Pathophysiology of Non-Communicable Diseases in Treated HIV Infection: Is there a common path? Peter W. Hunt, MD Associate Professor of Medicine Division.

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Presentation transcript:

Pathophysiology of Non-Communicable Diseases in Treated HIV Infection: Is there a common path? Peter W. Hunt, MD Associate Professor of Medicine Division of Experimental Medicine University of California San Francisco

Legarth/Obel, JAIDS, 2016 HIV- Controls HIV ~20 year shorter if CD4 nadir <350 (Samji, PLoS One, 2013) 10y Decreased Life Expectancy in Older HIV+ Adults in Modern ART Era Danish Cohort

Many age-associated morbidities also increased in treated HIV Cardiovascular disease [1-3] Cardiovascular disease [1-3] Cancer (non-AIDS) [4] Cancer (non-AIDS) [4] Bone fractures / osteoporosis [5,6] Bone fractures / osteoporosis [5,6] COPD [12] COPD [12] Liver disease [7] Liver disease [7] Kidney disease [8] Kidney disease [8] Cognitive decline [9] Cognitive decline [9] Non-AIDS infections [10] Non-AIDS infections [10] Frailty [11] 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

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, JID, 2003 & PLoS One, 2011; see also: Neuhaus, JID 2010; Wada, AIDS 2014) Innate Immune Activation and Inflammation also Remain Abnormal

A single measurement of IL-6 or D-dimer predicts morbidity/mortality over next 10y Grund, PLoS One, 2016, #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)

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

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 (Longo, CROI 2014, #763; Dirajlal-Fargo, Antiviral Therapy, 2016) Lifestyle Factors Contribute to Immune Activation in Treated HIV

Interventions on the Horizon?

Statins Decrease Immune Activation and Aortic Plaque in Treated HIV Infection sCD14 Declines with Rosuvastatin Plaque Regression with Atorvastatin Funderburg/McComsey, JAIDS, 2015Lo/Grinspoon, Lancet HIV, 2015 REPRIEVE Trial of Pitavastatin (n=6500) Now Enrolling! See also: Nakanjako, Trop Med Int Health, 2015

How do we develop more effective interventions?

Immune Activation As a Tree Roots HIV reservoirs CMV Microbial translocation Branches IL-6 / Inflammation D-dimer / Coagulation Lymphoid Fibrosis Leaves End-organ diseases

Individual Roots and Branches: The Whack-a-Mole Problem TLR Inhibition with Chloroquine ↑ HIV VL Jacobson for A5258 Team, ARHR, 2016

Can we find the tree trunk? Roots HIV reservoirs CMV Microbial translocation Branches Inflammation Coagulation Lymphoid Fibrosis Trunk IL-1b Jak/Stat IDO-1 Monocyte activation

Despite optimal ART, HIV shortens life expectancy and ↑ age-associated morbidities. Immune activation / inflammation persist despite ART and may predict these morbidities. Lifestyle interventions are important! Statins show promise in decreasing immune activation (await REPRIEVE) Need better interventions for roots (HIV, CMV, microbial translocation) and perhaps “tree trunk” Summary

Acknowledgements Core Immunology Lab/DEM Elizabeth Sinclair Lorrie Epling Jeff Milush Mike McCune SFGH Cardiology Priscilla Hsue UARTO Helen Byakwaga Priscilla Martinez Alex Tsai Sheri Weiser David Bangsberg Mark Siedner NIAID/VRC Jason Brenchley Danny Douek SCOPE/OPTIONS/UCSF Sulggi Lee Ma Somsouk Steve Deeks Jeff Martin Hiroyu Hatano Vivek Jain Rick Hecht Chris Pilcher Rebecca Hoh SCOPE and OPTIONS Teams UCSF Drug Studies Unit Yong Huang CWRU Michael Lederman Nick Funderburg Mike Freeman R01AI110271, R56AI100765, 1R21AI087035, 1R21AI07877, DDCF CSDA, CHRP IDEA Award; Roche, Inc.