HIV/AIDS and the Older Crowd Victor G. Valcour MD FACP University of Hawaii Department of Geriatric Medicine and Division of Neuroscience

HIV/AIDS and the Older Crowd

Victor G. Valcour MD FACPUniversity of Hawaii

Department of Geriatric Medicine and Division of Neuroscience

Overview Understanding HIV and aging is in

its infancy Review of literature

Outcomes, toxicities, response to HAART

Presentation of Hawaii data concerning neurocognitive and neurological outcomes

The Magnitude of the Issue

Magnitude of the Problem

As of December 2001, 90,513 cases of AIDS were reported in individuals 50+

Cumulative frequency of about 11% of the population

Where in the US are older HIV+ individuals living

Retirement phenomenon?

Where in the US are older HIV+ individuals living

Age and HIV-1 Infection in Miami-Dade County

Percentages of AIDS cases over age 50 increase consecutively from USA to State of Florida to Miami-Dade County Total AIDS cases 26,050

Total over age 50 3,935 (15.1%)

source: K Goodkin MD

AIDS Cases Reported in Hawaii

percent 50+ years old

0

5

10

15

20

25

before1996

1996 1997 1998 1999 2000 2001

% 50+ y/ o National data

Source: State of Hawaii quarterly surveillance

19%

Magnitude of the Problem Increase in non-HIV morbidity with

aging Vascular disease: heart attacks, stroke Metabolic and degenerative disease:

Osteoporosis, osteoarthritis, dementia Malignancies: prostate cancer Immunological changes: Involution of

thymus, change in delayed-type hypersentitivity

Issues related to aging and HIV

Will there be additional complications in older people with HIV?

Will it be in excess of an additive effect of aging related changes and HIV-related changes? Or synergistic?

Will medications work as well in older people with age-related changes in immune function?

Outcomes for Older Individuals: Survival

Prior to combination ART Age at AIDS diagnosis accounted for about 12%

of added risk for 1 and 5-year survival in a NYC cohort Rothenberg, NEJM 1987 ;317:1297

Older age was a strong predictor of AIDS diagnosis and survival in hemophiliacs with know HIV conversion dates Goedert, NEJM 1989;321:1141 and Darby,Lancet 1996;347:1573



After widespread use of combination ARV Probability of survival for people with AIDS in NYC is

inversely proportional to age Fordyce, JAIDS 2002;30:111 Of patients diagnosed between 1996-1998: 87% survival at

24 months for 13-24 years old decreasing to 59% for people over 55.

A combined analysis of individuals starting first ART regimen, adjusted for baseline CD4 and viral load

Hazard ratio for death increased to 3.09 for people over 50 compared to people 17 to 29 years old (defined HR pf 1)

This effect is less than that seen before ART Egger, Lancet 2002;360:119


This finding persists into age over 60 Hazard ratio is 1.70 for people 60+ years old

compared to people < 60 years old (n = 58) Adeel South Med J 2001:94(4):397

Is this due to background mortality? e.g.: Does the rate disappear when you

subtract out the mortality that would be expected for people without HIV at the same given age?

Finding remains even after adjustment Babiker J Clin Epi 2001; 54: S16


Is this due to a diagnostic lag bias? Rationale

HIV/AIDS is diagnosed later in older individuals El-Sadr Arch Intern Med 1995; 155: 184

An increased risk for AIDS progression is seen in older people enrolled in inception cohorts Belanger Int J Epi 1997; 26(6):1340

However, some data suggest access to care may be an issue

Outcomes for Older Individuals: Survival Moore clinic, Baltimore 259 older patients (n=259) compared to

younger (n=538) Median follow-up of 39.5 months Being on ARV was the only predictor within

groups There was no difference in survival between

the older compared to younger groups that were on ARV, when adjusted for baseline CD4 and gender

Perez 9th Conference on Retroviruses and Opportunistic Infections 2002

Outcomes for Older Individuals: Survival Summary

Mortality among patients with AIDS appears to increase with age, even when adjusted for background mortality

It is not clear that this it due to age alone as differences are not significance among patients treated.

Length of infection may be an emerging issue regarding survival

Older people with HIV have typically been infected longer (“chronic infection” in older people vs. “newly infected” older people)

Outcomes for Older Individuals: Adherence

Antiretroviral Medications (ARV)Overview – HAART Regimens

• Regimen 1Nelfinavir (Viracept)Stavudine (Zerit)Didanosine (Videx)

Regimen 2 Ritonavir (Norvir) Saquinavir

(Fortivase) Zidovudine

(Retrovir) Lamivudine

(Epivir)

Adherence to ARV may be better in older persons Valcour 2002 JAGS

83.984.4

64.557.8

0102030405060708090

100

Past 4 days Past month

Older groupYounger group

Both are not significance

Outcomes for Older Individuals: Adherence

Outcomes for Older Individuals: ARV Adherence In a controlled study of protease inhibitor treatment Paterson Ann Int Med

2000;133:21

Older age predicted greater adherence [OR 1.1 (1.0 –1.2)] These findings are true even though older patients have more side effects

In a controlled study of first HAART regimen Mocroft AIDS 2001;15:185

Older patients were are less likely to modify HAART [RH per 10 years: 0.73] Among older patients who modified, toxicities and compliance was less often the

issue than immunological/virological failure Mocroft AIDS 2001;15:185

Outcomes for Older Individuals: ARV Adherence

Summary Older patients appear to be more

adherent to ARV regimens than younger patients

When older patients change ARV regimens, it is less often due to compliance issues than is noted in younger patients

Outcomes for Older Individuals: Virological response to ARV

Prior to HAART In HIV positive hemophilia patients prior to

HAART, rate of viral load rise was higher in patients who were older at the time of seroconversion (although all patients in this sample were relatively young) Sabin,JAIDS 2000; 23:172-77


Since widespread use of HAART Retrospective analysis at 12 months (n = 21

patients at 55+) Viral load response was inferior at 6 months but

equal to those <35 years old at 12 months Manfredi R, AIDS 2000, 14 (10): 1475-1477

Retrospective analysis at 24 month (n = 28 patients at 60+)

Older patients had better adherence, more favorable VL outcome (undetectable VL at 24 months), more toxicities to medications, and more self-reported lipodystrophy Kobel, AIDS 2001, 15 (12): 1591-1593]



Summary Viral load decrease following HAART generally

adequate in the older patients Response at 24 months may be superior,

however, studies adjusting for adherence are needed (e.g.: this might be, in part, due to better adherence)

Outcomes for Older Individuals: Immunological response to ARV


Age related changes in the immunological system may have implications for response to HIV and HAART

Involution of the Thymus – critical to “training” new t-cells

Outcomes for Older Individuals: Immunological response to ARV Rationale: Aging and HIV share some common

immune dysfunction which include: Shift from a naïve to a memory T-cell phenotype 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]

Reduction in T-cell proliferative ability Negoro S, Mech Aging Dev 1986, 33:313-322; Eylar EH, J AIDS 1994, 7:124-128

Associated with reduced telomer length (T cell replicative senescence?) Bestilny LJ, AIDS 2000, 14 (7): 771-780

Increase in CD8 cell population that are CD28 – Choremi-Papadapoulou H, JAIDS 1994, 7:245-253, Fagnoni FF, Immunology 1996, 88:501-507

Decreased production of IL-2 and IL-2 receptor (involved in T-cell-mediated immune responses) Gillis S, J Clin Invest 1981, 67: 937-942; Eyler EH, Cell Mol Biol 1995, 41:S25-S33

Outcomes for Older Individuals: Immunological response to ARV With some exceptions [Hernando K, AIDS 2001, 15 (12): 1591]

most papers show a less favorable CD4 rise in older patients

At 12 months and 24 months in 55+ years old Goetz MB, AIDS 2001, 15 (12): 1576; Operskalski EA, JAIDS 1997, 15 (3): 243

From 3 to 36 months for maximal CD4 rise, maximal attained CD4 and time to maximum CD4 Viard JID 2001;183:1290

Is this explained by changes in thymic output? No significant difference in 1st phase (approx 4 – 8 weeks) response

to ARV; thought to be due to redistribution of existing cells; however, a decrease in naïve CD4 rise during the 2nd phase, thought to represent thymic production Lederman MM, AIDS 2000; 14: 2635

May be due to involution of the thymus with age as naïve cell rise correlates with thymic size Smith KY, JID 2000; 181:141 and thymic output (TRECs) Douek DC, Nature 1998, 396; 690-695


Summary CD4 T-cell response does occur in older patients with

substantial benefits, however, the magnitude of response appears to be inversely proportional to age

Lack of thymic production may be a significant issue Adherence to ARV remains a strong predictor of outcome,

regardless of age

Outcomes for Older Individuals: Co-morbidity and Medication toxicities


Rationale Co-morbidities potentially impact response

to therapy, mortality, and quality of life Increased co-morbid illnesses are seen in

older people with HIV The presence of co-existing illness could

act synergistically in infected patients


Increased co-morbid illnesses are seen in older people with HIV HIV and non-HIV related hospitalizations

MI, CHF, Peripheral vascular disease, COPD, Ulcer disease, diabetes Skiest, Am J Med 1996;101:605-11

HIV-related complications Oral candidiasis, peripheral neuropathy,

hyperlipidemia Kilbourne J Clin Epi 2001; 54:S22

Osteoporosis? Arnsten 2002 9th Conference on Retroviruses and Opportunistic Infections


Psychiatric co-morbidities One study indicated a lower rate of alcohol use,

drug use, depression and mania in older seropositive individuals. Kilbourne J Clin Epi 2001: 54:S22

Substance abuse Hawaii Aging with HIV Cohort Meet criteria for current substance dependence (DSM

IV) 11% of the younger patients and 7% of the older patients


Hepatitis Retrospective analysis of 222 patients treated with HAART in Spain Older age was an independent risk for hepatitis (RR, 1.11; 95% CI,

1.04–1.18;p = 0.001). Nunez,JAIDS 2001;27:426

Metabolic Complications Diabetes El-Sadr 2001;7th CROI#13

Asymptomatic hyperlactatemia Weak correlation with age, r= 0.11, p=0.009 McComsey 2002 9th

Conference on Retroviruses and Opportunistic Infections #710-T; Antela 2002 9th Conference on Retroviruses and Opportunistic Infections #711-T

Thrombosis Rate of thrombosis in persons with HIV reported to be 2.6/1000 Adjusted Odds Ration for age over 45 is 1.9 (1.4 – 2.7) Sullivan AIDS

2000;14:321


Lipodystrophy Rationale: Redistribution of fat is a

typical aspect of aging in HIV- people Includes an increase in total body fat,

thinning of limbs, and increase in waist/hip ratio

Age is a risk factor for lipodystrophy in patients with HIV Mallal, AIDS 2000; Martinez, Lancet 2001;357:592

Ten Year Risk of Ten Year Risk of Cardiovascular EventsCardiovascular Events

Egger, 40th ICAAC

0

2

4

6

8

10

12

14

16

Risk Factors

No Lipodys

Lipodys

No Lipodys 0.5 3.6 1.1 6.3 0.04 2.2 0.1 4.1

Lipodys 1.9 9.1 3.6 14 0.5 8.8 1.1 13.7

30 yo No

Smoke

30 yo Smoke

50 yo No

Smoke

50 yo Smoke

30 yo No

Smoke

30 yo Smoke

50 yo No

Smoke

50 yo Smoke

Men Women

Egger, 40th ICAAC Abs 1374


NRTI mediated Mitochondrial Toxicity: Differential Effect on the Elderly?

Induced mitochondrial dysfunction is the postulated mechanism for the toxic side effects of nucleoside reverse transcriptase inhibitors (NRTIs)

Peripheral Neuropathy Myopathy Cardiomyopathy Lactic Acidosis (acidemia) Hepatic Steatosis Pancreatitis Peripheral lipoatrophy


Decline of mitochondrial energy production resulting in increased oxidative stress and apoptosis play a significant role in degenerative diseases and aging Wallace DC, Novartis Foundation Symposium 235: 247-63

Age is an independent risk factor for the occurrence of peripheral neuropathy in the Era of HAART Watters, Valcour Amer Acad Neurol 2003, Cherry C, 9th CROI Abs 69

Lipoatrophy is in part a NRTI mediated mitochondrial toxicity issue

Age is a consistent risk factor for its development Lichtenstein K, AIDS 2001; 14:F25-32

Lipoatrophy is independently associated with insulin resistance

A Phase II Exploratory Study Examining Immunologic and Virologic Indicies of HIV-Infected Subjects to Explore the Basis of Accelerated HIV Disease Progression

ACTG 5015

Study Design

Prospective, multicenter, cohort study of older

(45yrs) and younger (30 yrs) HIV-infected subjects:

Naive to ARV CD4 cell counts < 600/L HIV-RNA > 2,000 copies/mL

All received: LPV/r, d4T and FTC A5113: Companion, age-matched, healthy

volunteers.

Endpoints

Primary: 5015: Naïve CD4 cell changes at 48 wks. 5113: Baseline comparison naïve CD4 cell counts.

Secondary (5015): Changes in CD4, CD8 and HIV-RNA Expanded T cell phenotypes, B cells, NK cells DTH Onset of Co-morbidities

Secondary (5113): Baseline comparison of other immune indicies.


Summary Aging is associated with an increased risk

for co-morbid conditions and toxicities associated with HAART

Despite this finding, adherence appears superior in older patients and virological outcomes appear adequate

Older patients started on HAART should be monitored closely for possible side effects

To date, there are no age-specific treatment recommendations regarding HAART

Neurological and Neurocognitive endpoints

The Hawaii Aging with HIV Cohort

What are fundamental neuro-epidemiological characteristics of HIV cognitive impairment in older seropositive individuals.

Prevalence, clinical presentation, progression

What are the determinants of increased neuro-cognitive dysfunction, if present, in older people infected with HIV?

co-morbidities host factors treatment toxicities immune reconstitution

The Cohort Goal: 150 Younger (<40) and 150 Older

(50+) seropositive individuals community-based broad recruitment

strategies Matched seronegative controls Annual neurological and

neuropsychological evaluations Risk profiles including immunologic

parameters.

Methods Neurocognitive Instruments

• Yearly Neurocognitive testing and neurological exams

• Neurocognitive testing battery • includes all used in the NEAD cohort • Modified to augment assessment of some

domains including working memory

• Domains tested Attention Verbal and Visual Memory Visuoconstruction Psychomotor, motor Executive function Working memory

Comprehensive Assessments HIV and Immunological parameters

Current and past CD4 including nadir CD4, CD8 Current and past viral load h/o ARS

Degenerative Disease Apo E genotype, MRI Imaging, past medical history

Metabolic Diseases B12, Thyroid function Stored fasting serum

Cerebrovascular Disease BP, HTN history, medical history, medications, smoking

history, fasting lipid profile, glucose, family history, Brain MRI Other possible mediators

Risk profile, duration of infection, medication history, adherence, education history

Banked PBMC Banked CSF specimens

Consensus Decision - Cognitive Impairment

Consensus Decision

3 Members with at least 1 physician and 1 neuropsychologist

•1991 AAN Criteria

•1996 Working criteria (Sacktor et al)

•Memorial Sloan Kettering Rating based on all clinical data**

•NEAD algorithm-based classification of MSK

NP testing, age, gender and education matched norms

Full Exam: medical history, neurological exam, function assessment (proxy?), vital signs, medications and history

Substance abuse profile based on ASI

Laboratory parameters: past and present

Chronic infection and chronic Immune activation

Baseline Demographics

Younger Group Older GroupNumber Enrolled 86 101Age 34.6 +/- 4.5 55.0 +/- 5.2Education 13.6 +/- 2. 15.1 +/- 2.6% female 29% 9%Current CD4 434 +/- 242 468 +/- 281 Yrs HIV+ 7.0 +/-5.2 11.4 +/-

4.9

As of May 2003

Age at Enrollment

0

2

4

6

8

10

12

14

16

20 28 38 52 60 68

Positive Negative

Baseline DemographicsAll Individuals (seropositive and seronegative)

Asian/ PI (55%)

Hispanic (19 %)

Hawaiian/ PH (20%)

Other (6 %)

Approximately 40% of enrolled participants are from minority populations

Comparison of Ethnic Groups

Ethnicity of Seropositive participants (20-39yrs)

Other (2%)

Guam/Chamarro (3%)

Haw aiian/Pt Haw (16%)

Mxd Asian Pac Is(5%)

Filipino (7%)

Samoan (2%)

Chinese (3%)

Native Amer/Alas(3%)

Hispanic (12%)

African Am (3%)

Caucasian (42 %)

Ethnicity of Seropositive participants (50+ years)

Caucasian (74%)

Hawaiian/Pt Haw (8%)

Mxd Asian Pac Is(4%)

Filipino (3%)

Chinese (1%)

Japanese/Okin. (4%)

Hispanic (4%)

African Am (1%)

Comparison of Risk Factors for HIV Hawaii and US

0

10

20

30

40

50

60

70

80

90P

ercen

t

MS

M

Hetero

sex

ua

l

IV

DU

MS

M +

IV

DU

Tra

nsfu

sio

n

Hem

op

hil

ia

No

t i

den

tif

ied

Risk Category

HI:HIV+ (50+)

HI:HIV+ (20-39)

US:HIV+ (13+)*

Note: *US totals include adolescents, Hawaii totals include adults only.

MSM= men who have sex with men; IVDU= injecting drug use.

Percentages for each group may not add up to 100 because multiple risk categories may be reported.

Length of time living in Hawaii

0

10

20

30

40

50

60

70

80

% o

f G

rou

p

<5

6 to10

11 to 15

16 to 20

20 +

Years in Hawaii

HIV+ (50+)

HIV- (50+)

HIV+ (20-39)

Note: Mean length of stay:

HIV + (50+) = 21.6, SD = 16.3

HIV- (50+) = 31.0, SD = 17

HIV + (20-39) = 16.5, SD = 12.0

Is there more cognitive impairment in the older compared to the younger group?

Definitional Criteria for Dementia and Minor Cognitive Motor Disorder

• Uses American Academy of Neurology 1991criteria

• Dementia• Difficulty in at least 2 domains on NP testing• Decline in motor, emotion, or motivation• Absence of other etiology• +/- functional decline

• MCMD• Must have 2 of:

• Impaired attention/concentration, mental slowing, impaired memory, slowed movements, incoordination

• Does not meet dementia criteria

Definition of Cognitive Impairment

• Memorial Sloan Kettering Rating Scale (MSK)

• 0 = Normal• 0.5 = Equivocal• 1 - 4 = mild to severe

• For the purpose of analysis

• 0 and 0.5 = No Dementia• 1 or greater = Dementia• Correlation with AAN 1991 criteria

very good

Cognitive Function DiagnosisDiagnosis by criteria of the

1991 American Academy of Neurology

28.3

53.7

17.919.5

47.632.9

020406080

100

No Impairment MCMD Dementia

Younger

Older

p = 0.0961 chi sq; unadjusted

Severity of Cognitive ProblemsMemorial Sloan Kettering Rating Scale

p = 0.0961 chi sq; unadjusted

28.4

01.5

19.4

50.8

1.2

13.420.7

17.1

47.6

0

1020

3040

50

6070

8090

100

0 0.5 1 2 3

Younger

Older

Conclusions

• Older individuals in this cohort are twice as likely to meet research criteria for HAD.

• Neuropsychological tests are age and education matched

• Ethnicity matched seronegative groups are also being enrolled

28.3

53.7

17.919.5

47.632.9

020406080

100

No Impairment MCMD Dementia

Younger

Older

Conclusions

• When analyzing only people with HAD

• Older individuals have greater severity of disease

• Almost all young individuals have mild dementia when diagnosed with HAD

28.4

01.5

19.4

50.8

1.2

13.420.7

17.1

47.6

0

1020

3040

50

6070

8090

100

0 0.5 1 2 3

Younger

Older

Predictive Factors• Univariate Logistic Regression

Analysis• Using Clinical MSK

0 and 0.5 No Impairment > = 1 Impaired

• Findings Age p = 0.021 Gender p = 0.343 Education p = 0.198 CD4 nadir p = 0.025 Yrs positive p = 0.863 Viral load p = 0.358

Predictive Factors• Multivariate Logistic

Regression Model• Findings

Age p = 0.0136 Education p = 0.3225 CD4 nadir p = 0.0373 Yrs positive p = 0.2090

Peripheral neuropathy All participants undergo formal

physician evaluation for the presence of distal sensory polyneuropathy Sensory exam (touch, pin, vibration) Motor exam Reflexes history

Peripheral Neuropathy Symptomatic DSPN

51.4% of older compared to 19.6% of younger, p = 0.002

There is a trend for vibration deficit greater than pin deficit in older compared to younger patients

Older group has a greater number of possible cofactors, such as alcohol use and drug exposure

Further analysis underway to asses possible cofactors, such as duration of illness

Wrap up Aging in conjunction with chronic HIV

infection is an emerging issue. Our understanding of the interaction is in its infancy

Hawaii appears to have a disproportionate rate of older seropositive individuals when compared to the mainland US – for factors that are not fully known

Wrap up Available data suggest

Greater rate of comorbid illness in older patients

Greater rates of adherence to medication regimens in older patients

Reasonably similar virologic response to HAART with a blunted immunological response

Greater rate of neurological and neuropsychological HIV-associated complications

THE MEMORY STUDY

LOOKING FOR: HIV+ MEN AND WOMEN WHO ARE 50+ OR LESS THAN 40

TAKES LESS THAN 4 HOURS ONCE A YEAR.

MONETARY COMPENSATION AND FLIGHT TO/FROM KAUAI PROVIDED.

Please Call Today

808-737-3012

Office of Neurology and Aging Research, University of Hawaii at Manoa

Our Staff

The Hawaii AIDS Clinical Research Program Established in 1991 Researchers with national and

international recognition for metabolic complications, mitochondrial dysfunction, and neurological complications

Currently enrolling participants into various research trials – see pink sheets

Clinical Research Staff CollaboratorsVictor Valcour, MD, Principal Investigator Ned Sacktor, MD, NeurologistCecilia Shikuma, MD, Program Director, ID Ola Selnes, PhD, NeuropsychologistPamela Wu Poff, PhD, Neuropsychologist Johns Hopkins UniversityMichael Watters, MD, NeurologistBruce Shiramizu, MD, Co-InvestigatorSilvia Ratto-Kim, PhD, Immunology

Special Thank you to allResearch Staff of our participantsJim Taylor Sheri Shimizu Julie Malin Shannon GeentyKatherine Fast Lorna Nagamine

Hawaii Aging with HIV

Cohort Study Geriatrics NeuroAIDS Immunology Infectious Ds

ANSWERS

This work supported by NINDS grant 1U54NS43049. Additional support from P20 RR11091 (NCRR) and RCMI grant G12 RR/AI 03061 (NCRR).

Documents

HIV/AIDS and the Older Crowd Victor G. Valcour MD FACP University of Hawaii Department of Geriatric Medicine and Division of Neuroscience