Toronto I-II 4:00 pm The end of AIDS: HIV as a chronic inflammatory disease Steven Deeks Professor of medicine in residence at the University of California, San Francisco, and a faculty member in the Positive Health Program at San Francisco General Hospital Moderator: Colin Kovaks Assistant Professor, Department of Medicine, University of Toronto, and a primary care physician currently practicing at the Maple Leaf Medical Clinic in Toronto

Toronto I-II 4:00 pm The end of AIDS: HIV as a chronic inflammatory disease Steven Deeks Professor of medicine in residence at the University of California, San Francisco, and a faculty member in the Positive Health Program at San Francisco General Hospital Moderator: Colin Kovaks Assistant Professor, Department of Medicine, University of Toronto, and a primary care physician currently practicing at the Maple Leaf Medical Clinic in Toronto

HIV as a Chronic Disease Steven G. Deeks Professor of Medicine University of California, San Francisco

HIV infection Antiretroviral treatment Restore Immune function Prevent AIDS Prolong life Prevent AIDS Prolong life Most of the research and clinical focus over the past 25 years has been on inhibiting HIV replication and preventing AIDS

AIDS and even most non-AIDS events (CAD, liver) has slowly declined, even during the late ART era

Despite unquestioned success, the risk for developing many morbidities remains higher than expected (~1.5 to 2.0 fold) Cardiovascular disease [1-3] Cancer (non-AIDS) [4] Bone fractures / osteoporosis [5,6] Liver disease [7] Kidney disease [8] Cognitive decline [9] Frailty (80% more common) [10] 1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30: ; Hsue P, et al. Circulation. 2004;109: Grinspoon SK, et al. Circulation. 2008;118: Patel P, et al. Ann Int Med, 2008;148: 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: Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62: ; … Also reviewed in Hunt, Curr HIV/AIDS Reports, (2012) 9:139–147.

Incident rate ratio for acute MI by age Impact of HIV on risk comparable to traditional risk factors including HTN, DM and hyperlipidemia Models adjusted for recognized risk factors

The excess risk of CAD in HIV disease increases with age, suggesting that problems will become more apparent in next decade RR adjusted for age, gender, race, hypertension, diabetes, and dyslipidaemia * Triant VA et al, J Clin Endocrinol Metab, 2007 HIV- HIV+

59 year old man less “robust” than father Gross G. AIDS Patients Face Downside of Living Longer. NY Times. Jan 6, 2008 France D. Another Kind of AIDS Crisis. New York. Nov 1, 2009 HIV associated with multiple morbidities of aging There is even a concern in the popular press that HIV “accelerates” aging

Does HIV influence the biology of aging and/or cause “premature” aging?

Stem cell exhaustion (HIV) Telomore/telomerase (HIV, NRTIs) Dysregulated nutrient sensing (ART) Mitochondrial toxicity (NRTIs) T cell senescence (HIV)

Integrative nature of geriatric syndromes (“aging”) General medicine: focus on specific disease (CAD, cancer, DM) with linear pathways Geriatric medicine: focus on functional status –Defined geriatric syndromes rather than specific diseases (frailty, incontinence, immobility, falls) –Loss of redundancy (or physiologic reserve) that arises as a consequence of multiple deficits that accumulate (often exponentially) with age

Frailty-like syndrome occurs earlier in HIV disease (predicted by CD4 nadir, duration of infection) Prevalence among those receiving modern treatment regimens unknown Frailty-like syndrome occurs earlier in HIV disease (predicted by CD4 nadir, duration of infection) Prevalence among those receiving modern treatment regimens unknown

Why is this happening?

After adjusting for traditional risk factors, inflammatory biomarkers remain elevated during long-term ART, although the increase is moderate Neuhaus JID 2010

Inflammation predicts disease in treated HIV infection, as it does in the general population Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011) Cardiovascular Disease (Baker, CROI 2013) Lymphoma (Breen, Cancer Epi Bio Prev, 2010) Venous Thromboembolism (Musselwhite, AIDS, 2011) Type II Diabetes (Brown, Diabetes Care, 2010) Cognitive Dysfunction (Burdo AIDS 2012) Frailty (Erlandson, JID 2013)

A single measurement of IL-6 or D-dimers predicts morbidity or mortality over several years

HIV-associated inflammation may cause vascular disease through several mechanisms (Hsue/Ganz) Deeks et al NEJM 12

It may be easier to prevent age-associated complications than reverse them

Multiple factors cause persistent inflammation during ART Deeks, Lewin, Havir; Lancet 2013

Therapeutic Options in Development Chemokine receptor inhibitors: maraviroc, TB-652 Anti-infective therapy: CMV, EBV, HSV, HCV/HBV Microbial translocation: sevelamer, colostrum, rifaximin, pre-biotics, probiotics, isotrentinoin Enhance T cell renewal: growth hormone, IL-7 Anti-fibrotic drugs: perfenidone, ACE inhibitors, ARBs Anti-aging: caloric restriction, sirtuin activators, vitamin D, omega-3 fatty acids, sirolimus, diet, exercise Anti-inflammatory drugs –Chloroquine, hydroxychloroquine –Minocycline –NSAIDs (COX-2 inhibitors), aspirin –Statins –Methotrexate (low-dose; CIRT) –Talidomide, lenalidomide, pentoxyfylin –Biologics (e.g., TNF inibitors, IL-6 inhibitors, anti-INF-alpha) Anti-coagulants: low dose warfarin, dabigatran, aspirin, clopidogrel

Early ART is associated with less inflammation during ART Will this result in benefit? ART-naïve with CD4+ count > 500 cells/mm 3 Early ART Group Initiate ART immediately N=2,300 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 N=2,300

Healthy aging requires aggressive risk factor management, exercise and diet

All cause mortality Cancer Cardiovascular Diabetes mellitus Over a mean duration of 8 years, higher intensity activity predicted reduced morbidity/mortality (N=416,175) Every additional 15 minutes of daily exercise reduced all- cause mortality by 4% (95% CI 2·5–7·0)

Do we have any useful biomarkers?

The VACS Index—which is includes HIV, hematology, liver, kidney markers—is correlated with inflammation Justice CID 2012

Most of the best validated markers (IL-6, D- dimers, sCD14, sCD163) have poor performance activities, but the CD4/CD8 ratio may prove the useful (Serrano-Villar and Sainz) Among those on ART with a “normal CD4”, a low CD4/CD8 ratio is associated with more “senescent” CD8+ T cells

Many factors know to influence aging are common in HIV disease, particularly the “first generation” of survivors

Many HIV-associated factors could affect healthy aging Deeks, Tracy, Douek. Immunity 2013

What are the public implications?

HIV Infection Antiretroviral Treatment Testing, linkage to care, retention Immune Dysfunction/Inflammation Treatment Toxicity Anti-inflammatory drugs Overburdened Health Care Delivery Systems Overburdened Health Care Delivery Systems Non-AIDS Morbidity Aging Non-AIDS Morbidity Aging Preventative medicine Healthy aging Operational research Research and clinical priorities in the era of “complete “ viral suppression: Test and treat, reduce inflammation, insure healthy aging, and provide chronic care until there is a cure

Acknowledgements