Crampin et al. AIDS. 2002 16: 1547

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Crampin et al. AIDS. 2002 16 1547
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Life expectancy at age 20
Hogg. CROI. 2007 Poster 972
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Life Expectancy ART-C-C

• Aged 20

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Increasing Percentage of Older (55 yrs or over)
Diagnosed, HIV-infected Individuals in the UK
Overall in the UK, a third of all adults (15)
are 55 yrs or over
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Age at estimated HIV seroconversion in CASCADE
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Complex
AGE
HAART
HIV
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Ageing Inevitable

• 2nd law of thermodynamics
• Darwinian evolution

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Molecular Mechanics of AGEING

• Senescence (Telomere shortening)
• Apoptosis
• Reactive Intermediates mitochondrial dysfunction

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Old Age and HIVImmune Characteristics

• Inverted CD4/CD8
• CD4 lymphopaenia
• ? thymic output
• ? naïve cells
• ? IL2 (? I ?)
• ? mitogen responses
• Shorter telomeres CD8
• Late differentiated CD4 CD8 accumulate
• (CD28- CD27- CCR7-)

Appay et al. Trends in Imunology. 2002
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Bender et al. AIDS. 2002
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Predictors of the Change in CD4 Cell Count
During First 8 Month in the IL-2 arm of ESPRIT
CD4 nadir /100 cell ? plt0.0001 CD4 count
prior to BL /100 cells ? plt0.0001 Tot. IL-2
dose in 1st cycle /15 MIU ?
plt0.0001 HIV-RNA (lt500 cps/ml) p0.003
White (ref.) p0.0005 Black
Asian Other Age /5 years older
p0.001 Time on ART
/year longer plt0.0001
CDC category C (Yes) p0.016
BMI /5 unit ? p0.012
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
160
Difference in CD4 count increase (cells /µl)
ESPRIT study group Fox et al. HIV Medicine. 2007
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Response to HAART and AGE

• CD4 count
• Adherence (viral load)
• Non-AIDS and AIDS mortality

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Role of Age on the Improvement in CD4 Cell Count
Number When Initiating cART
80
Age quartiles
lt37
70
gt37
60
50
with CD4 increase of ?200.106/L
40
30
20
10
P.0026, log-rank test
0
0
6
12
18
24
30
36
Months since starting HAART
Curves of time to increase in CD4 cell count of
?200 x 106 cels/L after start of HAART in
subjects in 2 age quartiles
Viard et al. J Infect Dis 2001 183 1290-4
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Adherence Some things do get better with Age
Hinkin. AIDS. 2004
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HIV-1 RNA lt500 at 6 months by Age
Grabar. AIDS. 2004
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Age survival and Response to Treatment
Mayer et al. CID. 2005 41
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Interactions of Chronic Disease, HIV and Age

• Social
• Chronic renal failure ?
• Liver disease ?
• Bone mineral density ?

Geriatric Giants

• Neoplasia
• Atheroma
• Dementia

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Risk factors for chronic renal failure
EuroSIDA Mocroft et al. AIDS. 2007
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AGE
GENES
Lipids (TG HDL)
ATHEROMA
Infection
SMOKING
ENDOTHELIUM
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Relative Rate of MI According to PI Exposure
Adjusted for NNRTI
Adjusted RR per year of PI 1.16 1.10-1.23
? Adjusted for sex, age, cohort, calendar year,
prior CVD, family history of CVD, smoking,
body-mass index, NNRTI exposure
DAD study Friis-Møller et al. NEJM
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Other Predictors Not Influenced by cART - of
MI in DAD
Better
Worse
Age per 5 years older Male gender Previous
CVD Smoking Family history
5
0.5
10
1
0.1
Relative rate of myocardial infarction (95
CI) Multivariable Poisson model Adjusted for BMI,
HIV risk, cohort, calendar year and race
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Relative Rates of Myocardial Infarction According
to Calendar Year Before and After Adjusting for
Changes in Risk Factors
Sabin et al. CROI. 2005
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Risk of CVD with ART Interruptions
SMART Study
20
15
10
with a Major CVD Event
DC
5
VS
0
0.5
1.5
2.5
3.5
0
1
2
3
4
Years from Randomization
No. at Risk
2752
1306
713
379
10
DC
2720
1292
696
377
10
VS
Phillips et al. 14th CROI. Los Angeles. CA.
February 25-28. 2007 Abst. 41.
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Risk of CVD with ART Interruptions
SMART Study
ART at Baseline
ART at Baseline
10
30
Off
On
Off
On
20
5
10
Change in HDL Cholesterol (mg/dL)
0
Change in Total Cholesterol (mg/dL)
0
VS
VS
VS
DC
-10
-5
DC
VS
-20
DC
DC
-10
-30
plt 0.0001
plt 0.0001
plt 0.0001
plt 0.0001
Phillips et al. 14th CROI. Los Angeles. CA.
February 25-28. 2007 Abst. 41.
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Bozetti et al. NEJM. 2004
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Aetiology of Atheroma
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Error bars represent 95 confidence intervals
(plt0.001)
Other studies have found a 2 fold increase
(95CI 1.62-2.52) JCO 03
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DAD HIV and Fatal Malignancies

• Types and risk factors for AIDS-defining
  malignancies (ADM) and non-ADM studied in DAD1
• 23,447 HIV patients 104,691 person-years of F/U
• Fatal non-ADM have become more common than ADM
• Incidence of both non-ADM and ADM increases with
  lower CD4 cell count but is not affected by HIV
  RNA
• Current smokers had a 2.92-fold higher risk of
  fatal non-ADM than those who never smoked (risk
  for ex-smokers 2.02-fold higher)
• Other cohorts have reported similar increases in
  non-ADM2
• HIV Atlanta VA Cohort study 3051 patients
  followed since 1982
• Annual incidence of prostate cancer has risen
  from 1/1000 before 2003 to 4.6/1000 since 2003
  (plt0.00006)

Fatal malignancies
Incidence of fatal ADM and non-ADM by latest CD4
count
25
20
ADM
Non-ADM
15
Event rate /1000 PFYU
10
5
0
lt50
50-99
100-199
200-349
350-499
500
Latest CD4 count (cells/mm3)
1. DArminio Monforte A, et al. 14th CROI, Los
Angeles 2007, 84 2. Rimland D, et al. ibid, 874
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Tumours and HIV
Loss of immune surveillance
Promotion of cancer intracellularly
Direct
Oncogenic viruses
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HIV and the 6 Steps to Cancer

• Self sufficiency in growth signals
• Insensitivity to antigrowth signals -
  retinoblastoma protein
• Evasion of apoptosis
• Limitless replication potential (avoidance of
  senescence) (telomerase function)
• Sustained angiogenesis (VEGF)
• Tissue invasion and metastasis (ICAM)

Hanahan et al. Cell. 100 257-70
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EBV, HHV-8, HBV/HCV and Helicobacter pylori
Related Cancers
Lancet. 2007
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HPV Related, or Possibly Related Cancers
Lancet. 2007
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Common Epithelial Cancers
Lancet. 2007
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Other Cancers Occurring at Increased Rates
Lancet. 2007
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HIV Ageing Dementia

• HAD may be changing
• Gliosis may continue despite HAART(proviral DNA
  correlates with HAD)
• HAART may contribute to dementia
• HIV may predispose to Alzheimers

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ADC in the HAART Era

• More cortical presentation
• PET scan temporal lobe gt Basal Ganglia
• CSF changes (VL ß2 micro globulin) lt sensitive

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Alzheimers in HIV

• ß amyloid deposition
• Extra amyloid plaques
• ?CSF ß amyloid
• Neprolysin inhibited by TAT
• ? apolipoprotein E4

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Age

• Death be not proud though some have called thee
  mighty and dreadful for thou art not so.

John Donne (1631)
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Maya Gazzard
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Non AIDS HIV Related Diseases

• Liver Disease
• Renal Disease
• Cardiovascular Disease

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Bozetti et al. New Engl. J. Med. 2003 702
207-76 admissions
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Late cells

• CD28 CD27 CD1 low high
• CCR7 CD4 Ra /-
• HIV specific cells CD27 28-
• EBV cells early C28 CCR7
• CMV cells late C28 ve CCR7-
• IRP phenotype

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Dementia
Toxic Products
N2O Superoxides Platelet activation
Activated Microglia
Cylokines
? E4 ? Amyloid
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Ageing

• Long term investment
• In soma reduces
• Darwinian fitness
• (need 2 hearts)
• Obeys the 2nd law of thermodynamics

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Immune Risk Phenotype

• CD4 CD8 lt 1
• ?CD8 CD28 cells
• (? CMVVE ?proinflammatory cytokines)

Akbar et al. Current opinion in immunology.
2005 450
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Non-AIDS Defying Cancers
(482 ex 14,210 adultsHAART 3,455 AIDS
defying) ?Risk (RH 2.9) ?Risk (RH 0.32)
Hessol et al. Am. J of Epidemiology. 2007 165
1143
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Why the Immunological Changes?

• Chronic activation
• Thymic function

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The Mechanism of AGEING

• The longer the process to maturity the longer the
  time to ageing.
• Senescence telomere shortening
• Telomerase

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Guesses

• Its all TAT
• Its all adhesion markers
• Its all telomerase
• What about free radicals?

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Tumours - Classic

• Kaposis Sarcoma
• Non-Hodgkins Lymphoma
• Cervical Cancer

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Tumours - Many Others

• Seminoma
• Anal carcinoma
• Head Neck Tumours
• Lung Cancer

Correct for smoking Correct for age
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Tumour Mechanisms
Oncogenic viruses
Interference with cell machinery
Common acquisition
Synergy with HIV
Immune suppression (NADIR CD4)
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HIV Ageing
Complexity
Biological Reductionism
HAART or HIV
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Atheroma
HIV
HAART
Smart
D.A.D.
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Age Sex

• It continues!
• No need for contraception
• Fewer negotiating skills
• Lack of targeted education

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Neoplasia HIV Ageing
Common acquisition
Molecular machinery
Immune surveillance
NKactivity
Oncogenic viruses
Longer to acquire
AGE worse
Run down
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Aetiology of Neoplasia
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Evading apoptosis
Sustained angiogenesis
Tissue invasion metastasis
Limitless replicative potential
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Contribution of Ageing on the Outcome of AIDS
Prior to the Introduction of cART
Scand J Infect Dis 1997 29337-343
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Odds Ratio (OR) of Contracting Selected AIDS-
Defining Events at the Time of AIDS Diagnosis
Scand J Infect Dis 1997 29337-343
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AIDS RatesEuroSIDA 1994 -2003
EuroSIDA, Lancet, 2003
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Factors Associated With HIV and Negatively
Influenced by Age

• Related to cART
• Impaired immunological response to cART and IL-2

• Related to general health condition
• Memory loss (ADC and other CNS diseases)
• Increased risk of diseases associated with the
  normal aging process but accelerated in presence
  of immunodeficiency
• Non-AIDS defining malignancies
• CVD
• Obesity and metabolic syndrome

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The Conondrum of Using cART

• Allow persons to get older
• Demasking chronic disease processes associated
  with HIV not perceived as an issue prior to the
  introduction of cART (eg. HBV, HCV)
• Allow the normal aging process to manifest itself
  clinically
• Exacerbate adverse effects of cART that interacts
  with the normal aging process

Focus of medical management has to expand and
take these issues into account !!!!
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Effect of Absolute vs. Delta-Viral Load from
Setpoint on Current CD4-Slope in 628 Patients
On-Treatment With Stable Viral Load in PLATO
Patients 88 177 308
394
284 376 188 159
Observations 177 410 705 1304
687 1005 441 427
150
100
50
Mean(95CI) CD4-slope
cells/mLyr
0
-50
3
4
lt2.5
gt4.5
1
2
lt0.5
gt2.5
VL
delta-VL from setpoint
log10copies/mL
log10copies/mL
PLATO study group, Ledergerber et al. Lancet 2004
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CD4 Slope in Triple Class Failures on Stable ART
PLATO study group, Ledergerber et al, Lancet, 2004
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Incidence of MI According to Age in DAD
50
40
30
Incidence / 1000 PY/ 95 CI
20
10
0
Age group
25-30
30-35
35-40
40-45
60-65
45-50
50-55
55-60
65-70
gt70
2 11 36 48
55 48 31 15 16 14
Events
3834 10801 20075 16900 9741
6687 3899 2093 989 641
PYFU
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Effect of cART (Per Year of Exposure) on Risk of
MI by Age and Gender in DAD
Adjusted for risk factors
P-val
RR
0.0006
1.14 (1.06-1.24)
Men
0.01
1.38 (1.07-1.76)
Women
0.003
1.18 (1.06-1.32)
Younger
0.006
1.15 (1.04-1.27)
Older
Age lt45 years in men / lt55 years in
women Formal tests of interaction gender
(p0.51), age (p0.41)
DAD study Friis-Møller et al, NEJM
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Predictors of the CD4 cell count response during
the first 8 months of follow up in the IL-2 arm
of ESPRIT
K Ruxrungtham, ZV Fox, F Antunes, JD Bebchuk, RT
Davey, B Gazzard, NG Klimas, AM Labriola, MH
Losso, JD Neaton, S Staszewski, L Weiss, AN
Phillips and JD Lundgren on behalf of the ESPRIT
study group
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Prevalence of Hepatitis C (1685/4957 patients
33.9)
North 346 24,5
East 412 47,7
Central 280 22,9
South 623 44,9
Rockstroh J et al. EACS 2003 F12/4
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Natural Course of Hepatitis C

• 60-85 of HCV-infected persons develop chronic
  infection
• Estimates of the proportion of chronically
  infected persons who develop cirrhosis 20 years
  after initial HCV infection vary widely
• 2-4 in young children and young women
• 20-30 in middle-aged transfused subjects

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Factors associated with fatalnon-AIDS-related
malignancies
DAD study DArminio Monforte et al. 14th CROI,
2007
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Summary

• cART has dramatically improved prognosis
• Hence, the HIV population will age
• Older age may adverse affect the response to cART
  and exacerbate the absolute risk of adverse
  events of cART linked to the aging process (like
  CVD)
• Older persons are at increased risk of mental
  impairment and hence at excess risk of
  non-adherence to cART
• As immunodeficiency may accelerate the
  progression of several pathologies associated
  with the aging process (eg. liver disease
  associated with chronic infection with HBV/HCV,
  non-AIDS defining malignacies (e.g. bronchial
  carcinoma), it is important to avoid this
  situation.

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Improved survival expectations by age at HIV
seroconversion
1.00
pre-1997
Estimated proportion alive at 10 years following
SC
0.75
16-24 64
Proportion alive
0.50
25-34 56
35-44 42
0.25
45 28
0
0
2
4
6
8
10
12
16-24 94
1.00
1999-2001
25-34 95
35-44 91
0.75
45 87
Proportion alive
0.50
0.25
0
0
2
4
6
8
10
12
Years from seroconversion
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Liver related death and HIV(DAD Study)

• Cohort study of gt23,000 patients in Europe,
  Australia, and the USA
• 1,248 (5.3) deaths 20002004(1.6/100
  person-years)
• Of these, 82 on ART
• Leading causes of death
• AIDS (30)
• Liver disease (14)
• Heart disease (9)
• Malignancy (8)

RR of death according to immune function and
specific cause
100
10
RR
1.0

• Predictors of liver-related death
• Age (RR 1.3 per 5 years older)
• IDU (RR 2 vs MSM)
• CD4 (RR 1.23 per halving of C4)
• Anti-HCV (RR 6.7)
• HBsAg (RR 3.7)

gt500
lt50
5099
100199
200349
350499
CD4 (cells/mm3)
0.1
Weber R, et al. 12th CROI, Boston 2005, 595.
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? Adiponectin Inhibition
Vasorelaxation ?
? Procoagulant activity
LDLR family ?
EPITHELIAL DYSFUNCTION
? eNos/No
ICAM I ?
? Reactive oxygen species
Reuse cholesterol transport ?
? Mitochondrial dysfunction
? PPAR?
Wang et al. JAIDS 2007
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• Much Literature
• Little Data

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Cohort Study - Bias

• Ascertainment Bias
• Induced Bias
• Channelling Bias

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Age and Other Factors Predicting Types of Death
in HIV Infected Persons
DAD study Weber et al, Arch Intern Med
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• Getting less with years
• Most of risk explained by lipid abnormality

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Questions

• Will HIV accelerate the process of ageing?
• Will HIV accelerate the degenerative diseases of
  ageing?
• Will ART reverse or accelerate these processes?

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Geriatric Giants

• Atheroma
• Neoplasia
• Dementia