A Closer Look: HIV in the Aging Population

HIV and Aging – Introduction

● By 2015, >50% 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.1. DHHS 2009. Medical management of older patients with HIV/AIDS. http://grants.nih.gov/grants/guide/pa-files/PA-09-017.html2. Dolan L, Zack E. International Workshop on HIV and Aging. Rev Antiretrov Ther Infect Dis. 2010;9. Abstract P_19.3. CDC 2008. HIV/AIDS among persons aged 50 and older. http://www.cdc.gov/hiv/topics/over50./resources/factsheets/over50.htm..

HIV and Aging – Clinical Considerations

● Patients >50 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. 2007;45(5):654-657. 2. Skiest DJ, Keiser PO. Arch Fam Med. 1997;6(3):289-294.3. Siegel K, et al. AIDS Care. 1999;11(5):525-535.

HIV and the Aging Process

● Aging and HIV associated with

– Increased prevalence of comorbidities

– Cognitive decline

– Social isolation

● Age affects body’s 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. 2010;110:43-47.

HIV and Aging: Shared Comorbidities

Non-HIV Comorbidities Account for More Deaths in Persons With HIV Than HIV Itself

CVD, cardiovascular disease; D:A:D, 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.

D:A:D database (N = 33,347)2192 deaths over 158,959 person-years

AIDS Related32%

Bacterial Infection

7%

Liver Related14%

Non-AIDS Cancers

12%

CVD Related11%

Non-natural9%

Lactic Acidosis/ Pancreatitis

1%

Renal1%

Other/ Unknown

13%

Genotoxicity and Mitochondrial Dysfunction

HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity

HIV Aging

Visceral obesity

• Risk factor for age-associated complications

• Source for chronic inflammatory proteins

• HIV infection and treatment can lead to lipodystrophy and lipoatrophy

• Chronic inflammatory proteins influence HIV disease outcomes

T-Cell Regenerative

Failure

Chronic Inflammation

Deeks SG. Annu Rev Med. 2011;62:141-155.

HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d)

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

T-Cell Regenerative

Failure

Chronic Inflammation

Deeks SG. Annu Rev Med. 2011;62:141-155.

HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d)

HIV Aging

• HIV may indirectly affect the stem cell environment through inflammatory damage

• HIV may directly infect hematopoietic stem cells; loss of stem cells can contribute to vascular dysfunction and cardiovascular disease

• Reduced ability to regenerate T-cells

• Progressive loss of hematopoietic progenitor cells cellular senescence

Chronic Inflammation

Deeks SG. Annu Rev Med. 2011;62:141-155.

HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d)

HIV Aging

• Associated with morbidity and mortality

• Persistent inflammation (eg, chronic viral infections) may result in compromised immune system

• Microbial translocation

• Immune dysregulation

• Low-level HIV replication

• Co-infection with CMV, herpes viruses, and other copathogens

Deeks SG. Annu Rev Med. 2011;62:141-155.

Common Comorbidities in the Aging Population of People With HIV

Metabolic Disorders

Cardiovascular Disease

Neurocognitive Disorders

Hepatic Dysfunction

Renal Dysfunction

Bone Disorders

Cancer

Common Comorbidities in the Aging Population of People With HIV (cont’d)

HAD, HIV-associated dementia.1. Simone MJ et al. Geriatrics. 2008;63:6-12.2. Wilkie FL et al. AIDS. 2003;33:S93–S105. 3. Bing EG et al. Arch Gen Psych. 2001;58:721-728. 4. Knobel H, Guelar A, Valldecillo G, et al. AIDS. 2001;15:1591-1593.

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

Common Comorbidities in the Aging Population of People With HIV (cont’d)

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

GFR, glomerular filtration rate.1. DHHS 2011. Panel on antiretroviral guidelines for adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 2. Arnsten JH, et al. AIDS. 2007;21:617-6233. Gallant JE, et al. JAMA. 2004;292:191-201

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

4. Guo X and Nzerue C. Clev Clin J Med. 2002;69:282-3125. Schambelan M, Benson CA, Carr A, et al. JAIDS. 2002;31:257-275.6. National Kidney Foundation. Am J Kidney Dis. 2002;39(Suppl 1):S76-S110.7. Hruz PW. Am J Infect Dis. 2006;2:187-192.

Distribution of Selected Comorbidities and Coinfections in a US Healthcare Claims Databasea

aImpact National Benchmark Database.Nkhoma E et al. International Workshop on HIV and Aging. Rev Antiretrov Ther Infect Dis. 2010;9. Abstract O_16.

Comorbid ConditionHIV -

≥ 50 Years (%) HIV+

18-49 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

HIV, Aging, and Immunosenescence

Aging of the Immune System (Immunosenescence)

Decreased production of IL-2 and IL-2 receptors1,2

Premature aging of immune system and eventual

immunologic “exhaustion”3

Diminished T-cell function2

Shift from naïve to terminally differentiated, impaired T-cells3

IL-2, interleukin-2.1. Casau NC. Clin Infect Dis. 2005;41:855-863.2. Simone MJ, Appelbaum J. Geriatrics. 2008;63:6-12.3. Cao W et al. J Acquir Immune Defic Syndr. 2009;50:137-147.

Similarities and Differences in T-Cell Compartment With Aging and HIV Infection

CD31− CD4+

naïve T-cells

Naïve CD4+ T-cells

Naïve CD8+ T-cells

CD28− CD8+ T-cells

CD31− CD4+ naïve T-cells

Stable proportion of T-cells

Decreased

IncreasedReprinted with permission from Rickabaugh TM, Jamieson BD. Immunol Res. 2010;48:59-71.

Aging HIV

The Effects of Aging on HIV Treatment

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 >350 cells/L is associated with a reduction in both opportunistic disease and serious non-AIDS events compared with patients (re)initiated with CD4+ cell counts of <250 cells/L1

● HIV treatment associated with greater risk of toxicity and drug–drug interactions secondary to2

– Effects of normal aging

– HIV infection

– Comorbid conditions

● HIV treatment may be complicated by medications prescribed for non–HIV-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. 2008;197:1133-1144.2. Simone MJ, Appelbaum J. Geriatrics. 2008;63:6-12.

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. 2001;93:243-250.2. Silverberg MJ et al. Arch Intern Med. 2007;167:684-691.3. Wellons MF et al. J Am Geriatr Soc. 2002;50:603-607.

Effect of Age on Baseline CD4+ and CD8+ Cells

Shaefer M et al. International Workshop on HIV and Aging. Rev AntiretrovTher Infect Dis. 2010;9. Abstract O_05.

CD4+/CD8+ ratios at baseline Patients < 50 years old = 0.33 Patients ≥ 50 years old = 0.27

CD4+/CD8+ ratios at 48 weeks Patients < 50 years old = +0.3 Patients ≥ 50 years old = +0.2

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 6 cells/L)1

Within first 6 months of HAARTa After 6 months of HAARTa

Age < 50 yearsAge ≥ 50

yearsAge < 50

yearsAge ≥ 50 years

Baseline HIV-1 RNA < 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

IQR, interquartile range. aP < 0.0001 for age < 50 years vs age ≥ 50 years in all subgroups. 1. Grabar S et al. AIDS. 2004;18:2029-2038. 2. Gras L et al. J Acquir Immune Defic Syndr. 2007;456:183-192.

ATHENA Group: Estimated Median CD4+ Cell Count Following 5 Years of HAART (cells/mm3)2

Age < 50 years Age ≥ 50 years

631 (IQR = 459-812) 489 (IQR = 412-725)

Clinical Progression of HIV in Patients Aged ≥ 50 Years

• 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 < 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. 2004;18:2029-2038.

Achievement of HIV RNA Levels < 500 Copies/mL Within 1 Year of HAART Initiation

● Patients ≥ 50 years had a 15% increased probability of achieving HIV-1 RNA levels < 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. 2007;167:684-691.

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

Incidence of Laboratory Abnormalities After HAART Initiation by Age Group

LDL, low-density lipoprotein; TC, total cholesterol

LDL, low-density lipoprotein; TC, total cholesterol.Silverberg MJ. Arch Intern Med. 2007;167:684-691.

Drugs Metabolized by Cytochrome P450 That May Interact With PIs and NNRTIs

PIs, protease inhibitors; NNRTIs, non-nucleoside reverse transcription inhibitors; SSRI, selective serotonin reuptake inhibitor.

Simone MJ, Appelbaum J. Geriatrics. 2008;63:6-12.

Medication Use and Potential Drug Interactions in Older vs Younger Patients With HIV

Tseng A et al. International Workshop on HIV and Aging. Rev Antiretroviral Ther Infect Dis. 2010;9. Abstract O_08.

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