lichtner et al, JID, 2015 (see also Hsue, AIDS, 2006)
Microbial Translocation Persists on ART
Particularly in Those with Low CD4 Nadirs
and Poor CD4 Recovery
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
Somsouk, AIDS, 2014 (also Marchetti, AIDS, 2008; Jiang et al, JID, 2009 )
Theoretical Model for Drivers of Immune
Activation during Suppressive ART
CD4 Nadir
500
350
200
100
HIV
Reservoir
in
Lymphoid
Tissues
Adaptive
Immune Defects
Microbial
Transl.
HIV
in
Myeloid
Cells
CMV
Multiple
Morbidities
CNS, Liver,
Metabolic Dz
Vascular Dz
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!
Aspirin Fails to Reduce Immune Activation
or Improve Vascular Function
(A5331)
Serum thromboxane
(cyclooxygenase inhibition)
Placebo
100mg ASA
300mg ASA
sCD14
O’Brien, CROI 2016, Abstract 44LB
Lifestyle Factors Contribute to
Immune Activation in Treated HIV
• 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)
Summary
• 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)