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 age 1 ●Many persons with HIV have survived to older ages and experience health-related challenges resulting from 2 – HIV disease itself – Non-HIV comorbidities – Potential adverse effects of long-term ARV therapy ●Of all persons with HIV in 2005, adults ≥50 years represented 3 – 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 Medical management of older patients with HIV/AIDS. 2.Dolan L, Zack E. International Workshop on HIV and Aging. Rev Antiretrov Ther Infect Dis. 2010;9. Abstract P_19. 3.CDC HIV/AIDS among persons aged 50 and older.

HIV and Aging – Clinical Considerations ●Patients >50 years are at greater risk for delayed testing than younger patients 1 ●Family practitioners are less likely to discuss risk factors for HIV/AIDS with older patients 2 ●Older HIV-infected individuals are less likely to seek out testing and medical care in the absence of symptoms 3 ●Symptomatic older HIV-infected individuals are more likely to misattribute HIV-related symptoms to the normal aging process or other illnesses 3 1. Cuzin L, et al. Clin Infect Dis. 2007;45(5): Skiest DJ, Keiser PO. Arch Fam Med. 1997;6(3): Siegel K, et al. AIDS Care. 1999;11(5):

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 D:A:D database (N = 33,347) 2192 deaths over 158,959 person-years AIDS Related 32% Bacterial Infection 7% Liver Related 14% Non-AIDS Cancers 12% CVD Related 11% Non-natural 9% Lactic Acidosis/ Pancreatitis 1% Renal 1% Other/ Unknown 13%

Visceral Fat, Insulin Resistance, and Metabolic Syndrome Genotoxicity and Mitochondrial Dysfunction HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity HIVAging 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: Visceral Fat, Insulin Resistance, and Metabolic Syndrome

Visceral Fat, Insulin Resistance, and Metabolic Syndrome Genotoxicity and Mitochondrial Dysfunction HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d) HIVAging 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: Genotoxicity and Mitochondrial Dysfunction

T-Cell Regenerative Failure T-Cell Regenerative Failure Visceral Fat, Insulin Resistance, and Metabolic Syndrome Genotoxicity and Mitochondrial Dysfunction HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d) HIVAging 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:

Visceral Fat, Insulin Resistance, and Metabolic Syndrome Genotoxicity and Mitochondrial Dysfunction HIV and Aging Influence the Pathogenesis of Non-AIDS Morbidity (cont’d) T-Cell Regenerative Failure Chronic Inflammation HIVAging 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: Chronic Inflammation

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: Wilkie FL et al. AIDS. 2003;33:S93–S Bing EG et al. Arch Gen Psych. 2001;58: Knobel H, Guelar A, Valldecillo G, et al. AIDS. 2001;15: 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 HAD 2 Mood disorders are between ~5 and ~7.5 times higher in the HIV population 3 Hepatic Dysfunction 4 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 Disease 1 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 recommendations 1 Dose-adjustment recommendations, however, are made for renal dysfunction 1 Drug-induced nephrotoxicity and polypharmacy are important considerations 4 Older age is associated with decreases in renal function as measured via GFR 6 GFR, glomerular filtration rate. 1. DHHS Panel on antiretroviral guidelines for adults and adolescents Arnsten JH, et al. AIDS. 2007;21: Gallant JE, et al. JAMA. 2004;292: Metabolic Disorders Certain lifestyle and hormonal factors, which increase the risk of disordered bone metabolism, are prevalent in older HIV-infected patients 2 Drug-induced metabolic changes can lead to decreases in bone mineral density 3 Cases of severe hyperlactatemia have been reported in association with certain ARV therapies 5 Elevated incidence of insulin resistance in HIV cohorts with and without HAART therapy has been observed 7 4. Guo X and Nzerue C. Clev Clin J Med. 2002;69: Schambelan M, Benson CA, Carr A, et al. JAIDS. 2002;31: National Kidney Foundation. Am J Kidney Dis. 2002;39(Suppl 1):S76-S Hruz PW. Am J Infect Dis. 2006;2:

Distribution of Selected Comorbidities and Coinfections in a US Healthcare Claims Database a a Impact National Benchmark Database. Nkhoma E et al. International Workshop on HIV and Aging. Rev Antiretrov Ther Infect Dis. 2010;9. Abstract O_16. Comorbid Condition HIV - ≥ 50 Years (%) HIV Years (%) HIV + ≥ 50 Years (%) Congestive heart failure5411 Renal failure126 Liver disease3713 Lymphoma Coagulopathy27 Depression81718 Ischemic heart disease1125 Peripheral vascular disorders27 Diabetes823 Tumors413 Metastatic cancer13 Stroke14 Bone loss715 Hepatitis B virus0.23 Hepatitis C virus138 Herpes simplex virus18

HIV, Aging, and Immunosenescence

Aging of the Immune System (Immunosenescence) Decreased production of IL-2 and IL-2 receptors 1,2 Premature aging of immune system and eventual immunologic “exhaustion” 3 Diminished T-cell function 2 Shift from naïve to terminally differentiated, impaired T-cells 3 IL-2, interleukin-2. 1.Casau NC. Clin Infect Dis. 2005;41: Simone MJ, Appelbaum J. Geriatrics. 2008;63: Cao W et al. J Acquir Immune Defic Syndr. 2009;50:

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 Increased Reprinted with permission from Rickabaugh TM, Jamieson BD. Immunol Res. 2010;48: Aging HIV

The Effects of Aging on HIV Treatment

Benefits and Challenges of Treating HIV in Aging 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/  L 1 ●HIV treatment associated with greater risk of toxicity and drug–drug interactions secondary to 2 – 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: 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 adherent 1,2 ●Retrospective case control study 3 – 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: Silverberg MJ et al. Arch Intern Med. 2007;167: Wellons MF et al. J Am Geriatr Soc. 2002;50:

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 6 Mean CD4+ Cell Count Increase/Month (x 10 6 cells/L) 1 Within first 6 months of HAART a After 6 months of HAART a Age < 50 years Age ≥ 50 years Age < 50 years Age ≥ 50 years Baseline HIV-1 RNA < 5 log 10 copies/mL Baseline HIV-1 RNA ≥ 5 log 10 copies/mL IQR, interquartile range. a P < for age < 50 years vs age ≥ 50 years in all subgroups. 1. Grabar S et al. AIDS. 2004;18: Gras L et al. J Acquir Immune Defic Syndr. 2007;456: ATHENA Group: Estimated Median CD4+ Cell Count Following 5 Years of HAART (cells/mm 3 ) 2 Age < 50 yearsAge ≥ 50 years 631 (IQR = )489 (IQR = )

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 = ) – Lower CD4+ cell count (P = ) – Higher HIV-1 RNA level (P = ) Grabar S et al. AIDS. 2004;18:

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 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: AgeAge 40-49Age ≥ 50 Age Age + Adherence Age + Modified Charlson Comorbitity All Predictors

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:

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