Scott Letendre, MD, of the UC San Diego HIV Neurobehavioral Research Program, presents "Overview of HIV & Aging" for AIDS Clinical Rounds at UC San Diego

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AIDS CLINICAL ROUNDS

2. Overview of HIV & Aging
Scott Letendre, M.D.
Professor of Medicine
University of California, San Diego

3. People with HIV Are Living Longer
but Survival Still Lags Behind
Lohse et al, Ann Intern Med
2007, 2007;146:87-95
Losina et al, Clinical Infectious Diseases
2009; 49:1570–8

4. Number of PLWH Older than 50 Nearly
Doubled Between 2004 and 2008
http://www.aoa.gov

5. Improved longevity is only
part of the explanation
• New infections are also occurring
– Many older adults are newly single, widowed,
or have grown children and have more time
for sexual activity
– New treatments for erectile dysfunction
– Older adults may be unfamiliar with condom
use or reluctant to use them
– Vaginal dryness is common, which may
increase HIV transmission
HRSA CARE Action, February 2009

6. Important Questions to Consider
• Do PLWH truly have premature or accelerated aging?
• …or are the complications linked to factors that increase
risk for HIV transmission?
– Substance use
– Sex and injection transmitted diseases
– Lower socioeconomic status
• …or do HIV and its treatment increase risk for these
complications without actually altering the biological
process of aging?
• What is successful aging and how do we achieve it?
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26

7. Successful Aging is Multidimensional
• Typical elements of successful aging
– Avoidance of disease and disability
– Maintenance of high physical and cognitive
function
– Sustained engagement in social and
productive activities
• Subjective quality of life may be more
important than the absence of disease
Rowe & Kahn, Gerontologist. 1997;37(4):433-40
http://en.wikipedia.org/wiki/Successful_Aging, Accessed 8 November 2013

8. 36% of the General Population Age
Successfully and this May be Lower in PLWH
Depp & Jeste, American Journal of Geriatric Psychiatry. 2006; 14: 6-20
Moore et al, J Clinical Psychiatry 2013, 74: e417-23
p = .005
Most frequent correlates of SA: Nonsmoking and
absence of disability, arthritis, and diabetes
Higher self-rated SA in PLWH was associated with
better physical and emotional functioning but
not HIV disease or negative life events
27 studies in HIV negative people

9. AIDS Defining Illnesses Are Declining
but HANA Are Increasing
• AIDS-defining illnesses are increasingly rare in those
taking effective ART
• HIV-associated non-AIDS (HANA) conditions are
increasing
• A common theme among currently identified HANA
conditions is their association with advancing age
and chronic inflammation
• Whether PLWH will develop these conditions earlier
in their life course remains uncertain
High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18

10. AIDS Defining Illnesses Are Declining
but HANA Are Increasing
• AIDS-defining illnesses are increasingly rare in those
taking effective ART
• HIV-associated non-AIDS (HANA) conditions are
increasing
• A common theme among currently identified HANA
conditions is their association with advancing age
and chronic inflammation
• Whether PLWH will develop these conditions earlier
in their life course remains uncertain
High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18
“Any comparison between people with and
without HIV infection must be accomplished
with careful study design as these populations
tend to differ in a number of behavioral and
biologic factors that are known to affect the
aging process.”

11. Nearly Every Organ System
Can Be Affected by Aging in PLWH
• Endocrine/Metabolic
– Diabetes
– Hypogonadism
• Vascular System
– Cardiovascular
– Cerebrovascular
• Nervous System
– Cognitive Disorders
– Depression
– Neuropathy
– Sleep Disorders
• Liver
– ↓ Drug Metabolism
– ↓ Synthetic Function
• Kidney
– ↓ Drug Elimination
• Musculoskeletal
– Osteoporosis
– Frailty
• Pulmonary System
• Cancer
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26
Onen et al, HIV Clin Trials. 2010;11(2):100-109; Womack et al, PLoS ONE. 2011;6(2): E17217;
Desquilbet et al, J Gerontol A Biol Sci Med Sci. 2007;62(11):1279---1286.

12. Incidence of Diabetes Increased in
the Early HAART Era, then Declined
Capeau et al, AIDS 2012, 26(3): 303-14
Calendar Year Interval
• Prospective study of 1046 patients
• 111 patients developed diabetes
• Incidence of 14.1/1000 PYFU
• Correlates: older age, overweight,
larger waist-to-hip ratio, exposure to
indinavir, stavudine, or didanosine
Janiszewski et al, PLoS ONE 2011, 6(9): e25032
• Cross-sectional study of 2322 patients
evaluated between 2005 and 2009
• 184 patients had diabetes
• Subjects with waist circumference ÷ 90
cm and triglycerides ≥ 2.0 mmol/L had
the highest prevalence
b

13. NCEP–ATP III Definition of
Metabolic Syndrome
http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf

14. Metabolic Syndrome Linked to
Longer Durations of ART in 2008-9
Wu et al, J Antimicrob Chemother 2012; 67: 1001–1009
*Associations were present after adjusted for age, gender, smoking, family history, baseline plasma viral load, and CD4

15. Multiple Studies Have Identified Increased
Risk of Cardiovascular Disease in PLWH
• PLWH have greater 10-year risk of cardiovascular
events (CVEs) and higher rates of atherosclerosis
than HIV-negative persons
• HIV disease itself is associated with greater risk of
atherosclerosis independent of viral load, type of
ART, or severity of immunodeficiency
• Whether the increased risk of cardiovascular
disease can be modified by ART remains uncertain
– We still need randomized clinical trial data
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Hsue et al, IDS. 2009;23 :1059-1067;
Kaplan et al, Clin Infect Dis. 2007;45(8):1074-1081; El-Sadr et al, Ann Intern Med. 2008;149(5):289-299;
Triant et al, Clin Infect Dis. 2012; 54:408-413

16. Myocardial Infarctions are More
Common in PLWH
• More than 80,000 veterans
with nearly 6 years of follow-up
had 871 acute myocardial
infarctions (AMIs)
• Across 3 decades of age,
mean AMIs per 1000 person-
years was consistently higher
for PLWH than HIV negative
people
• Hazard ratio was 1.5 after
adjusting for Framingham risk
factors, comorbidities, and
substance use
0
2
4
6
8
10
12
30-39 40-49 50-59 60-69 70-79
HIV-
HIV+
Rate
per
1000
Person-Years
Freiberg et al, JAMA Intern Med. 2013;173(8):614-622
Age Range (Years)

17. Aging PLWH More Frequently
Develop Multiple Comorbidities
• In a US cohort
comparing HIV
positive and negative
people, PLWH were
more likely to have
nearly every comorbid
condition assessed
including heart
disease, bone loss,
and diabetes
Hasse et al, Clinical Infectious Disease 2011, 53: 1130-9
Nkhoma et al, 1st International Workshop on HIV & Aging 2010, Presentation O_16

18. Vascular Disease May Increase Risk
for Neurocognitive Impairment
• 428 HIV+ and 207
HIV- in the U.S.
Multicenter AIDS
Cohort Study
• Greater intima media
thickness was
associated with worse
psychomotor speed
and memory
• 292 HIV+ people in
the START study
• Prior vascular disease
was associated with
6.2-fold higher odds
of neurocognitive
impairment
Wright EJ, et al.
Neurology 2010;75:864–873
Becker JT, et al.
Neurology 2009;73:1292–1299

19. Metabolic Syndrome May Also Be
Associated with Neurocognitive
Impairment
• Cross-sectional analysis of
130 subjects who provided
fasting blood samples in
the CHARTER project
• Neurocognitive impairment
was associated with older
age, longer duration of HIV
infection, obesity, larger
waist circumference, and
diabetes in univariable
analyses
McCutchan, et al. Neurology 2012. 78:485–492
Multivariable Analysis of
Neurocognitive Impairment

20. Most Studies Support that Older Age is
Associated with Worse Neurocognitive
Functioning in HIV
Modified from Valcour et al,
Neurology 2004;63:822–827
Heaton et al, J NeuroVirology,
2012, 18(Suppl 1): S46
HIV x Age Interaction p = 0.004

21. Aging Accelerates Loss of
White Matter Integrity
Chang et al, J Neuroimmune
Pharmacol (2008) 3:265–274

22. Stroke Risk is Also Higher in
People with HIV
Variable HR p Value
Age 1.06 < .001
Atrial fibrillation 3.15 .01
NNRTI Use .38 .006
HIV RNA 1.10 .001
CNS Infection or
Malignancy
2.75 .01
Ischemic Stroke
Ovbiagele, et al. Neurology 2011;76:444–450 Chow, et al. JAIDS 2012; 60:351–358
• Using a hospital database of
9,664,892 people, US stroke
hospitalizations declined 7%
while stroke hospitalizations
with HIV rose 60%
• 4,308 people with HIV and 32,423
people without HIV
• Incidence rate of ischemic stroke was
40% higher in people with HIV
• HIV: 5.27 per 1000 PY
• Non-HIV: 3.75 per 1000 PY

23. Possible Causes of
Premature Aging in PLWH

24. Unsuccessful
Aging
Poly
pharmacy
Stimulant &
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Chronic
Infection-
Related
Viral
Hepatitis
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Immune
Activation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Reduced
Liver
Synthetic
Function

25. Deeks, Tracy, & Douek, Immunity 2013, 39: 633-45
Inflammation Plays a Central Role
in Unsuccessful Aging of PLWH

26. Older PLWH Often Present with
More Advanced Immune Suppression
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26
Althoff et al.AIDS Res Ther. 2010;7:45

27. Why is Presenting with Advanced
Immune Suppression Important?
• Advanced immune suppression – even
in the past – is associated with higher
risk of HIV disease complications
– Neurocognitive impairment
– Cardiovascular disease
– Cancer
– Bone loss
Ho et al, AIDS. 2012 Jun 1;26(9):1115-20; Ellis, et al. AIDS, 2011, 25: 1747-51;
Cutrell & Bedimo. Curr HIV/AIDS Rep. 2013; 10: 207-16; Borderi et al, New Microbiol. 2002 Jul;25(3):375-
84; Gazzola et al., J Transl Med. 2013 Feb 28;11:51; Ganesan et al, HIV Med. 2013;14: 65-76;
Galli et al, Eur J Epidemiol. 2012 Aug;27(8):657-65;
– Diabetes
– Kidney disease

28. Older PLWH Have Worse Immune
Responses to Antiretroviral Therapy
• Older patients typically
adhere better to ART
but appear only equally
likely to achieve
virologic suppression
compared with
younger patients
• Older patients with
virologic suppression
can have less robust
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Silverberg et al, Arch Intern Med.
2007;167: 684-691; Althoff et al, AIDS. 2010;24: 2469-2479; Sabin et al, HIV Med. 2009; 10: 35-43
immune recovery
– Possibly because the thymus atrophies with age

29. Aging and HIV affect the Immune
System in Similar Ways
• In addition to loss of thymus tissue, aging
is associated with decreases in the
number of naive T-cells, reduced T-cell
responsiveness, and B cell dysfunction
• Immune senescence in the general
population has been linked to many of the
same end-organ disorders occurring in
aging PLWH
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26
Effros RB, Clin Infect Dis. 2008;47(4):542-553; Kaplan et al, J Infect Dis. 2011; 203: 452-463

30. CMV May be an Important
Infection in Biological Aging
• In large cohorts of HIV negative elders,
higher CMV IgG levels and larger
numbers of CMV-specific CD4+ T-cells
were associated with…
– Cardiovascular disease
– Neurocognitive decline
– Worse survival
Pawelec et al, Virus Research, 2011, 157: 175; Vescovini et al, J Immunology, 2010, 184: 3242;
Aiello et al, JAGS, 2006, 54:1046; Roberts et al, American J Epidemiology, 2010, 172:363.

31. CMV-Specific Immune Responses Are
Associated with Atherosclerosis in PLWH
Hsue et al, AIDS 2006, 20: 2275-83

32. Letendre, et al. Clinical Infectious Diseases 2013, Submitted
Higher CMV Antibody Levels Are
Associated with Lower CD4+ T-Cell
Nadirs and Neurocognitive Impairment

33. CMV Shedding is Associated with
higher HIV DNA levels in PBMCs,
which are Associated with NCI
Shiramizu et al, Int J Med Sci 2006, 6;4(1):13-8
• In the SEARCH 001 study in Thailand,
HAD was associated with
higher HIV DNA levels in PBMCs
• With HAD (n=15; median=4.27
log10/104 PBMCs)
• Without HAD (n=15; median=2.28
log10/104 PBMCs)
p<0.001
Gianella et al, J Infect Dis 2013, 207: 898–902
• In 113 antiretroviral (ART)–naive
PLWH, CMV replication in blood and
semen was associated with higher
levels of HIV DNA in PBMCs

34. The Liver may be the Most
Sensitive Organ to Aging
• HIV and aging are each associated with…
– Decrease in liver volume
– Impaired blood flow to the liver
– Decreased drug metabolism
– Increased amount of fat in the liver, which
alters metabolic rate
– Decline in regenerative response of
hepatocytes following injury
Slide Courtesy D. Dieterich; Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al.
Res Virol 1990; Banerjee et al. AIDS 1992; Blackard JT et al. J viral hepat. 2008; Hong F et al. Hepatology 2010

35. How Can We Improve the
Likelihood of Successful Aging?

36. Unsuccessful
Aging
Poly
pharmacy
Stimulant &
Opiate Use
ART
Toxicity
Drug-
Related
Behavior
Comorbidities
Genetic
Host-
Related
CMV
Chronic
Infection-
Related
Viral
Hepatitis
Microbiome
Viral
Proteins
Persistent HIV
Replication
HIV-
Related
Advanced
Immune
Suppression
Immune
Activation
Coagulation
Imbalance
Cellular
Toxins
Protein
Glycation
Reduced
Liver
Synthetic
Function

37. Intervention for HIV-Related Factors
• Diagnose HIV earlier in disease
• Initiate ART early in disease
before patients advance to
severe immune impairment
• Support ART adherence
• Regularly check viral loads and
CD4+ T-cell counts
History of
Advanced
Immune
Disease
Persistent
HIV
Replication

38. Gardner et al, Clin Infect Dis. 2011; 52(6):793-800
59% 67% 80% 75% 80%
79%
19% of people with HIV
in the US are taking ART
and have undetectable
plasma viral load

39. Initiation of ART in Older PLWH
• ART…“is recommended in patients > 50
years of age, regardless of CD4 cell
count…because the risk of non-AIDS related
complications may increase and the
immunologic response to ART may be
reduced in older HIV-infected patients”
• Further research is needed to identify
preferred regimens for this age group
– Limit toxicity
– Avoid interactions with other drugs
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26;
Department of Health and Human Services, Guidelines for the Use of Antiretroviral Agents in HIV-1-
Infected Adults and Adolescents; Thompson et al, JAMA. 2010; 304: 321-333

40. Letendre et al, 18th CROI, 2011, Abstract 408
Blood-Brain Barrier Permeability Increases
with Age, which may Increase Drug
Distribution into the CNS
Croteau et al, 19th CROI, 2012, Abstract 592
p = .004
p = .05

41. Host-Related Factors
Behavior
Chronic
Infections
Immune
Activation
Genetics
• Follow guidelines for checking and controlling
vascular risk factors (cholesterol, blood
pressure)
– Kidney, liver, bone health assessments
– Daily aspirin
• Actively support smoking cessation
• Support regular exercise regularly, healthful
diet, maintenance of healthy weight
• Cancer screening
• Avoid or treat co-infections
– Viral hepatitis, syphilis, tuberculosis
– Vaccinations
– No current recommendations for CMV

42. Stopping Smoking Reduces
Risk for Cardiovascular Events
• More than 27,000
patients had a total of
3,680 CVEs or mortality
• Adjusted incidence rate
ratio in patients who
stopped smoking
decreased from 2.3
within the first year to
1.5 after > 3 years
compared with those
who never smoked
Petoumenos et al, HIV Medicine 2011, 12:412–421
Myocardial infarction
Cardiovascular Disease

43. Samaras K. Curr HIV/AIDS Rep (2012) 9:206–217

44. Metabolic Toxicity
Lower Intermediate Higher
NRTIs Abacavir
Emtricitabine
Lamivudine
Tenofovir
Didanosine
Zidovudine
Stavudine
NNRTIs Nevirapine Efavirenz
Etravirine
PIs Atazanavir
Saquinavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Tipranavir
Entry Inhibitors Enfuvirtide
Maraviroc
Integrase Inhibitors Raltegravir
Blanco et al, AIDS Reviews 2010; 12: 231-41

45. • Assess all patients with HIV (CEBM 5; GOR D)
– Can assist in treatment and management decisions, provide
reassurance, and detect cognitive, behavioral and mood changes
before symptoms arise (CEBM 2b)
– No rationale for screening only symptomatic patients (CEBM 2b)
• Assess neurocognitive functioning early in the
disease using a sensitive screening tool (CEBM 5,
GOR D)
– All patients with HIV should be screened for HAND within 6 months of
diagnosis (CEBM 5; GOR D)
• Screen before the initiation of ART (CEBM5; GOR D)
Mind Exchange Working Group, Clinical Infectious Diseases 2013 Apr;56(7):1004-17

46. Drug-Related Factors
Stimulant
& Opiate
Use
ART
Toxicity
Poly
pharmacy
• Abstain from substance use
– Methamphetamine, cocaine, heroin
• Consider modifying ART that is causing
undesired side effects
• Avoid unnecessary medications
• Review medications with a pharmacist
familiar with HIV care to identify drug
interactions
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26;
Bowman et al, Pharmacoepidemiol Drug Saf. 1996; 5: 9-18; Egger et al, Drugs Aging. 2003;20(10):
769---776; Justice AC. Top HIV Med. 2006;14(5):159---163.

47. Methamphetamine is Associated with
Worse Neurocognitive Functioning in
Older but not Younger PLWH
42
44
46
48
50
52
54
56
T-Score
H-M- (n=36)
H+M- (n=49)
H+M+ (n=31)
42
44
46
48
50
52
54
56
T-Score
H-M- (n=28)
H+M- (n=34)
H+M+ (n=34)
**
*
*
**
*p < 0.05; **p < 0.01
Woods et al, 4th International Workshop on HIV and Aging, 2013
Slide courtesy Steven Woods, Psy.D.
Older (≥ 50 years old) Younger (≤ 40 years old)

48. Summary and Conclusions
• People living with HIV are older than in the past
• Evidence supports that PLWH are more
susceptible than the general population to immune
senescence and disease of multiple organ
systems
• Prevention, early diagnosis, and early treatment
are important for managing these complications
– Avoid polypharmacy
• New research is needed to define optimal
management
• Greater education of patients and providers is

49. Internet Resources
• CDC.gov: Persons Aged
50 and Older
– http://www.cdc.gov/hiv/topics
/over50/protection.htm
• AIDS.gov: Aging with
HIV/AIDS
– http://www.aids.gov/hiv-aids-
basics/staying-healthy-with-
hiv-aids/taking-care-of-
yourself/aging-with-hiv-aids/
• New England Association
on HIV over 50
– hivoverfifty.org
• Services & Advocacy for
Gay, Lesbian, Bisexual, &
Transgender Elders
– http://www.sageusa.org
• HIV Wisdom for Older
Women
– www.hivwisdom.org
• ACRIA Center on HIV &
Aging
– www. acria.org
• AIDS Foundation of
Chicago
– http://www.aidschicago.org/p
df/2005/prev_over_50.pdf

50. Acknowledgements & Conflicts
UC San Diego
• Ronald J. Ellis
• J. Allen McCutchan
• Igor Grant
• Bob Heaton
• Edmund Capparelli
• Brookie Best
• Jennifer Marquie
• Florin Vaida
CHARTER or NNTC
• David Clifford
• Justin McArthur
• Ned Sacktor
• Ann Collier
• David Clifford
National
Institutes of
Health
 …Mental Health
 …Drug Abuse
 …Allergy and
Infectious Diseases
Industry
 ViiV
 Abbvie
 Merck, Inc.
 Steven Woods
 Davey Smith
 David Moore
 Tom Marcotte
 Cris Achim
 Eliezer Masliah
 Debra Rosario
 Mariana Cherner
 Christina Marra
 Susan Morgello
 David Simpson
 Ben Gelman
 Donald Franklin
Study Volunteers

52. Summary of Suggestions
• Stop smoking
• Exercise regularly
• Achieve & maintain
healthy weight
• Manage insulin
resistance/diabetes
• Manage vascular
disease risk factors
• Treat depression
• Treat co-infections
• Cognitive training
Petoumenos et al, HIV Medicine 2011, 12:412–421;
McCutchan et al., Neurology 2012, 78(7):485-92;
Valcour et al., J Acquir Immune Defic Syndr. 2006;43(4):405-10;
Weber et al., J Int Neuropsychol Soc. 2012 Jan;18(1):128-33;
Weber et al., Neuropsychol Rev 2013, DOI 10.1007/s11065-013-9225-6;
Dufour et al, J Neurovirol 2013, DOI 10.1007 s13365-013-0184-8

53. Cardiovascular Disease Appears
to be More Common in PLWH
• Forest plots of studies
and pooled estimate of
relative risk of
cardiovascular disease
– In untreated people
living with HIV versus
HIV-uninfected people
– In people living with HIV
exposed to ART versus
HIV-uninfected people
Islam et al, HIV Medicine 2012, 13: 453–468

54. HIV and Aging Cause Similar
Changes to the Immune System
• Shift from a naive to a memory T-cell
phenotype
• Reduction in the ability of T-cells to proliferate
• Associated with reduced telomere length
Decreased production of IL-2 and IL-2 receptor
(involved in T-cell-mediated immune
responses)
DePaoli P, Clin Immunol Immunopathol 1988, 48: 290-296; Lerner A, J Immunol 1989, 19:977-982;
Ernst DN, J Immunol 1993, 151: 575-587; Negoro S, Mech Aging Dev 1986, 33:313-322;
Eylar EH, J AIDS 1994, 7:124-128; Bestilny LJ, AIDS 2000, 14 (7): 771-780;
Choremi-Papadapoulou H, JAIDS 1994, 7:245-253, Fagnoni FF, Immunology 1996, 88:501-507;
Gillis S, J Clin Invest 1981, 67: 937-942; Eyler EH, Cell Mol Biol 1995, 41:S25-S33

55. Virologic Responses to ART May
Differ in Older Individuals
• Prior to the HAART era, viral loads were
higher in patients who were older at the
time of seroconversion
• In the HAART era, older patients had:
– Better adherence and more favorable viral
load outcomes at 24 months
– But also more toxicities to medications and
more self-reported lipodystrophy
Sabin et al, JAIDS 2000; 23:172-77; Kobel, AIDS 2001, 15 (12): 1591-1593

56. Immune Responses to ART May
Be Worse in Older Individuals
• Most studies show a less favorable CD4+
T-cell rise in older patients (≥ 55 years)
following initiation of ART
• May be due to loss of thymus tissue with
age as naive cell rise correlates with
thymic size and thymic output
Goetz MB, AIDS 2001, 15 (12): 1576;
Operskalski EA, JAIDS 1997, 15 (3): 243; Viard JID 2001;183:1290;
Smith KY, JID 2000; 181:141; Douek DC, Nature 1998, 396; 690-695

57. Summary Findings from U.S.
Consensus Report
• By 2015, half the people living with HIV infection in the
United States will be 50 years of age or older
• People with HIV experience excess morbidity and
mortality compared with the general population
– Even those receiving effective ART with suppression of
virus to levels below typical detection limits
• On average, a 20-year-old initiating ART may have
already lost one-third of the expected remaining years
of life compared with demographically similar HIV-
uninfected persons
High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18

58. Example of Survival Estimates
from the HIV Research Network
Losina et al, Clinical Infectious Diseases 2009; 49:1570–8

59. Factors That Can Differ Based on
HIV Disease Status
• People aging with HIV disease are more likely to continue
substance use than the general population
– Tobacco, alcohol, opioids, and other psychoactive substances
• People with HIV disease are also more likely to be infected
with chronic viruses such as hepatitis C and CMV
– Interacts with HIV or alcohol to hasten cirrhosis and liver cancer
• People with HIV disease differentially represent sexual and
racial minorities that may have constrained economic and
social resources
– Homelessness, food insecurity, and social isolation may exacerbate
substance use and complicate the aging process
High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18

60. Stroke May Be Increasing As
People Live Longer with HIV
• Large hospital database of people
admitted with stroke in the U.S.
between 1997 and 2006 (N =
9,664,892)
• Overall US stroke hospitalizations
lessened 7% while stroke
hospitalizations with HIV rose 60%
– Patients with stroke and HIV
increased over time from 0.08% to
0.15% of all strokes (p < 0.0001)
• Those with HIV were more likely
to have dementia, liver disease,
renal disease, cancer, and urban
hospital location
Ovbiagele, et al. Neurology 2011;76:444–450
Ischemic Stroke

61. Confirmation of Greater Hazard of
Stroke from Another Cohort
• 4,308 people with HIV and 32,423
people without HIV seen between
1996 and 2009
• Primary endpoint was ischemic stroke
defined by ICD codes
• Incidence rate of ischemic stroke was
40% higher in people with HIV
– HIV: 5.27 per 1000 PY
– Non-HIV: 3.75 per 1000 PY
• HIV remained a predictor of stroke
after controlling for demographics and
stroke risk factors (1.21, P=0.04)
Chow, et al. JAIDS 2012; DOI: 10.1097/QAI.0b013e31825c7f24
Variable HR p Value
Age 1.06 < .001
Atrial fibrillation 3.15 .01
NNRTI Use .38 .006
HIV RNA 1.10 .001
CNS Infection or
Malignancy
2.75 .01
Multivariable Analysis of
Correlates of Stroke

62. Heart Attacks are More Common in
PLWH than in HIV Negative People
• More than 80,000 veterans with
nearly 6 years of follow-up had
871 acute myocardial infarctions
(AMIs)
• Across 3 decades of age, mean
AMIs per 1000 person-years was
consistently higher for PLWH
than HIV negative people
• Hazard ratio was 1.5 after
adjusting for Framingham risk
factors, comorbidities, and
substance use
0
2
4
6
8
10
12
30-39 40-49 50-59 60-69 70-79
HIV-
HIV+
Rate
per
1000
Person-Years
Freiberg et al, JAMA Intern Med. 2013;173(8):614-622
Age Range (Years)

63. ART may also
Play a Role in CVD Risk
• Some antiretroviral drugs predispose to an adverse
cholesterol profile
• Increase in risk conferred by certain antiretrovirals is
generally moderate compared with the risk conferred
by traditional risk factors as well as by HIV itself
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Friis-Møller et al, N Engl J Med.
2007;356(17):1723-1735; Sabin et al, Lancet. 2008;371(9622):1417-1426; Lichtenstein et al, Clin Infect
Dis. 2010;51(4):435-447; Niaura et al, Clin Infect Dis. 2000;31(3):808-812

64. Unimpaired 48%
Confounded 12%
ANI 29%
MND 8%
HAD 3%
HAND is
Common
Among
People
with HIV
Disease
Heaton et al, Neurology. 2010; 75: 2087-96

65. Depression is Also More Common in
PLWH than in the General Population
• Depression is the most common psychiatric disorder
affecting PLWH, among whom it is under-recognized
and under-treated
• Both depressive symptoms and suicide are most
common among older persons, especially aged 65
years and older
• Treatment of depression in PLWH correlates with
improvements in ART adherence, virologic
responses, and survival
Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Pence et al, AIDS. 2012; 26:656-
658; Horberg et al, J Acquir Immune Defic Syndr. 2008;47:384-390;
Althoff et al, lin Infect Dis 2010;50: 1512---1520.

66. Capeau et al, AIDS 2012, 26(3): 303-14
Calendar Year Period

67. Objectives
• Provide an overview of information on the aging
of people living with HIV (PLWH) disease
• Provide an overview of information on the organs
affected by aging and the data supporting
premature aging in PLWH
• Review data on cardiovascular and
neurocognitive disease in aging PLWH
• Review suggestions for medical prevention and
management of aging-related complications

68. Impact of ART on CVD Risk may be
Explained by other Factors
• Cross-sectional analysis of more
than 1,000 PLWH
• Risk factor contributing most to
CVD risk was high cholesterol
• For patients on their first ART
regimen, higher coronary heart
disease risk was associated with
longer duration of ART but this
association weakened after
adjusting for other influential
factors
ART Use Non-Use P value
Age > 40 55% 32% < .001
↑Cholesterol 42% 18% < .001
Non-MSM 60% 44% < .001
Non-white 52% 41% .003
↓HDL 19% 37% < .001
Aboud et al, Intl J Clin Practice 2010, 64:1252–9
Odds
ratio

69. Older Americans: The Changing Face of
HIV/AIDS in America
U.S. Senate Hearing, September 2013
• U.S.: more than 50% of PLWH will be older than 50
and 30% will be older than 60 by 2015
Older than 50 years
• New York: 37% in 2008;
increased by 45% in men and by 58% in women
• Florida: 30% in 2013, more than 50% in 2015
• San Francisco: 52% in 2010
• Massachusetts: 52% in 2013
Reported by NATAP.org, 21 September 2013

70. Smoking May Play a Particularly
Prominent Role for CVD in PLWH
• 569 adults in 2 parallel
cohorts
• Risk factors for acute
coronary syndrome
– PLWH: Smoking and
family history of CVD
– HIV-negative: Smoking,
diabetes, and
hypertension
Calvo-Sanchez et al, HIV Medicine (2013), 14: 40–48
• Attributable risk for smoking was 54.4 vs. 30.6

71. Older People with HIV Also Have Smaller
Subcortical Gray Matter Volumes and
Less Cerebral Blood Flow
Ances et al, J Acquir Immune
Defic Syndr 2012; 59: 469-77
Ances et al, Journal of Infectious
Diseases 2010; 201:336–40

72. Recent Reports on Polypharmacy
• Greater use of 8 classes of commonly prescribed
medications occurs in both younger and older PLWH
than in HIV negative adults
– More than 5 non-ARV medications:
Younger (<50): 35% (HIV+) vs.19% (HIV-)
Older (≥50): 54% (HIV+) vs. 34% (HIV-)
• In the large VACS database, increasing hazard of
death when ≥ 3 medications were prescribed
– Reached nearly 2-fold for PLWH prescribed ≥ 5 medications
Edelman JE, et al.. ID Week 2013, San Francisco, 2013, abstract 76.
Koram N, et al. ID Week 2013, San Francisco, 2013, abstract 323.

73. • Regularly evaluate all PLWH for lipid and
glucose abnormalities, hypertension, obesity,
renal disease, smoking, and bone loss
• Define absolute risk for coronary disease
• Undertake comprehensive therapeutic
measures, including changing ART to improve
lipid and glucose abnormalities
Blanco et al, AIDS Reviews 2010; 12: 231-41

74. Age-Related
Complications
History of
Advanced
Immune
Disease
Persistent
HIV
Replication
HIV Related
Stimulant
& Opiate
Use
ART
Toxicity
Drug Related
Poly-
pharmacy
Poor
Nutrition
&
Exercise
Chronic
Infections
Patient Related
Persistent
Immune
Activation
Genetic
Predis-
position

75. Age-Related
Complications
History of
Advanced
Immune
Disease
Persistent
HIV
Replication
HIV Related
Stimulant
& Opiate
Use
ART
Toxicity
Drug Related
Poly-
pharmacy
Poor
Nutrition
&
Exercise
Chronic
Infections
Patient Related
Persistent
Immune
Activation
Genetic
Predis-
position

76. Older Americans: The Changing Face of
HIV/AIDS in America
U.S. Senate Hearing, 18 Sept 2013
• Diet and exercise are for now the best
intervention to prevent early onset of
comorbidities & inflammation
• Early start of vigorous exercise
– 250+ minutes a week of vigorous aerobic exercise
• Diet resembling a Mediterranean diet
– Fish, chicken, vegetables, fruit, beans, nuts
Reported by NATAP.org, 21 September 2013

77. Incidence of Diabetes Increased in
the Early HAART Era, then Declined
Capeau et al, AIDS 2012, 26(3): 303-14
Calendar Year Period
• Prospective study of 1046 patients at 47 clinical sites in France
• 111 patients developed diabetes
• Incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women)
• Correlates: older age, overweight, larger waist-to-hip ratio, time-updated
lipoatrophy, and exposure to indinavir, stavudine, or didanosine
All subjects ART experienced
ART naive