A Closer Look: HIV in the Aging Population

1
A Closer Look HIV in the Aging Population
2
HIV and Aging Introduction

• By 2015, gt50 of all persons with HIV in the
  United States will be over 50 years of age1
• Many persons with HIV have survived to older ages
  and experience health-related challenges
  resulting from2
• HIV disease itself
• Non-HIV comorbidities
• Potential adverse effects of long-term ARV
  therapy
• Of all persons with HIV in 2005, adults 50 years
  represented3
• 15 of all new diagnoses of HIV or AIDS
• 24 of those living with HIV or AIDS
• 35 of AIDS-related deaths

• ART, antiretroviral therapy.
• DHHS 2009. Medical management of older patients
  with HIV/AIDS. http//grants.nih.gov/grants/guide/
  pa-files/PA-09-017.html
• Dolan L, Zack E. International Workshop on HIV
  and Aging. Rev Antiretrov Ther Infect Dis.
  20109. Abstract P_19.
• CDC 2008. HIV/AIDS among persons aged 50 and
  older. http//www.cdc.gov/hiv/topics/over50./resou
  rces/factsheets/over50.htm..

3
HIV and Aging Clinical Considerations

• Patients gt50 years are at greater risk for
  delayed testing than younger patients1
• Family practitioners are less likely to discuss
  risk factors for HIV/AIDS with older patients2
• Older HIV-infected individuals are less likely to
  seek out testing and medical care in the absence
  of symptoms3
• Symptomatic older HIV-infected individuals are
  more likely to misattribute HIV-related symptoms
  to the normal aging process or other illnesses3

1. Cuzin L, et al. Clin Infect Dis.
200745(5)654-657. 2. Skiest DJ, Keiser PO.
Arch Fam Med. 19976(3)289-294. 3. Siegel K, et
al. AIDS Care. 199911(5)525-535.
4
HIV and the Aging Process

• Aging and HIV associated with
• Increased prevalence of comorbidities
• Cognitive decline
• Social isolation
• Age affects bodys ability to metabolize and use
  drugs
• Decreased efficiency in clearing drugs and poorer
  absorption result in irregular medication levels
• Despite successful HIV therapy, long-term
  suppressed, chronically infected HIV persons have
  a shorter expected lifespan compared to
  uninfected individuals

Vance DE. Am J Nurs. 201011043-47.
5
HIV and Aging Shared Comorbidities
6
Non-HIV Comorbidities Account for More Deaths in
Persons With HIV Than HIV Itself
DAD database (N 33,347) 2192 deaths over
158,959 person-years
Renal1
Lactic Acidosis/ Pancreatitis1
Other/ Unknown13
Bacterial Infection7
AIDS Related32
Non-natural9
CVD Related11
Liver Related14
Non-AIDS Cancers12
CVD, cardiovascular disease DAD, Data
Collection on Adverse Events of Anti-HIV
Drugs. Adapted from Smith C et al. 16th CROI
February 8-11, 2009, Montreal, Canada. Abstract
145. http//www.natap.org/2009/CROI/croi_28.htm.
7
HIV and Aging Influence the Pathogenesis of
Non-AIDS Morbidity
Genotoxicity and Mitochondrial Dysfunction
T-Cell Regenerative Failure
Chronic Inflammation
Deeks SG. Annu Rev Med. 201162141-155.
8
HIV and Aging Influence the Pathogenesis of
Non-AIDS Morbidity (contd)
T-Cell Regenerative Failure
Chronic Inflammation
HIV
Aging

• DNA damage and telomere shortening are strong
  determinants of cellular aging
• Mitochondria dysfunction may contribute to
  cellular aging

• Nucleoside analogs inhibit mitochondria synthesis
  
• Release of mitochondrial DNA
• Increase risk of oxidative damage

Deeks SG. Annu Rev Med. 201162141-155.
9
HIV and Aging Influence the Pathogenesis of
Non-AIDS Morbidity (contd)
Chronic Inflammation
Deeks SG. Annu Rev Med. 201162141-155.
10
HIV and Aging Influence the Pathogenesis of
Non-AIDS Morbidity (contd)
Deeks SG. Annu Rev Med. 201162141-155.
11
Common Comorbidities in the Aging Population of
People With HIV
Neurocognitive Disorders
Metabolic Disorders
Bone Disorders
Cardiovascular Disease
Hepatic Dysfunction
Cancer
Renal Dysfunction
12
Common Comorbidities in the Aging Population of
People With HIV (contd)
Neurocognitive/Psychiatric Disorders
Older age puts persons with HIV at greater risk of neuropsychological impairment
Increasing age is a significant risk factor for certain neurocognitive disorders such as HAD2
Mood disorders are between 5 and 7.5 times higher in the HIV population3
Hepatic Dysfunction4
Older age is associated with decreases in hepatic function, leading to higher serum levels of HIV drugs
Drug-related toxicity in the older age group is thought to be due to age-related decreases in albumin levels and changes in cytochrome P450
Cardiovascular Disease1
HIV itself is a risk factor for CVD
Some ARV therapies have been associated with increased CVD risks
Appropriate management may reduce the risk of CVD in patients with HIV
HAD, HIV-associated dementia. 1. Simone MJ et al.
Geriatrics. 2008636-12. 2. Wilkie FL et al.
AIDS. 200333S93S105. 3. Bing EG et al. Arch
Gen Psych. 200158721-728. 4. Knobel H, Guelar
A, Valldecillo G, et al. AIDS. 2001151591-1593.
13
Common Comorbidities in the Aging Population of
People With HIV (contd)
Renal Dysfunction
In the 2011 guidelines for the treatment of HIV/AIDS, there are no age-specific differences in recommendations1
Dose-adjustment recommendations, however, are made for renal dysfunction1
Drug-induced nephrotoxicity and polypharmacy are important considerations4
Older age is associated with decreases in renal function as measured via GFR6
Metabolic Disorders
Certain lifestyle and hormonal factors, which increase the risk of disordered bone metabolism, are prevalent in older HIV-infected patients2
Drug-induced metabolic changes can lead to decreases in bone mineral density3
Cases of severe hyperlactatemia have been reported in association with certain ARV therapies5
Elevated incidence of insulin resistance in HIV cohorts with and without HAART therapy has been observed7
GFR, glomerular filtration rate. 1. DHHS 2011.
Panel on antiretroviral guidelines for adults and
adolescents. http//www.aidsinfo.nih.gov/ContentFi
les/AdultandAdolescentGL.pdf. 2. Arnsten JH, et
al. AIDS. 200721617-623 3. Gallant JE, et al.
JAMA. 2004292191-201
4. Guo X and Nzerue C. Clev Clin J Med.
200269282-312 5. Schambelan M, Benson CA, Carr
A, et al. JAIDS. 200231257-275. 6. National
Kidney Foundation. Am J Kidney Dis. 200239(Suppl
1)S76-S110. 7. Hruz PW. Am J Infect Dis.
20062187-192.
14
Distribution of Selected Comorbidities and
Coinfections in a US Healthcare Claims Databasea
Comorbid Condition HIV - 50 Years () HIV18-49 Years () HIV 50 Years ()
Congestive heart failure 5 4 11
Renal failure 1 2 6
Liver disease 3 7 13
Lymphoma 0.6 3.1
Coagulopathy 2 7
Depression 8 17 18
Ischemic heart disease 11 25
Peripheral vascular disorders 2 7
Diabetes 8 23
Tumors 4 13
Metastatic cancer 1 3
Stroke 1 4
Bone loss 7 15
Hepatitis B virus 0.2 3
Hepatitis C virus 1 3 8
Herpes simplex virus 1 8
aImpact National Benchmark Database. Nkhoma E et
al. International Workshop on HIV and Aging. Rev
Antiretrov Ther Infect Dis. 20109. Abstract
O_16.
15
HIV, Aging, and Immunosenescence
16
Aging of the Immune System (Immunosenescence)
Decreased production of IL-2 and IL-2 receptors1,2
Diminished T-cell function2
Shift from naïve to terminally differentiated,
impaired T-cells3
Premature aging of immune system and eventual
immunologic exhaustion3

• IL-2, interleukin-2.
• Casau NC. Clin Infect Dis. 200541855-863.
• Simone MJ, Appelbaum J. Geriatrics. 2008636-12.
• Cao W et al. J Acquir Immune Defic Syndr.
  200950137-147.

17
Similarities and Differences in T-Cell
Compartment With Aging and HIV Infection
Aging
HIV
Naïve CD4 T-cells Naïve CD8 T-cells CD28-
CD8 T-cells
CD31- CD4 naïve T-cells
CD31- CD4 naïve T-cells
Stable proportion of T-cells
Decreased
Increased
Reprinted with permission from Rickabaugh TM,
Jamieson BD. Immunol Res. 20104859-71.
18
The Effects of Aging on HIV Treatment
19
Benefits and Challenges of Treating HIV inAging
Patients

• Untreated HIV increases risk of diseases
  associated with aging
• A SMART study subgroup analysis suggested that
  (re)initiation of ART for patients with CD4 cell
  counts of gt350 cells/mL is associated with a
  reduction in both opportunistic disease and
  serious non-AIDS events compared with patients
  (re)initiated with CD4 cell counts of lt250
  cells/mL1
• HIV treatment associated with greater risk of
  toxicity and drugdrug interactions
  secondary to2
• Effects of normal aging
• HIV infection
• Comorbid conditions
• HIV treatment may be complicated by medications
  prescribed for nonHIV-associated conditions
  (eg, diabetes, hypertension, hyperlipidemia)2
• Aging process may alter pharmacokinetics, in turn
  increasing potential for toxicity (eg, reduced
  cytochrome P450 metabolism)2

1. Emery S, et al. J Infect Dis. 20081971133-1144.
2. Simone MJ, Appelbaum J. Geriatrics. 2008636-12.

20
Older Patients With HIV and Treatment Adherence

• Studies show that older patients with HIV are
  more treatment adherent1,2
• Retrospective case control study3
• 101 patients with HIV (mean age, 57 years)
  matched with 202 younger patients with HIV (mean
  age, 33 years)
• Older patients were less likely to interrupt ARV
  therapy than younger patients (11 vs 26)

1. Wutoh AK et al. J Natl Med Assoc.
   200193243-250.
2. Silverberg MJ et al. Arch Intern Med.
   2007167684-691.
3. Wellons MF et al. J Am Geriatr Soc.
   200250603-607.

21
Effect of Age on Baseline CD4 and CD8 Cells
CD4/CD8 ratios at baseline Patients lt 50
years old 0.33 Patients 50 years old
0.27
CD4/CD8 ratios at 48 weeks Patients lt 50
years old 0.3 Patients 50 years old
0.2
Shaefer M et al. International Workshop on HIV
and Aging. Rev AntiretrovTher Infect Dis. 20109.
Abstract O_05.
22
Immunologic Response to HAART in Patients Aged
50 Years

• Increases in monthly CD4 cell count
  significantly lower in patients aged 50 years

Viral Load Stratum Mean CD4 Cell Count Increase/Month (x 106 cells/L)1 Mean CD4 Cell Count Increase/Month (x 106 cells/L)1 Mean CD4 Cell Count Increase/Month (x 106 cells/L)1 Mean CD4 Cell Count Increase/Month (x 106 cells/L)1
Viral Load Stratum Within first 6 months of HAARTa Within first 6 months of HAARTa After 6 months of HAARTa After 6 months of HAARTa
Viral Load Stratum Age lt 50 years Age 50 years Age lt 50 years Age 50 years
Baseline HIV-1 RNA lt 5 log10 copies/mL 17.3 14.1 11.1 9.8
Baseline HIV-1 RNA 5 log10 copies/mL 42.9 36.9 17.9 15.6
ATHENA Group Estimated Median CD4 Cell Count Following 5 Years of HAART (cells/mm3)2 ATHENA Group Estimated Median CD4 Cell Count Following 5 Years of HAART (cells/mm3)2
Age lt 50 years Age 50 years
631 (IQR 459-812) 489 (IQR 412-725)

• IQR, interquartile range. aP lt 0.0001 for age lt
  50 years vs age 50 years in all subgroups.
• Grabar S et al. AIDS. 2004182029-2038. 2.
  Gras L et al. J Acquir Immune Defic Syndr.
  2007456183-192.

23
Clinical Progression of HIV in Patients Aged 50
Years
Outcome Adjusted HR P Value
Progression to AIDS-defining event or death 1.52 0.0035
Progression to new AIDS-defining event or death 1.50 0.0087
HIV-1 RNA lt 500 copies/mL 1.23 lt 0.05

• Prospective cohort study of 3015 treatment-naïve
  patients initiating ARV therapy
• Higher risk of clinical progression but improved
  virologic response in patients 50 years old
  vs patients lt 50 years old
• At baseline, older patients more likely to have
• AIDS-defining event (P 0.0001)
• Lower CD4 cell count (P 0.0002)
• Higher HIV-1 RNA level (P 0.0001)

Grabar S et al. AIDS. 2004182029-2038.
24
Achievement of HIV RNA Levels lt 500 Copies/mL
Within 1 Year of HAART Initiation
Age Age 40-49 Age 50
Age 0.97 1.15
Age Adherence 0.95 1.03
Age Modified Charlson Comorbitity 0.97 1.15
All Predictors 0.97 1.07

• Patients 50 years had a 15 increased
  probability of achieving HIV-1 RNA levels lt 500
  copies/mL versus patients 18-39 years, even when
  adjusting for comorbidities
• Adherence was the key factor in older patients
  achieving better viral response and similar
  long-term CD4 cell counts

Silverberg MJ et al. Arch Intern Med.
2007167684-691.
25
Incidence of Laboratory Abnormalities After HAART
Initiation by Age Group
Parameter With Abnormality With Abnormality With Abnormality With Abnormality
Parameter 18-39 years 40-49 years 50 years P value
TC and LDL 21.0 26.4 34.0 0.04
Glucose 6.0 11.4 14.4 lt 0.001
Creatinine 3.2 5.8 8.3 NR
LDL, low-density lipoprotein TC, total
cholesterol
LDL, low-density lipoprotein TC, total
cholesterol. Silverberg MJ. Arch Intern Med.
2007167684-691.
26
Drugs Metabolized by Cytochrome P450 That May
Interact With PIs and NNRTIs
Drugs Metabolized by Cytochrome P450 Drugs Metabolized by Cytochrome P450
Antihistamines Methadone
Azole antifungals Proton-pump inhibitors
Benzodiazepines Rifabutin
Beta-blockers Rifampin
Calcium channel blockers Statins
Corticosteroids SSRI antidepressants
H2-blockers St. Johns wort
PIs, protease inhibitors NNRTIs, non-nucleoside
reverse transcription inhibitors SSRI, selective
serotonin reuptake inhibitor. Simone MJ,
Appelbaum J. Geriatrics. 2008636-12.
27
Medication Use and Potential Drug Interactions in
Older vs Younger Patients With HIV
Drug Category Age 60 Years () Age lt 60 Years () P Value
Antiretrovirals 95 87
Gastrointestinal 63 38 lt 0.01
Cardiovascular 55 24 lt 0.0001
Anticoagulants/antiplatelets 18 7 0.01
Systemic hormonal agents 16 5 0.01
Musculoskeletal agents 24 9 0.01
Narcotics/analgesics 39 17 lt 0.001
PI Cardiovascular 34 13 0.001
PI/NNRTI Cardiovascular 42 20 0.003
PI/NNRTI Anticonvulsant 16 5 0.02
PI Warfarin 8 1 0.01
Tseng A et al. International Workshop on HIV and
Aging. Rev Antiretroviral Ther Infect Dis.
20109. Abstract O_08.
28
Summary

• Incidence and prevalence of HIV/AIDS in older
  persons is increasing, a trend expected to
  continue
• Relationship between HIV and aging is complex,
  synergistic, and influenced by numerous factors
• Immunologic abnormalities present in HIV are
  consistent with certain changes to the immune
  system in elderly
• Persons with HIV have a higher than expected risk
  for numerous conditions commonly associated with
  aging
• Presence of comorbidities in older patients with
  HIV has important implications for antiretroviral
  selection