The Long and Winding
Road of HIV Complications:
Aging with HIV
Luis A. Espinoza, MD
Associate Professor of Clinical Medicine
University of Miami Miller School of Medicine
Faculty, Florida/Caribbean AETC
Disclosure of Financial Relationships
This speaker has the following financial
relationships with commercial entities to
disclose:
•
• Consultant: Gilead, Tibotec, ViiV – Terminated
Speaker’s Bureau: Abbott, Boehringer, Gilead, Tibotec – Terminated
This speaker will not discuss any off-label use or
investigational product during the program.
This slide set has been peer-reviewed to ensure that there are no
conflicts of interest represented in the presentation.
HIV and Aging
Objectives
• Discuss the evolving complications being
seen in the aging HIV population
• Improve patient education in reduction of
risk factors in disease seen in the aging
population
• Implement appropriate recommendations
in screening and monitoring in the aging
HIV population
As estimated by the CDC: The percentage of HIV infected
individuals older than 50 years, in the year 2015 will be:
45%
A. 20%
B. 25%
C. 30%
D. 40%
E. > 50%
32%
13%
10%
0%
A.
B.
C.
D.
E.
Prevalence of HIV Infection in US
From: www.cdc.gov/hiv/topics/over50
Estimated Percentage of New Cases of
HIV/AIDS by Age, 2005
From: www.cdc.gov/hiv/topics/over50
Aging and Comorbidities
• Common disorders in older adults
– Cardiovascular disease
– Hypertension
– Metabolic disorders, obesity
– Neurocognitive decline
– Hepatic and/or renal impairment
– Bone fractures/Osteopenia/osteoporosis
– Malignancies
Biology of Aging in Humans
Vijg and Campisi, Nature 2008
Telomeres
and
Telomerase
Appendix C: Human
Embryonic Stem Cells and
Human Embryonic Germ
Cells . In Stem Cell
Information. Bethesda, MD:
NIH US DHHS, 2010
Telomeres and Telomerase
Human Telomeric and Subtelomeric Regions
http://AtlasGeneticsOncology.org/Deep/SubTelomereID20025.html June 2009
Telomeres, senescence and organismal aging
http://AtlasGeneticsOncology.org/Deep/SubTelomereID20025.html June 2009
Haematopoietic stem cells experience
functional decline with aging
Sahin and DePinho, Nature 2010
Aging of the Immune System
“Immunosenescence”
T cell characteristics that predict morbidity/mortality in the
very old:
•
•
•
•
•
•
•
•
Reduced regenerative capacity (stem cells, thymus)
Low naïve/memory T cell ratios
Low CD4/CD8 ratio
Increased T cell activation
Increased inflammatory markers (IL-6, CRP)
Clonal expression of CD28-CD57+ T cells
Expanded CMV specific T cell responses
Reduced T cell proliferation
Weng N. Immunity, 2006;24:495-499
Cao W. JAIDS 2009; 50:137-147
Linton PJ. Nat Immunol. 2004; 2:133-139
Barrier to HIV Diagnosis
in Older Adult
• Physicians are less likely to discuss HIV
related risk factors with older adults
• HIV-associated symptoms and other
illnesses
• Late presentation for diagnosis and care
• CDC recommendations
Patel D. Curr Inf Dis Rep 2011
Lindau ST. NEJM 2007
Gebo KA. Drugs Aging 2006
MMWR Recomm Rep 2006
Risk for Older HIV-Uninfected Adults
• National Survey of Sexual Health and
Behavior (2008)
Among all persons aged 50 years or older,
condoms were not used during most recent
intercourse with:
91.5% of casual partners
76.0% of friends
69.6% of new acquaintances
33.3% of transactional sexual partners
Schick V et al. J Sex Med. 2010;7(Suppl 5):315-329
Issues Specific to
Older Persons With HIV Disease
• Unprotected sex
– No concern about pregnancy
– “I’m too old to catch HIV”
•
•
•
•
•
•
Delay in testing
Limited incomes
Immune restoration
Comorbid illnesses
Polypharmacy
Insufficient data on drug interactions in older
population
Luther VP, et al. Clin Geriatr Med.
2007;23:567-583.
Illa L, et al. AIDS Behav. 2008;12:935-942.
NIH Statement on National HIV/AIDS and
Aging Awareness Day - September 18, 2010
“Older HIV-infected adults face
unique health challenges
stemming from age-related
changes to the body
accelerated by HIV infection,
the side effects of long-term
treatment for HIV, the
infection itself and often,
treatments for ageassociated illnesses”
NIH statement on National HIV/AIDS and Aging Awareness Day Sept. 18, 2010
http://www.nih.gov/news/health/sep2010/niaid-09.htm.
Barriers to HIV Management
in Older Adults
• Age as independent predictor on clinical
progression on HAART
• Significantly slower CD4 cell reconstitution
• Older patients are more susceptible to the
adverse events of therapy
• Older patients have greater number of comorbid conditions
• Viral suppression and adherence
Kirk JB: J Am Geriatr Soc. 2009;57:2129-2138
Hinkin, CH: AIDS 2001; 15:1576-9
Grabar,S: JAC; Jan 2006; 57:4-7
Time to AIDS Diagnosis After a Diagnosis
of HIV Infection in 2008 (40 States)
AIDS diagnosis After
Diagnosis of HIV Infection (%)
90
84.6
< 12 months (overall:32.8%)
> 12 months (overall: 67.2%)
75.9
80
70
61.4
60
54.1
45.9
50
38.6
40
30
20
24.1
15.4
10
0
< 20 (n=2246)
20 to 34
(n=16,557)
35 to 49
(n=16,287)
> 50 (n=6,894)
Age at HIV Diagnosis
CDC. HIV Surveillance Report, 2009.
http://www.cdc.gov/hiv/surveillance/resources/reports/2009report/.
Survival After AIDS Diagnosis
(1998-2005)
1
Age at
Time of
Diagnosis
<13
13-24
25-34
35-44
45-54
Proportion Surviving
0.8
0.6
>55
0.4
0.2
0
0
12
24
36
48
60
72
84
96
Months After AIDS Diagnosis
CDC. HIV Surveillance Report, 2009.
Available at: http://www.cdc.gov/hiv/surveillance/resources/reports/2009report/.
108
Factors of and Obstacles to
Successful Aging With HIV
Vance DE, et al. Clin Interv Aging. 2011;6:181-192
Successful Aging
• Length of life
– Number of years one remains alive
– Decreased compared to general population
– Lower in men, IVDU, lower initial CD4 count
• Biological Health
– How well is the interaction and function of
the different systems of the body
– Compromise of the immune system
– Bacterial translocation and alcohol
Vance DE, et al. Clin Interv Aging. 2011;6:181-192
Successful Aging
• Cognitive efficiency
– Optimal neurological integrity
– Cognitive decline versus same-aged peers
– Substance use
• Mental Health
– Emotional equilibrium
– HIV and poor mental health
– HIV and stigma
– Coping with HIV while aging
Vance DE, et al. Clin Interv Aging. 2011;6:181-192
Aging in HIV Infection
•
•
•
•
Chronic inflammatory stimulation
Bone fractures/Osteoporosis/Osteopenia
Increase in cardiovascular disease
Increased rates of non-AIDS associated
malignancies
• Faster neurocognitive decline
• Functional decline
Polypharmacy in Older HIV-Infected Patients
Variables
Total
Age Group
< 50
50-64
P Value
>65
Non-ART medication,
n (%)
Antihypertensives
(not ACE inhibitors)
785 (9.7)
300 (5.4)
341 (15.9)
144 (33.4)
<0.001
Antihypertensives
(ACE inhibitors)
874 (10.7)
311 (5.6)
415 (19.3)
148 (34.3)
<0.001
Lipid-lowering agents 1013 (12.4)
324 (5.8)
511 (23.8)
178 (41.3)
<0.001
Oral antidiabetics
170 (2.1)
49 (0.9)
82 (3.8)
39 (9.1)
<0.001
Insulin
118 (1.5)
39 (0.7)
52 (2.4)
27 (6.3)
<0.001
Antiplatelets drugs
473 (5.8)
110 (2.0)
233 (10.8)
130 (30.2)
<0.001
Antidepressants
792 (9.7)
514 (9.3)
240 (11.2)
38 (8.8)
0.140
Hasse B, et al. 18th CROI; 2011; Boston, MA. Abstract 792
Inflammation and Aging:
Therapeutic Strategies
• Reduce inflammation
–
–
–
–
–
–
–
Residual HIV replication (ART intensification?)
Prednisone, HU, cyclosporine, mycophenolic acid
Chronic/persistent co-infections (HCV, CMV)
Microbial translocation (sevelamer, colostrum)
CCR5 inhibitors
Chloroquine (reduced PDC mediated IFNα)
NSAIDs (COX-2 inhibitors)
Inflammation and Aging:
Therapeutic Strategies
• Enhance T-cell renewal
– GH, IL-7, stem cell transplant, perfenidone,
leuprolide (Lupron®)
• Anti-aging interventions
– Caloric restrictions
– Sirtuin activators, Telomerase activators
– Vitamin D, omega-3 fatty acids, sirolimus
(Rapamycin®)
Treating HIV Does Not Fully restore Life expectancy
Losina et al. CID 2009
T cell activation in human immunodeficiency virus
(HIV)-infected and HIV-uninfected adults
Hunt P W et al. J Infect Dis. 2003;187:1534-1543
© 2003 by the Infectious Diseases Society of America
Comorbidities Associated With
Aging and HIV Infection
Percent of Prevalence
40-49 Years
50-59 Years
> 60 Years
50
45
40
35
30
25
20
15
10
5
0
Hypertension
Diabetes
Vascular
disease
Goulet JL, et al. Clin Infect Dis. 2007;45:1593-1601
Pulmonary
disease
Renal Disease
Diabetes Mellitus in HIV and Aging
• Incidence is higher in HIV-infected patients
• Most important prevention is to avoid
excess weight gain.
• It could be related to the use of certain
antiretrovirals
• Screening for glucose intolerance should be
performed regularly
Summary Report from the HIV and Aging Consensus Project
JAGS 60:974-979, May2012
Cardiovascular Disease in HIV and Aging
• HIV-infected patients have greater 10year risk of cardiovascular disease
• Higher rates of atherosclerosis
independent of viral load, ARV or extent
of immunodeficiency (SMART)
• Smoking
• Dyslipidemia and metabolic syndrome
• Overweight
Brooks et al. Am J Public Health 2012;102:1516-1526
Pathogenesis of CV Disease in HIV
Insulin
HIV
cART
HIV
Dyslipidemia
Lipodystrophy
Inflammation
Resistance
Diabetes
Mellitus
Endothelial
CVD
van Wijk at al. Int J Vasc Med. 2012; ID201027
dysfunction
Risk Factors Contributing
to Development of Kidney Disease
Modifiable risk factors
•
•
•
•
•
Diabetes mellitus
High blood pressure
Kidney stones
Inflammation (eg GMN)
Allergic reaction to med (eg,
antibiotics)
• Medications (eg, NSAIDs)
• Drug abuse
• Use of creatine, hGH
testosterone
Non-modifiable risk
factors
• Age
• Family history of kidney
disease
• Trauma or accident
• Presence of other
diseases:
– HIV/AIDS, hepatitis C,
lupus, sickle cell anemia,
cancer, congestive heart
failure
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p7_risk_g13.htm
HIV and Age as Renal Risk Factor
• Among 2159 HIV-infected patients
enrolled in ACTG studies
• 30% of patients had low baseline glomerular
filtration rate (GFR)
• Median age was significantly higher in
patients with low versus normal GFR
• 42 versus 36 years, respectively; P<.0011
Kalayjian R. 14th CROI. 2007. Abstract 827.
HIV and Age as Renal Risk Factor
• In the EuroSIDA cohort, the rate of
chronic renal failure at baseline ranged
from 3.5% to 4.7% depending on the
method of GFR calculation
• By multivariate analysis, age was a strong
predictor of chronic renal failure at baseline
• OR 5.47, 95% CI 4.4-6.72; P<.00012
Mocroft A. AIDS. 2007;21(9):1119-1127.
Bone Health in HIV and Aging
• Among HIV-infected adults up to 60%
have osteopenia, and up to 15%
osteoporosis
• Higher rates of fragility fractures
• Rates of fracture 60% greater on those
with nadir CD4 < 200
• BMD assessment
Triant VA. J Clin Endocrinol Metab 2008:93(9):3499-3504
Sharma A. AIDS. 2010;24(15):2337-2345
BMD is Lower in HIV-Infected Women
> 40 Years of Age
Percent With Low BMD
30
27
HIV Infected
25
20
Control
19
21
15
15
12
10
7
5
0
Femur neck and lumbar
spine
Femoral neck only
Arnsten JH, et al. Clin Infect Dis. 2006;42:1014-1020
Lumbar Spine only
BMD is Lower in HIV-Infected Older Men
BMD at First DEXA (g/cm2)
1.4
1.2
HIV infected (n=230)
Control (n=159)
1
0.8
0.6
0.4
0.2
0
Femoral Neck
Total Hip
Lumbar Spine
Sharma A et al. AIDS. 2010, 24:2337-2345
Osteopenia incidence per 100 person-years at risk was 2.6 for HIV-uninfected
Men and 7.2 for HIV-infected men
Frailty in HIV and Aging
•
•
•
•
•
•
Weakness
Low physical activity
Slow motor performance
Weight loss
Weak grip strength
Factors associated with frailty: higher
depression score, unemployment,
greater comorbid conditions, past OIs
Brooks et al. Am J Public Health.2012;102:1516-1526
Psychiatric and Neurocognitive Disorders
•
•
•
•
Alcohol and drug use
Thought and mood disorders
Depression and suicide
Decrease memory
• UPDRS motor scores were 40.7% in HIV
infected vs 15.7% in HIV– Slowness of hand movement, body
bradykinesia, tremor
Valcour V at al. J Neurovirol. 2008;14:362-367
Vance et al. Clin Interv Aging 2011:6 181-192
Neurocognitive Complications in HIV
5%
42%
53%
Valcour V, et al. CROI 2012. Abstract 498
Asymptomatic Neurocognitive
Impairment (ANI)
Mild Neurocognitive Disorder
(MND)
HIV-associated Dementia (HAD)
Cancer in HIV and Aging
Patel P. Ann Intern Med. 2008;148(10):728-736
• Higher incidence among HIV-infected
–
–
–
–
–
–
–
–
–
–
Anal
Vaginal
Hodgkin’s lymphoma
Liver
Lung
Melanoma
Oropharyngeal
Leukemia
Colorectal
Renal
Higher Cancer Risk in HIV infection
•
•
•
•
•
•
Kaposi’s sarcoma
Non-Hodgkin lymphoma
Anal cancer
Hodgkin lymphoma
Melanoma
Liver cancer
Silverberg MJ. CEBP. Dec2011 20:2551-2559
199-fold
15-fold
55-fold
19-fold
1.8-fold
1.8-fold
Cancer Screening
•
•
•
•
•
•
Cervical cancer
Colon cancer
Anal cancer
Liver cancer
Skin cancer
Cancer screening should be in
accordance with current guidelines for
the general population
Cancer Screening
• Cervical cancer
– PAP smear upon starting care and again in
six months
– If abnormal: Colposcopy and biopsy
• Anal cancer
– RR increases 37-fold among HIV+ men
– RR increased 60-fold among HIV+ MSM
USPSTF, CDC, HIVMA Recommendations
Aberg JA et al. CID 2004 39(5)609-29
Frisch M et al. J NCI 2000 92(18)1500-10
Colorectal Cancer Screening
90
HIV +
HIV -
Proportion Tested (%)
80
77.8
66.6
70
65.6
60
50
55.6
49.3
43
40
27.5
30
17.5
20
10
5.3
17.2
2.6
7.9
0
Fecal Occult
Blood Test
Flexible
Sigmoidoscopy
Air Contrast
Barium Enema
Colonoscopy
Reinhold JP et al. Am J Gastroenterol. 2005;100:1805-1812
At least 1 CRC
Screening Test
UTD with at least 1
CRC Screening Test
Performed
Summary
• HIV population is aging
• Providers should ask all patients about
high-risk behaviors and educate them on
the risks
• Management of older HIV-infected patients
may be complicated by comorbidities
• Comorbidities attributed to increasing age
may overlap with morbidity from HIV
disease and toxicity from ART
Summary
• Current ARV therapies are effective in reducing
progression of the disease and mortality
• Life expectancy is shorter than normal despite
optimal ART.
– It appears to be predicted by lower CD4 and higher
inflammation.
• Markers of inflammation and T cell activation
remain higher in ART than non-HIV infected
• Early diagnosis, and probably early therapy
initiation, may improve outcomes in this
population