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