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Scott Letendre, MD, of the UC San Diego HIV Neurobehavioral Research Program, presents "Overview of HIV & Aging" for AIDS Clinical Rounds at UC San Diego

Scott Letendre, MD, of the UC San Diego HIV Neurobehavioral Research Program, presents "Overview of HIV & Aging" for AIDS Clinical Rounds at UC San Diego

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  • 1. AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
  • 2. Overview of HIV & Aging Scott Letendre, M.D. Professor of Medicine University of California, San Diego
  • 3. People with HIV Are Living Longer but Survival Still Lags Behind Lohse et al, Ann Intern Med 2007, 2007;146:87-95 Losina et al, Clinical Infectious Diseases 2009; 49:1570–8
  • 4. Number of PLWH Older than 50 Nearly Doubled Between 2004 and 2008 http://www.aoa.gov
  • 5. Improved longevity is only part of the explanation • New infections are also occurring – Many older adults are newly single, widowed, or have grown children and have more time for sexual activity – New treatments for erectile dysfunction – Older adults may be unfamiliar with condom use or reluctant to use them – Vaginal dryness is common, which may increase HIV transmission HRSA CARE Action, February 2009
  • 6. Important Questions to Consider • Do PLWH truly have premature or accelerated aging? • …or are the complications linked to factors that increase risk for HIV transmission? – Substance use – Sex and injection transmitted diseases – Lower socioeconomic status • …or do HIV and its treatment increase risk for these complications without actually altering the biological process of aging? • What is successful aging and how do we achieve it? Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26
  • 7. Successful Aging is Multidimensional • Typical elements of successful aging – Avoidance of disease and disability – Maintenance of high physical and cognitive function – Sustained engagement in social and productive activities • Subjective quality of life may be more important than the absence of disease Rowe & Kahn, Gerontologist. 1997;37(4):433-40 http://en.wikipedia.org/wiki/Successful_Aging, Accessed 8 November 2013
  • 8. 36% of the General Population Age Successfully and this May be Lower in PLWH 27 studies in HIV negative people p = .005 Most frequent correlates of SA: Nonsmoking and absence of disability, arthritis, and diabetes Higher self-rated SA in PLWH was associated with better physical and emotional functioning but not HIV disease or negative life events Depp & Jeste, American Journal of Geriatric Psychiatry. 2006; 14: 6-20 Moore et al, J Clinical Psychiatry 2013, 74: e417-23
  • 9. AIDS Defining Illnesses Are Declining but HANA Are Increasing • AIDS-defining illnesses are increasingly rare in those taking effective ART • HIV-associated non-AIDS (HANA) conditions are increasing • A common theme among currently identified HANA conditions is their association with advancing age and chronic inflammation • Whether PLWH will develop these conditions earlier in their life course remains uncertain High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18
  • 10. AIDS Defining Illnesses Are Declining but HANA Are Increasing • AIDS-defining illnesses are increasingly rare in those taking effective ART “Any comparison between people with and • without HIV infection must be accomplished HIV-associated non-AIDS (HANA) conditions are increasing with careful study design as these populations • tend to differ in a number of behavioral HANA A common theme among currently identified and conditions is their association with advancing the biologic factors that are known to affectage and chronic inflammation aging process.” • Whether PLWH will develop these conditions earlier in their life course remains uncertain High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18
  • 11. Nearly Every Organ System Can Be Affected by Aging in PLWH • Endocrine/Metabolic – Diabetes – Hypogonadism • Vascular System – Cardiovascular – Cerebrovascular • Nervous System – – – – Cognitive Disorders Depression Neuropathy Sleep Disorders • Liver – ↓ Drug Metabolism – ↓ Synthetic Function • Kidney – ↓ Drug Elimination • Musculoskeletal – Osteoporosis – Frailty • Pulmonary System • Cancer Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26 Onen et al, HIV Clin Trials. 2010;11(2):100-109; Womack et al, PLoS ONE. 2011;6(2): E17217; Desquilbet et al, J Gerontol A Biol Sci Med Sci. 2007;62(11):1279---1286.
  • 12. Incidence of Diabetes Increased in the Early HAART Era, then Declined b Calendar Year Interval • Prospective study of 1046 patients • 111 patients developed diabetes • Incidence of 14.1/1000 PYFU • Correlates: older age, overweight, larger waist-to-hip ratio, exposure to indinavir, stavudine, or didanosine • Cross-sectional study of 2322 patients evaluated between 2005 and 2009 • 184 patients had diabetes • Subjects with waist circumference ÷ 90 cm and triglycerides ≥ 2.0 mmol/L had the highest prevalence Capeau et al, AIDS 2012, 26(3): 303-14 Janiszewski et al, PLoS ONE 2011, 6(9): e25032
  • 13. NCEP–ATP III Definition of Metabolic Syndrome http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf
  • 14. Metabolic Syndrome Linked to Longer Durations of ART in 2008-9 *Associations were present after adjusted for age, gender, smoking, family history, baseline plasma viral load, and CD4 Wu et al, J Antimicrob Chemother 2012; 67: 1001–1009
  • 15. Multiple Studies Have Identified Increased Risk of Cardiovascular Disease in PLWH • PLWH have greater 10-year risk of cardiovascular events (CVEs) and higher rates of atherosclerosis than HIV-negative persons • HIV disease itself is associated with greater risk of atherosclerosis independent of viral load, type of ART, or severity of immunodeficiency • Whether the increased risk of cardiovascular disease can be modified by ART remains uncertain – We still need randomized clinical trial data Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Hsue et al, IDS. 2009;23 :1059-1067; Kaplan et al, Clin Infect Dis. 2007;45(8):1074-1081; El-Sadr et al, Ann Intern Med. 2008;149(5):289-299; Triant et al, Clin Infect Dis. 2012; 54:408-413
  • 16. Myocardial Infarctions are More Common in PLWH 12 Rate per 1000 Person-Years • More than 80,000 veterans with nearly 6 years of follow-up had 871 acute myocardial infarctions (AMIs) • Across 3 decades of age, mean AMIs per 1000 personyears was consistently higher for PLWH than HIV negative people • Hazard ratio was 1.5 after adjusting for Framingham risk factors, comorbidities, and substance use 10 HIVHIV+ 8 6 4 2 0 30-39 40-49 50-59 60-69 70-79 Age Range (Years) Freiberg et al, JAMA Intern Med. 2013;173(8):614-622
  • 17. Aging PLWH More Frequently Develop Multiple Comorbidities • In a US cohort comparing HIV positive and negative people, PLWH were more likely to have nearly every comorbid condition assessed including heart disease, bone loss, and diabetes Nkhoma et al, 1st Hasse et al, Clinical Infectious Disease 2011, 53: 1130-9 International Workshop on HIV & Aging 2010, Presentation O_16
  • 18. Vascular Disease May Increase Risk for Neurocognitive Impairment Becker JT, et al. Neurology 2009;73:1292–1299 • 428 HIV+ and 207 HIV- in the U.S. Multicenter AIDS Cohort Study • Greater intima media thickness was associated with worse psychomotor speed and memory Wright EJ, et al. Neurology 2010;75:864–873 • 292 HIV+ people in the START study • Prior vascular disease was associated with 6.2-fold higher odds of neurocognitive impairment
  • 19. Metabolic Syndrome May Also Be Associated with Neurocognitive Impairment • Cross-sectional analysis of 130 subjects who provided fasting blood samples in the CHARTER project • Neurocognitive impairment was associated with older age, longer duration of HIV infection, obesity, larger waist circumference, and diabetes in univariable analyses Multivariable Analysis of Neurocognitive Impairment McCutchan, et al. Neurology 2012. 78:485–492
  • 20. Most Studies Support that Older Age is Associated with Worse Neurocognitive Functioning in HIV HIV x Age Interaction p = 0.004 Modified from Valcour et al, Neurology 2004;63:822–827 Heaton et al, J NeuroVirology, 2012, 18(Suppl 1): S46
  • 21. Aging Accelerates Loss of White Matter Integrity Chang et al, J Neuroimmune Pharmacol (2008) 3:265–274
  • 22. Stroke Risk is Also Higher in People with HIV Age 1.06 < .001 3.15 .01 .38 .006 HIV RNA 1.10 .001 CNS Infection or Malignancy Ovbiagele, et al. Neurology 2011;76:444–450 p Value NNRTI Use • Using a hospital database of 9,664,892 people, US stroke hospitalizations declined 7% while stroke hospitalizations with HIV rose 60% HR Atrial fibrillation Ischemic Stroke Variable 2.75 .01 • 4,308 people with HIV and 32,423 people without HIV • Incidence rate of ischemic stroke was 40% higher in people with HIV • HIV: 5.27 per 1000 PY • Non-HIV: 3.75 per 1000 PY Chow, et al. JAIDS 2012; 60:351–358
  • 23. Possible Causes of Premature Aging in PLWH
  • 24. Advanced Immune Suppression Genetic HostRelated Comorbidities HIVRelated Immune Activation Behavior Viral Proteins Protein Glycation Microbiome Persistent HIV Replication Chronic InfectionRelated Viral Hepatitis CMV Unsuccessful Aging Cellular Toxins ART Toxicity Coagulation Imbalance Reduced Liver Synthetic Function DrugRelated Stimulant & Opiate Use Poly pharmacy
  • 25. Inflammation Plays a Central Role in Unsuccessful Aging of PLWH Deeks, Tracy, & Douek, Immunity 2013, 39: 633-45
  • 26. Older PLWH Often Present with More Advanced Immune Suppression Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26 Althoff et al. AIDS Res Ther. 2010;7:45
  • 27. Why is Presenting with Advanced Immune Suppression Important? • Advanced immune suppression – even in the past – is associated with higher risk of HIV disease complications – Neurocognitive impairment – Cardiovascular disease – Cancer – Diabetes – Bone loss – Kidney disease Ho et al, AIDS. 2012 Jun 1;26(9):1115-20; Ellis, et al. AIDS, 2011, 25: 1747-51; Cutrell & Bedimo. Curr HIV/AIDS Rep. 2013; 10: 207-16; Borderi et al, New Microbiol. 2002 Jul;25(3):37584; Gazzola et al., J Transl Med. 2013 Feb 28;11:51; Ganesan et al, HIV Med. 2013;14: 65-76; Galli et al, Eur J Epidemiol. 2012 Aug;27(8):657-65;
  • 28. Older PLWH Have Worse Immune Responses to Antiretroviral Therapy • Older patients typically adhere better to ART but appear only equally likely to achieve virologic suppression compared with younger patients • Older patients with virologic suppression can have less robust immune recovery – Possibly because the thymus atrophies with age Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Silverberg et al, Arch Intern Med. 2007;167: 684-691; Althoff et al, AIDS. 2010;24: 2469-2479; Sabin et al, HIV Med. 2009; 10: 35-43
  • 29. Aging and HIV affect the Immune System in Similar Ways • In addition to loss of thymus tissue, aging is associated with decreases in the number of naive T-cells, reduced T-cell responsiveness, and B cell dysfunction • Immune senescence in the general population has been linked to many of the same end-organ disorders occurring in aging PLWH Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26 Effros RB, Clin Infect Dis. 2008;47(4):542-553; Kaplan et al, J Infect Dis. 2011; 203: 452-463
  • 30. CMV May be an Important Infection in Biological Aging • In large cohorts of HIV negative elders, higher CMV IgG levels and larger numbers of CMV-specific CD4+ T-cells were associated with… – Cardiovascular disease – Neurocognitive decline – Worse survival Pawelec et al, Virus Research, 2011, 157: 175; Vescovini et al, J Immunology, 2010, 184: 3242; Aiello et al, JAGS, 2006, 54:1046; Roberts et al, American J Epidemiology, 2010, 172:363.
  • 31. CMV-Specific Immune Responses Are Associated with Atherosclerosis in PLWH Hsue et al, AIDS 2006, 20: 2275-83
  • 32. Higher CMV Antibody Levels Are Associated with Lower CD4+ T-Cell Nadirs and Neurocognitive Impairment Letendre, et al. Clinical Infectious Diseases 2013, Submitted
  • 33. CMV Shedding is Associated with higher HIV DNA levels in PBMCs, which are Associated with NCI p<0.001 • In 113 antiretroviral (ART)–naive PLWH, CMV replication in blood and semen was associated with higher levels of HIV DNA in PBMCs Gianella et al, J Infect Dis 2013, 207: 898–902 • In the SEARCH 001 study in Thailand, HAD was associated with higher HIV DNA levels in PBMCs • With HAD (n=15; median=4.27 log10/104 PBMCs) • Without HAD (n=15; median=2.28 log10/104 PBMCs) Shiramizu et al, Int J Med Sci 2006, 6;4(1):13-8
  • 34. The Liver may be the Most Sensitive Organ to Aging • HIV and aging are each associated with… – Decrease in liver volume – Impaired blood flow to the liver – Decreased drug metabolism – Increased amount of fat in the liver, which alters metabolic rate – Decline in regenerative response of hepatocytes following injury Slide Courtesy D. Dieterich; Schmucker DL. Exp Gerontol. 2005; Maclean AJ et al. J Pathol 2003; Housset et al. Res Virol 1990; Banerjee et al. AIDS 1992; Blackard JT et al. J viral hepat. 2008; Hong F et al. Hepatology 2010
  • 35. How Can We Improve the Likelihood of Successful Aging?
  • 36. Advanced Immune Suppression Genetic HostRelated Comorbidities HIVRelated Immune Activation Behavior Viral Proteins Protein Glycation Microbiome Persistent HIV Replication Chronic InfectionRelated Viral Hepatitis CMV Unsuccessful Aging Cellular Toxins ART Toxicity Coagulation Imbalance Reduced Liver Synthetic Function DrugRelated Stimulant & Opiate Use Poly pharmacy
  • 37. Intervention for HIV-Related Factors History of Advanced Immune Disease Persistent HIV Replication • Diagnose HIV earlier in disease • Initiate ART early in disease before patients advance to severe immune impairment • Support ART adherence • Regularly check viral loads and CD4+ T-cell counts
  • 38. 19% of people with HIV in the US are taking ART and have undetectable plasma viral load 79% 59% 67% 80% 75% 80% Gardner et al, Clin Infect Dis. 2011; 52(6):793-800
  • 39. Initiation of ART in Older PLWH • ART…“is recommended in patients > 50 years of age, regardless of CD4 cell count…because the risk of non-AIDS related complications may increase and the immunologic response to ART may be reduced in older HIV-infected patients” • Further research is needed to identify preferred regimens for this age group – Limit toxicity – Avoid interactions with other drugs Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Department of Health and Human Services, Guidelines for the Use of Antiretroviral Agents in HIV-1Infected Adults and Adolescents; Thompson et al, JAMA. 2010; 304: 321-333
  • 40. Blood-Brain Barrier Permeability Increases with Age, which may Increase Drug Distribution into the CNS p = .05 p = .004 Letendre et al, 18th CROI, 2011, Abstract 408 Croteau et al, 19th CROI, 2012, Abstract 592
  • 41. Host-Related Factors Immune Activation Chronic Infections Genetics Behavior • Follow guidelines for checking and controlling vascular risk factors (cholesterol, blood pressure) – Kidney, liver, bone health assessments – Daily aspirin • Actively support smoking cessation • Support regular exercise regularly, healthful diet, maintenance of healthy weight • Cancer screening • Avoid or treat co-infections – Viral hepatitis, syphilis, tuberculosis – Vaccinations – No current recommendations for CMV
  • 42. Stopping Smoking Reduces Risk for Cardiovascular Events • More than 27,000 patients had a total of 3,680 CVEs or mortality • Adjusted incidence rate ratio in patients who stopped smoking decreased from 2.3 within the first year to 1.5 after > 3 years compared with those who never smoked Petoumenos et al, HIV Medicine 2011, 12:412–421 Myocardial infarction Cardiovascular Disease
  • 43. Samaras K. Curr HIV/AIDS Rep (2012) 9:206–217
  • 44. Metabolic Toxicity Lower Intermediate Higher Abacavir Emtricitabine Lamivudine Tenofovir Didanosine Zidovudine Stavudine NNRTIs Nevirapine Efavirenz Etravirine PIs Atazanavir Saquinavir Darunavir Fosamprenavir Entry Inhibitors Enfuvirtide Maraviroc Integrase Inhibitors Raltegravir NRTIs Indinavir Lopinavir Tipranavir Blanco et al, AIDS Reviews 2010; 12: 231-41
  • 45. • Assess all patients with HIV (CEBM 5; GOR D) – Can assist in treatment and management decisions, provide reassurance, and detect cognitive, behavioral and mood changes before symptoms arise (CEBM 2b) – No rationale for screening only symptomatic patients (CEBM 2b) • Assess neurocognitive functioning early in the disease using a sensitive screening tool (CEBM 5, GOR D) – All patients with HIV should be screened for HAND within 6 months of diagnosis (CEBM 5; GOR D) • Screen before the initiation of ART (CEBM5; GOR D) Mind Exchange Working Group, Clinical Infectious Diseases 2013 Apr;56(7):1004-17
  • 46. Drug-Related Factors Stimulant & Opiate Use ART Toxicity Poly pharmacy • Abstain from substance use – Methamphetamine, cocaine, heroin • Consider modifying ART that is causing undesired side effects • Avoid unnecessary medications • Review medications with a pharmacist familiar with HIV care to identify drug interactions Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Bowman et al, Pharmacoepidemiol Drug Saf. 1996; 5: 9-18; Egger et al, Drugs Aging. 2003;20(10): 769---776; Justice AC. Top HIV Med. 2006;14(5):159---163.
  • 47. Methamphetamine is Associated with Worse Neurocognitive Functioning in Older but not Younger PLWH Younger (≤ 40 years old) Older (≥ 50 years old) 56 56 * 54 T-Score 50 48 46 52 * T-Score 52 54 ** H-M- (n=36) H+M- (n=49) H+M+ (n=31) H-M- (n=28) 50 48 ** H+M- (n=34) H+M+ (n=34) 46 44 44 42 42 *p < 0.05; **p < 0.01 Woods et al, 4th International Workshop on HIV and Aging, 2013 Slide courtesy Steven Woods, Psy.D.
  • 48. Summary and Conclusions • People living with HIV are older than in the past • Evidence supports that PLWH are more susceptible than the general population to immune senescence and disease of multiple organ systems • Prevention, early diagnosis, and early treatment are important for managing these complications – Avoid polypharmacy • New research is needed to define optimal management • Greater education of patients and providers is
  • 49. Internet Resources • CDC.gov: Persons Aged 50 and Older – http://www.cdc.gov/hiv/topics /over50/protection.htm • AIDS.gov: Aging with HIV/AIDS – http://www.aids.gov/hiv-aidsbasics/staying-healthy-withhiv-aids/taking-care-ofyourself/aging-with-hiv-aids/ • New England Association on HIV over 50 – hivoverfifty.org • Services & Advocacy for Gay, Lesbian, Bisexual, & Transgender Elders – http://www.sageusa.org • HIV Wisdom for Older Women – www.hivwisdom.org • ACRIA Center on HIV & Aging – www. acria.org • AIDS Foundation of Chicago – http://www.aidschicago.org/p df/2005/prev_over_50.pdf
  • 50. Acknowledgements & Conflicts Study Volunteers UC San Diego • • • • • • • • Ronald J. Ellis J. Allen McCutchan Igor Grant Bob Heaton Edmund Capparelli Brookie Best Jennifer Marquie Florin Vaida         Steven Woods Davey Smith David Moore Tom Marcotte Cris Achim Eliezer Masliah Debra Rosario Mariana Cherner David Clifford Justin McArthur Ned Sacktor Ann Collier David Clifford       …Mental Health  …Drug Abuse  …Allergy and Infectious Diseases Industry CHARTER or NNTC • • • • • National Institutes of Health Christina Marra Susan Morgello David Simpson Ben Gelman Donald Franklin  ViiV  Abbvie  Merck, Inc.
  • 51. Summary of Suggestions • Stop smoking • Exercise regularly • Achieve & maintain healthy weight • Manage insulin resistance/diabetes • Manage vascular disease risk factors • Treat depression • Treat co-infections • Cognitive training Petoumenos et al, HIV Medicine 2011, 12:412–421; McCutchan et al., Neurology 2012, 78(7):485-92; Valcour et al., J Acquir Immune Defic Syndr. 2006;43(4):405-10; Weber et al., J Int Neuropsychol Soc. 2012 Jan;18(1):128-33; Weber et al., Neuropsychol Rev 2013, DOI 10.1007/s11065-013-9225-6; Dufour et al, J Neurovirol 2013, DOI 10.1007 s13365-013-0184-8
  • 52. Cardiovascular Disease Appears to be More Common in PLWH • Forest plots of studies and pooled estimate of relative risk of cardiovascular disease – In untreated people living with HIV versus HIV-uninfected people – In people living with HIV exposed to ART versus HIV-uninfected people Islam et al, HIV Medicine 2012, 13: 453–468
  • 53. HIV and Aging Cause Similar Changes to the Immune System • Shift from a naive to a memory T-cell phenotype • Reduction in the ability of T-cells to proliferate • Associated with reduced telomere length Decreased production of IL-2 and IL-2 receptor (involved in T-cell-mediated immune responses) 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; Negoro S, Mech Aging Dev 1986, 33:313-322; Eylar EH, J AIDS 1994, 7:124-128; Bestilny LJ, AIDS 2000, 14 (7): 771-780; Choremi-Papadapoulou H, JAIDS 1994, 7:245-253, Fagnoni FF, Immunology 1996, 88:501-507; Gillis S, J Clin Invest 1981, 67: 937-942; Eyler EH, Cell Mol Biol 1995, 41:S25-S33
  • 54. Virologic Responses to ART May Differ in Older Individuals • Prior to the HAART era, viral loads were higher in patients who were older at the time of seroconversion • In the HAART era, older patients had: – Better adherence and more favorable viral load outcomes at 24 months – But also more toxicities to medications and more self-reported lipodystrophy Sabin et al, JAIDS 2000; 23:172-77; Kobel, AIDS 2001, 15 (12): 1591-1593
  • 55. Immune Responses to ART May Be Worse in Older Individuals • Most studies show a less favorable CD4+ T-cell rise in older patients (≥ 55 years) following initiation of ART • May be due to loss of thymus tissue with age as naive cell rise correlates with thymic size and thymic output Goetz MB, AIDS 2001, 15 (12): 1576; Operskalski EA, JAIDS 1997, 15 (3): 243; Viard JID 2001;183:1290; Smith KY, JID 2000; 181:141; Douek DC, Nature 1998, 396; 690-695
  • 56. Summary Findings from U.S. Consensus Report • By 2015, half the people living with HIV infection in the United States will be 50 years of age or older • People with HIV experience excess morbidity and mortality compared with the general population – Even those receiving effective ART with suppression of virus to levels below typical detection limits • On average, a 20-year-old initiating ART may have already lost one-third of the expected remaining years of life compared with demographically similar HIVuninfected persons High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18
  • 57. Example of Survival Estimates from the HIV Research Network Losina et al, Clinical Infectious Diseases 2009; 49:1570–8
  • 58. Factors That Can Differ Based on HIV Disease Status • People aging with HIV disease are more likely to continue substance use than the general population – Tobacco, alcohol, opioids, and other psychoactive substances • People with HIV disease are also more likely to be infected with chronic viruses such as hepatitis C and CMV – Interacts with HIV or alcohol to hasten cirrhosis and liver cancer • People with HIV disease differentially represent sexual and racial minorities that may have constrained economic and social resources – Homelessness, food insecurity, and social isolation may exacerbate substance use and complicate the aging process High et al, J Acquir Immune Defic Syndr 2012, 60: S1-18
  • 59. • Stroke May Be Increasing As People Live Longer with HIV Large hospital database of people admitted with stroke in the U.S. between 1997 and 2006 (N = 9,664,892) • Overall US stroke hospitalizations lessened 7% while stroke hospitalizations with HIV rose 60% Ischemic Stroke – Patients with stroke and HIV increased over time from 0.08% to 0.15% of all strokes (p < 0.0001) • Those with HIV were more likely to have dementia, liver disease, renal disease, cancer, and urban hospital location Ovbiagele, et al. Neurology 2011;76:444–450
  • 60. Confirmation of Greater Hazard of Stroke from Another Cohort • 4,308 people with HIV and 32,423 people without HIV seen between 1996 and 2009 Multivariable Analysis of Correlates of Stroke Variable HR p Value • Primary endpoint was ischemic stroke defined by ICD codes Age 1.06 < .001 Atrial fibrillation 3.15 .01 • Incidence rate of ischemic stroke was 40% higher in people with HIV NNRTI Use .38 .006 HIV RNA 1.10 .001 CNS Infection or Malignancy 2.75 .01 – HIV: 5.27 per 1000 PY – Non-HIV: 3.75 per 1000 PY • HIV remained a predictor of stroke after controlling for demographics and stroke risk factors (1.21, P=0.04) Chow, et al. JAIDS 2012; DOI: 10.1097/QAI.0b013e31825c7f24
  • 61. Heart Attacks are More Common in PLWH than in HIV Negative People Rate per 1000 Person-Years • More than 80,000 veterans with nearly 6 years of follow-up had 871 acute myocardial infarctions (AMIs) • Across 3 decades of age, mean AMIs per 1000 person-years was consistently higher for PLWH than HIV negative people • Hazard ratio was 1.5 after adjusting for Framingham risk factors, comorbidities, and substance use 12 10 HIVHIV+ 8 6 4 2 0 30-39 40-49 50-59 60-69 70-79 Age Range (Years) Freiberg et al, JAMA Intern Med. 2013;173(8):614-622
  • 62. ART may also Play a Role in CVD Risk • Some antiretroviral drugs predispose to an adverse cholesterol profile • Increase in risk conferred by certain antiretrovirals is generally moderate compared with the risk conferred by traditional risk factors as well as by HIV itself Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Friis-Møller et al, N Engl J Med. 2007;356(17):1723-1735; Sabin et al, Lancet. 2008;371(9622):1417-1426; Lichtenstein et al, Clin Infect Dis. 2010;51(4):435-447; Niaura et al, Clin Infect Dis. 2000;31(3):808-812
  • 63. HAND is Common Among People with HIV Disease Unimpaired 48% HAD 3% Confounded 12% ANI 29% MND 8% Heaton et al, Neurology. 2010; 75: 2087-96
  • 64. Depression is Also More Common in PLWH than in the General Population • Depression is the most common psychiatric disorder affecting PLWH, among whom it is under-recognized and under-treated • Both depressive symptoms and suicide are most common among older persons, especially aged 65 years and older • Treatment of depression in PLWH correlates with improvements in ART adherence, virologic responses, and survival Brooks et al, American Journal of Public Health 2012, 102(8): 1516-26; Pence et al, AIDS. 2012; 26:656658; Horberg et al, J Acquir Immune Defic Syndr. 2008;47:384-390; Althoff et al, lin Infect Dis 2010;50: 1512---1520.
  • 65. Calendar Year Period Capeau et al, AIDS 2012, 26(3): 303-14
  • 66. Objectives • Provide an overview of information on the aging of people living with HIV (PLWH) disease • Provide an overview of information on the organs affected by aging and the data supporting premature aging in PLWH • Review data on cardiovascular and neurocognitive disease in aging PLWH • Review suggestions for medical prevention and management of aging-related complications
  • 67. Impact of ART on CVD Risk may be Explained by other Factors ART Use Non-Use P value Age > 40 55% 32% < .001 ↑Cholesterol 42% 18% < .001 Non-MSM 60% 44% < .001 Non-white 52% 41% .003 ↓HDL 19% 37% < .001 Odds ratio • Cross-sectional analysis of more than 1,000 PLWH • Risk factor contributing most to CVD risk was high cholesterol • For patients on their first ART regimen, higher coronary heart disease risk was associated with longer duration of ART but this association weakened after adjusting for other influential factors Aboud et al, Intl J Clin Practice 2010, 64:1252–9
  • 68. Older Americans: The Changing Face of HIV/AIDS in America U.S. Senate Hearing, September 2013 • U.S.: more than 50% of PLWH will be older than 50 and 30% will be older than 60 by 2015 Older than 50 years • New York: 37% in 2008; increased by 45% in men and by 58% in women • Florida: 30% in 2013, more than 50% in 2015 • San Francisco: 52% in 2010 • Massachusetts: 52% in 2013 Reported by NATAP.org, 21 September 2013
  • 69. Smoking May Play a Particularly Prominent Role for CVD in PLWH • 569 adults in 2 parallel cohorts • Risk factors for acute coronary syndrome – PLWH: Smoking and family history of CVD – HIV-negative: Smoking, diabetes, and hypertension • Attributable risk for smoking was 54.4 vs. 30.6 Calvo-Sanchez et al, HIV Medicine (2013), 14: 40–48
  • 70. Older People with HIV Also Have Smaller Subcortical Gray Matter Volumes and Less Cerebral Blood Flow Ances et al, J Acquir Immune Defic Syndr 2012; 59: 469-77 Ances et al, Journal of Infectious Diseases 2010; 201:336–40
  • 71. Recent Reports on Polypharmacy • Greater use of 8 classes of commonly prescribed medications occurs in both younger and older PLWH than in HIV negative adults – More than 5 non-ARV medications: Younger (<50): 35% (HIV+) vs.19% (HIV-) Older (≥50): 54% (HIV+) vs. 34% (HIV-) • In the large VACS database, increasing hazard of death when ≥ 3 medications were prescribed – Reached nearly 2-fold for PLWH prescribed ≥ 5 medications Edelman JE, et al.. ID Week 2013, San Francisco, 2013, abstract 76. Koram N, et al. ID Week 2013, San Francisco, 2013, abstract 323.
  • 72. • Regularly evaluate all PLWH for lipid and glucose abnormalities, hypertension, obesity, renal disease, smoking, and bone loss • Define absolute risk for coronary disease • Undertake comprehensive therapeutic measures, including changing ART to improve lipid and glucose abnormalities Blanco et al, AIDS Reviews 2010; 12: 231-41
  • 73. Chronic Infections Genetic Predisposition Persistent Immune Activation History of Advanced Immune Disease Age-Related Complications Poor Nutrition & Exercise Persistent HIV Replication ART Toxicity Polypharmacy Stimulant & Opiate Use Patient Related HIV Related Drug Related
  • 74. Chronic Infections Genetic Predisposition Persistent Immune Activation History of Advanced Immune Disease Age-Related Complications Poor Nutrition & Exercise Persistent HIV Replication ART Toxicity Polypharmacy Stimulant & Opiate Use Patient Related HIV Related Drug Related
  • 75. Older Americans: The Changing Face of HIV/AIDS in America U.S. Senate Hearing, 18 Sept 2013 • Diet and exercise are for now the best intervention to prevent early onset of comorbidities & inflammation • Early start of vigorous exercise – 250+ minutes a week of vigorous aerobic exercise • Diet resembling a Mediterranean diet – Fish, chicken, vegetables, fruit, beans, nuts Reported by NATAP.org, 21 September 2013
  • 76. Incidence of Diabetes Increased in the Early HAART Era, then Declined All subjects ART experienced ART naive Calendar Year Period • Prospective study of 1046 patients at 47 clinical sites in France • 111 patients developed diabetes • Incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women) • Correlates: older age, overweight, larger waist-to-hip ratio, time-updated lipoatrophy, and exposure to indinavir, stavudine, or didanosine Capeau et al, AIDS 2012, 26(3): 303-14