Immune Activation: Impact on Outcomes Peter W. Hunt, MD. Associate Professor of Medicine University of California San Francisco

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1 Immune Activation: Impact on Outcomes Peter W. Hunt, MD Associate Professor of Medicine University of California San Francisco

2 10y Decreased Life Expectancy in Older HIV+ Adults in Modern ART Era ~9y shorter life expectancy even among those with no comorbidity HIV- Controls HIV Legarth/Obel, JAIDS, 2016 (see also Samji, PLoS One, 2013)

3 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): ; Tseng, Z, et al. JACC. 2012;59(21): Grinspoon SK, et al. Circulation. 2008;118: Silverberg, M., et al. AIDS, 2009;23(17): Triant V, et al. J Clin Endocrinol Metab. 2008;93: Arnsten JH, et al. AIDS ;21: Odden MC, et al. Arch Intern Med. 2007;167: Choi A, et al. AIDS, 2009;23(16): McCutchan JA, et a. AIDS ;21: Sogaard, CID, 2008; 47(10): Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62: ; 12 Attia, Chest,2014

4 Increased Multi-morbidity in Older HIV+ Individuals (AGE h IV) Morbidities: CAD / MI HTN PAD CVD / Stroke COPD T2DM Renal Dz Non-AIDS CA Osteoporosis Schouten, CID, 2014

5 Potential Role of Inflammation in Driving Morbidity in Older HIV+ Individuals Lifestyle ART Toxicity Persistent Inflammation Ageassociated Morbidity Deeks and Phillips, BMJ, 2009

6 An Important Clue from Nature Sooty Mangabey Infect with SIV High Levels of Viral Replication No AIDS, normal lifespan Rhesus Macaque Infect with SIV High Levels of Viral Replication AIDS and death Minimal Immune Activation Silvestri, Immunity, 2003 Massive Immune Activation

7 T Cell Activation Remains Abnormally High During ART-mediated Viral Suppression Hunt et al, JID, 2003; PLoS One, 2011

8 Inflammatory markers are higher in treated HIV disease compared with HIV seronegatives, adjusted for demographics and CV risk factors Participants years of age Neuhaus J, et al. JID, (also see: French, JID, 2009)

9 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

10 What are the clinical consequences of persistent immune activation and inflammation during ART?

11 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

12 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)

13 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)

14 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 Non-infectious causes 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 Infectious causes

15 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

16 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

17 Immune activation setpoint may be lower if ART is started very early. Does morbidity and mortality also decline?

18 Reduced but Persistently High Risk of TB with Early ART: Temprano Trial CD4>500 Danel et al, Temprano trial, NEJM, 2015

19 Reduced but Persistently High Risk of Infections and Cancer with Early ART: START Trial AIDS Events ~1% of Immediate ART arm had an AIDS Event by Year 5 Non-AIDS Events Outcome HR TB 0.29 Bacterial Infection 0.38 KS 0.09 Lymphoma 0.30 Non-AIDS Cancer 0.50 START trial, NEJM, 2015

20 Risk of infections decreases with very early ART, but remains abnormally high. What about non-infectious morbidities?

21 No Difference in Cognitive Improvement with Early vs. Delayed ART Wright, EACS 2015, #PS10/6

22 START: No Difference in Cardiovascular Outcomes with Early vs. Delayed ART Cardiovascular Events (Early vs. Delayed): Small Artery Elasticity (higher better) HR 0.84 ( ) 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

23 In Contrast, Interrupting ART Strongly Increased CAD, Renal, Liver Disease SMART Trial HR for Drug Conservation vs. VL Suppression: 1.7 ( ), P=0.009 El-Sadr, SMART Trial, NEJM, 2007

24 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

25 What are the potential drivers of persistent immune activation during suppressive ART? And which ones are established early vs. late?

26 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.

27 Blocking Asymptomatic CMV Replication with Valganciclovir Immune Activation in HIV+ Patients with CD4<350 despite ART -4.4% HIV- Median 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

28 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)

29 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 )

30 Theoretical Model for Drivers of Immune Activation during Suppressive ART CD4 Nadir HIV Reservoir in Lymphoid Tissues Microbial Transl. HIV in Myeloid Cells CMV Adaptive Immune Defects Multiple Morbidities CNS, Liver, Metabolic Dz Vascular Dz

31 What can we do to reverse immune activation during suppressive ART?

32 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!

33 Aspirin Fails to Reduce Immune Activation or Improve Vascular Function (A5331) Serum thromboxane (cyclooxygenase inhibition) scd14 Placebo 100mg ASA 300mg ASA O Brien, CROI 2016, Abstract 44LB

34 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)

35 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)

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