Toronto I-II 4:00 pm

The end of AIDS: HIV as a chronic inflammatory disease

Steven DeeksProfessor 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 KovaksAssistant 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 DeeksProfessor 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 KovaksAssistant 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. DeeksProfessor of Medicine

University of California, San Francisco

HIV infection

Antiretroviral treatment

Restore Immune function

Prevent AIDSProlong 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;30:471-477. 2; Hsue P, et al. Circulation. 2004;109:316-319. 3. Grinspoon SK, et al. Circulation. 2008;118:198-210. 4. Patel P, et al. Ann Int Med, 2008;148:728-736. 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. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286; … Also reviewed in Hunt, Curr HIV/AIDS Reports, (2012) 9:139–147.

Incident rate ratio for acute MI by age30-39 40-49 50-59 60-69 70-79

2.2 1.3 1.8 1.5 1.5

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+

B

0

20

40

60

80

100

18-34 35-44 45-54 55-64 65-74

Age Group (Years)

Even

ts P

er 1

000

PYs

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

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/mm3

Early ART GroupInitiate ART immediately

N=2,300

Deferred ART GroupDefer ART until the CD4+ count

declines to < 350 cells/mm3

N=2,300

START

Healthy aging requires aggressive

risk factor management,

exercise and diet

Haza

rd ra

tio

Haza

rd ra

tio

A All cause 1·00

B All cancer

0·90

0·80

0·70

0·60

0·50

0·40

0·30

0·20

0·10

0

C

1·00

Cardiovascular disease D Diabetes mellitus

0·90

0·80

0·70

0·60

0·50

0·40

0·30

0·20

0·10

0

Inactive Low

Medium High Very high Inactive Low Medium

Activ ity level Activ ity level

High Very high

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?

eGFR

Age

HIV-1 RNA

Hemoglobin

FIB-4

CD4 count

Rest. index

VACS index

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50

IL-6sCD14d-Dimer

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

Non-AIDS MorbidityAging

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