None. Financial Disclosures

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1 Aging with HIV Damani A. Piggott, MD, PhD Division of Infectious Diseases Johns Hopkins University School of Medicine Department of Epidemiology Johns Hopkins University School of Public Health

2 None Financial Disclosures

3 Objectives To describe epidemiologic trends in aging with HIV To define the burden of aging-related non- AIDS disease in HIV To provide an overview of the epidemiology and clinical management of aging-related syndromes in HIV

4 Increasing Number of People Receiving Antiretroviral Therapy Globally Global AIDS Response Progress Reporting (WHO/UNAIDS/UNICEF) and UNAIDS/WHO Estimates

5 Projected Increase in HIV+ Aged 50+ Current Burden HIV+ 50 years of age Low and Middle Income Countries: 12% High Income Countries: 30% 2040 HIV Prevalence in 50+ will double # HIV+ Persons 50+ will triple in Era of Antiretroviral Therapy Mills EJ et al. NEJM 2012; 366:1270-3

6 Increasing Age and Number of Persons Living with HIV in the U.S. % U.S. Persons Living with HIV (2012) 45+: 59% 55+: 24%

7 Improved but Persistent Gaps in Life Expectancy for HIV+ vs. HIV- Adults Marcus JL et al. Conference on Retroviruses and Opportunistic Infections (CROI) 2016: HIV positive adults matched to HIV negative adults by age, sex, medical center, year (Kaiser Permanente California Cohort)

8 Persistent Survival Deficits in HIV+ with Age Gaps in antiretroviral therapy coverage to maintain virologic suppression Increasing burden of chronic Non-AIDS comorbid disease with age

9 Gaps in HIV Continuum of Care in the U.S. 80% 62% 41% 36% 28% CDC: MMWR 2011; 60:

10 Improved but Persistent Deficits in Global Antiretroviral Therapy Coverage 60% HIV+ not on Antiretroviral Therapy in 2014 Global AIDS Response Progress Reporting (WHO/UNAIDS/UNICEF) and UNAIDS/WHO Estimates

11 Gaps in HIV Detection and Screening among Older HIV-infected Adults New HIV diagnoses in older adults in U.S. 45+: 26% 55+: 17% Deficits in HIV screening in older adults Less tested Later diagnosis Shorter time to death Reducing screening deficits in older adults Opt-out HIV screening regardless of age Regular risk assessment Sexual history at each visit Annual screening based on risk assessment

12 Increased Burden of Non-AIDS Disease in HIV-infected Population Cardiovascular disease Renal disease Obstructive lung disease Cancer Neurocognitive disorders Diabetes Osteoporosis

13 Increased Non-AIDS comorbidity among HIV+ with Age in Brazil Torres TS et al. The Brazilian Journal of Infectious Diseases 2013; 17:

14 Precipitants of Increased Burden of Non-AIDS Disease in HIV Coinfection Hepatitis C Lifestyle/Behavioral Factors Tobacco EtOH Substance Use Physical Inactivity Direct HIV Effect Immune Activation Inflammation Microbial Translocation Immunosenescence Medication Toxicity

15 Epidemiology and Clinical Management of Non-AIDS Disease in HIV Cardiovascular disease Renal disease Obstructive lung disease Cancer Neurocognitive disorders Diabetes Osteoporosis

16 Epidemiology and Clinical Management of Non-AIDS Disease in HIV Cardiovascular disease Renal disease Obstructive lung disease Cancer Neurocognitive disorders Diabetes Osteoporosis

17 HIV and Cardiovascular Disease

18 Increased Risk of Coronary Artery Disease/Myocardial Infarction in HIV+ 2X Risk with HIV Nou E. et al. Lancet Diabetes & Endocrinology 2016

19 Pathophysiology of Cardiovascular Disease in HIV Nou E. et al. Lancet Diabetes & Endocrinology 2016 HIV Risk CD4 count CD4 nadir + Viremia ART Risk Older regimens Other Physical activity Tobacco Cocaine Hypertension Diabetes Genetics

20 Increased Risk of Stroke in HIV+ Chow F et al. JAIDS Boston, U.S. - 40% Higher Rate of Stroke in HIV+ vs. HIV- Benjamin LA et al. Neurology Malawi - Increased risk of stroke: ART< 6 months Low CD4 count

21 Pathophysiology of Stroke in HIV CNS opportunistic infections (e.g. tuberculosis, varicella, syphilis) CNS neoplasm (lymphoma) Cardioembolic events Bacterial endocarditis HIV associated cardiomyopathy Ischemic heart disease HIV vasculopathy Aneurysmal formation Vasculitis Accelerated atherosclerosis

22 Management: HIV and Cardiovascular Disease Choice of friendly ART regimen Aspirin per risk/benefit Blood pressure control Glycemic control (prediabetes/diabetes) Cholesterol/lipid control Lifestyle modification Nutritional counseling Physical activity Tobacco cessation

23 HIV and Renal Disease

24 HIV and Renal Disease HIV+ prevalence of: Acute kidney injury Chronic kidney disease (CKD) End stage renal disease (ESRD) 3X risk of ESRD 7X risk of ESRD w/ AIDS + Age Age-related nephropathy risk of rapid kidney decline Other major risks Diabetes Hypertension Viral hepatitis Direct HIV effect HIV associated nephropathy (HIVAN) HIV immune complex disease Primary Diagnosis n (%) HIV-associated nephropathy (collapsing FSGS) 72 (29) Noncollapsing FSGS 46 (19) Acute interstitial nephritis 26 (11) HIV-associated immune complex GN 19 (8) Hypertensive nephropathy 14 (6) Diabetic nephropathy 14 (6) Postinfectious GN 12 (5) Acute tubular necrosis 10 (4) IgA nephropathy 6 (2) Membranoproliferative GN (hepatitis C related) 5 (2) Membranous GN 4 (2) Amyloidosis (AA) 4 (2) Other 9 (4) No diagnosis 2 (1) Tabatabai S. et al. Clin J Am Soc Nephrol 2009; 4:

25 HIV Immune Activation predicts Chronic Kidney Disease Kirkegaard-Klitbo DM et al. Soluble CD163 predicts incident chronic lung and kidney disease in HIV-1 infection. CROI 2016

26 Nephrotoxicity and Antiretroviral Therapy Unadjusted and Adjusted Incidence Rates per Year of Additional Exposure to Potentially Nephrotoxic Antiretrovirals Tenofovir alafenamide (TAF) vs. Tenofovir disoproxil (TDF) creatinine increase proteinuria Mocroft A et al. Lancet HIV 2016; 3: e23-32 Sax PE et al. Lancet 2015; 385:

27 Albuminuria and Glomerular Filtration Rate (GFR) independently predict risk of ESRD, Cardiovascular Disease and Mortality Lucas GM et al. CID 2014; 59: e96-138

28 Management: HIV and Renal Disease Gaps in care for HIV+ Delayed diagnosis Late referral for dialysis Annual assessment of GFR and urine albumin/protein excretion frequency with ART initiation/ modification Avoid nephrotoxic drugs Urgent ART for HIVAN Blood pressure & diabetes control Consider dialysis referral for stage IV CKD (as for HIV negative) Consider kidney transplantation U.S. HIV Organ Policy Equity (HOPE) Act November 2013 (HIV+ to HIV+ organ transplants)

29 HIV and Obstructive Lung Disease

30 HIV and Obstructive Lung Disease 50% prevalence of chronic obstructive lung disease (COPD) in HIV+ Burden increases with age Diffusion capacity (DLCO) common in HIV+ (50-64%) HIV+ risk of acute COPD exacerbations

31 Accelerated Lung Decline with Poorly Controlled HIV Drummond MB et al. Lancet Respir Med 2014; 2:

32 Immune Activation predicts Onset of Chronic Lung Disease in HIV+ Kirkegaard-Klitbo DM et al. Soluble CD163 predicts incident chronic lung and kidney disease in HIV-1 infection. CROI 2016

33 HIV + Chronic Obstructive Pulmonary Disease: Risk of Tuberculosis, Pneumocystis and Bacterial Pneumonia in HIV Attia EF et al. JAIDS 2015; 70: 280-8

34 Management: HIV and Obstructive Lung Disease Inhaled steroid therapy risk of oral candidiasis, bacterial pneumonia, tuberculosis Hypercortisolism with boosted protease inhibitors Pneumococcal and influenza vaccination Pulmonary rehabilitation to improve physical function Tobacco cessation

35 HIV and Cancer

36 HIV and Cancer Trends AIDS malignancies KS, NHL Cervical cancer advanced dz at pres survival post dx age - likelihood pap smear Non-AIDS malignancies (NADC) 2X risk Common NADC Lung cancer (2x ) Hodgkin (11x ) Anal carcinoma (28x ) Colorectal ca ( ) Liver ca (5.6x ) Infectious related HPV: anal, vaginal, penile, nasopharyngeal, laryngeal, oral HBV, HCV: liver EBV: Hodgkin, nasopharyngeal Tobacco related Lung, renal, gastric, laryngeal, oral

37 HIV+ in Latin America Risk of Invasive Cervical Cancer Diagnosis after ART initiation Rohner E et al. Global burden of Cervical Cancer in HIV-Positive Women on Antiretroviral Therapy. CROI 2016

38 HIV+ with Cancer Die at Higher Rates than Expected Coghill AE et al. Excess mortality rates among HIV-infected cancer patients in the United States. NCI. CROI 2016

39 HIV + Age: Cancer Cancer screening Cancer incidence Risk of death Need for enhanced cancer screening Screening mostly as per general population cervical cancer screening Monitor for drug-drug interactions with chemotherapy Prophylaxis for HIV-related and chemotherapyrelated opportunistic infections

40 HIV-associated Neurocognitive Impairment

41 Classification of HIV-associated Neurocognitive Disorders (HAND) Type Asymptomatic neurocognitive impairment Mild neurocognitive disorder HIV-associated dementia Neurocognitive domains Clinical Presentation Characteristics Impairment in 2 neurocognitive domains Normal daily functioning Impairment in 2 neurocognitive domains Mild to moderate impairment in daily functioning Severe impairment in 2 neurocognitive domains Severe impairment in daily functioning Learning/Memory, Attention, Psychomotor speed, Executive function, Info Processing Memory loss, gait impairment, apathy, depression OVERALL PREVALENCE: Up to 50-60%; ¾ asymptomatic

42 Change in HAND Prevalence before and after ART Nightingale S et al. Lancet Neurol 2014; 13:

43 Asymptomatic Neurocognitive Impairment increases Risk of Progression to Symptomatic Neurocognitive Disorder Grant I et al. Neurology 2014; 82:

44 Pathophysiology of HIV associated neurocognitive disorders HIV-specific Advanced disease - CD4 nadir ART - Suboptimal CNS penetration - Neurotoxicity Non HIV-specific Prior CNS disease Cardiovascular disease risk factors Coinfection (hepatitis) Substance use w/ Age Nightingale S et al. Lancet Neurol 2014; 13:

45 Abnormal Lipid Profile Associated with Greater Midlife Cognitive Decline in HIV+ than HIV- Multicenter AIDS Cohort Study years of age 273 HIV+, 516 HIV- subjects Cognitive summary score (executive function, perceptual speed, memory, attention, motor/processing speed) Higher total cholesterol, LDL and triglycerides associated with a faster rate of cognitive decline in HIV+ men compared to HIV- men Mukerji SS et al. Lipid profiles and APOE4 allele impact midlife cognitive decline in HIV+ men on ART. CROI 2016

46 Management: HIV-associated Neurocognitive Disorders Screening No gold standard IHDS, MHDS, Montreal cognitive assessment Diagnosis Neuropsychologic testing Assessment of activities of daily living Rule out secondary causes of CNS disease (CNS OIs, viral hepatitis, stroke, endocrine or sleep disorders, substance use, medication toxicity, nutritional deficiency) Treatment ART Manage risk factors for cerebrovascular disease Manage depression/psychiatric disease Promote social engagement

47 Aging Syndromes and HIV Rising burden of aging syndromes among HIV+ in era of ART Multimorbidity Polypharmacy Frailty

48 HIV and Multimorbidity Diabetes Multimorbidity Sum>Parts Bone disease HAND Syndrome of co-occurring serious health conditions that cannot be cured to any great extent occurring in an older person and engendering functional or cognitive disability HIV and Aging Consensus Group Kidney disease HIV Cancer CVD COPD HTN

49 Increased Multimorbidity with Age in HIV+ versus HIV- 2/3 Persons with HIV Living with Multimorbidity Smit M. et al. Lancet Infect Dis. 2015; 15:

50 HIV and Polypharmacy Multimorbidity increases medication burden for HIV+ -> Polypharmacy Daily utilization of multiple classes of medication Polypharmacy increases risk of Adverse drug reactions Medication errors Drug-drug interactions Poor medication adherence Hospitalization

51 Management: Multimorbidity and Polypharmacy in HIV Prioritize and tailor interventions Clinical feasibility Informed patient preference Therapeutic choice Optimize benefit Minimize harm Enhance quality of life Interdisciplinary care Frequent medication reconciliation Reduce medication burden when possible Stop medications inappropriate for older adults

52 Frailty: Reducing Vulnerability Beyond Multimorbidity and HIV Disease Stage Multimorbidity Sum>Parts Frail/Older HIV+ Adult Kidney disease Diabetes Bone disease HIV HAND Cancer Hospitalization Institutionalization Disability Death CVD HTN COPD

53 Frailty : An Aging-Related Syndrome of Vulnerability to Poor Health Syndrome of vulnerability to adverse health outcomes Mortality New or worsening chronic disease -> hospitalization Disability First characterized among HIV-uninfected adults 65 years and older Decreased resilience to internal and external stressors - diminished homeostatic response Frailty: aging-related chronologic age

54 Frailty Phenotype (Fried et al.) Cardiovascular Health Study Weight Loss Weakness Exhaustion Slow walking speed Low physical activity Frail if 3 of 5 present (critical mass) Prefrail if 1-2 present

55 Frailty Predicts Adverse Outcomes in HIV-uninfected Populations 65+ CHS* WHAS I/II* Death 2.24 (1.51, 3.33) 6.03 (3.00, 12.08) First Hospitalization Worsening ADL Disability Worsening Mobility 1.29 (1.09, 1.54) 0.67 (0.33, 1.35) 1.98 (1.54, 2.55) (5.83, 42.78) 1.50 (1.23, 1.82) (3.51, 31.00) Incident Fall 1.29 (1.00, 1.68) 1.18 (0.63, 2.19) *Adjusted Hazard Ratios Fried LP et al. J Gerontol A Biol Med Sci 2001 Bandeen-Roche K et al J Gerontol A Biol Med Sci 2006

56 Frailty Prevalence among 60+ Adults in Latin America and Caribbean Brazil 35,4 44,1 Chile 31,7 48,2 Mexico 30,4 45,5 Female Male Cuba 26,2 46,7 Barbados 21, Project SABE : Health, Well Being and Aging Study Alvarado BE et al. J Gerontol A Biol Sci Med Sci 2008; 63 :

57 Frailty in HIV: AIDS Linked to the IntraVenous Experience (ALIVE) Cohort Community based, prospective observational cohort Frailty Phenotype in ALIVE HIV+ and HIV- Adults ( 18 yrs) with history of injection drug use Enrollment: 1988-Present

58 Frailty Burden in HIV+ % ,4 14,5 12,3 HIV- HIV+ Overall HIV+ 66% more likely to be frail than HIVcontrols ALIVE Piggott DA et al. PLoS One 2013; 8: e54910

59 Frailty Associations in HIV Cohorts Increasing age Heightened socioeconomic challenge Low educational attainment, unemployment Increased comorbidity Poorly controlled HIV infection/aids Desquilbet L et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci Terzian AS et al. Factors associated with preclinical disability and frailty among HIV-infected and HIV-uninfected women in the era of cart. J Womens Health 2009 Onen NF et al. Frailty among HIVinfected persons in an urban outpatient care setting. J Infect Pathai S et al. Frailty in HIV-infected adults in South Africa. JAIDS 2013 Althoff KN et al. Age, comorbidities, and AIDS predict a frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci. 2014

60 Frailty Predicts Hospitalization Risk in HIV Independent of Comorbidity and HIV Disease Stage Time to Hospitalization

61 Frailty Predicts Mortality Risk in HIV Adjusted Hazard Ratio (95% CI) HIV-/Frail- HIV-/Frail+ HIV+/Frail- HIV+/Frail+ Ref 2.63 (1.23, 5.66) 3.29 (1.85, 5.88) 7.06 (3.49, 14.3) Piggott DA et al. PLoS One 2013; 8: e54910

62 Inflammatory Markers in Older Adults: Risk Factors and Consequences Singh T, Newman AB. Ageing Res Rev. 2011; 10:319-29

63 Annual Reviews

64 Inflammatory Index Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults Ravi Varadhan, 1 Wenliang Yao, 1 Amy Matteini, 1 Brock A. Beamer, 2 Qian-li Xue, 1 Huanle Yang, 1 Bhavish Manwani, 1 Alexander Reiner, 3 Nancy Jenny, 4 Neel Parekh, 1 M. Daniele Fallin, 5 Anne Newman, 6 Karen Bandeen-Roche, 7 Russell Tracy, 4 Luigi Ferrucci, 8 and Jeremy Walston 1 J Gerontol A Biol Sci Med Sci 2014 February;69(2): Biologically informed aggregate marker derived from NFkB related cytokines Validated to best capture inflammation effect on mortality (InCHIANTI/CHS: adults 65+) Inflammatory Index Score = (ln IL-6 + 2*ln stnfr1)/3

65 Inflammatory Index Predicts Mortality Risk in HIV Piggott DA et al. J Gerontol Biol Med Sci 2015

66 Inflammation may be a target to reduce Multimorbidity and Frailty Burden in HIV Odds of Frailty Per Standard Deviation Increase in Inflammatory Index Score Adjusted Odds Ratio (95% CI) Piggott DA et al. J Gerontol Biol Med Sci 2015; 70:

67 SUMMARY HIV-infected persons are living longer Increased survival has brought an increased burden of non- AIDS chronic disease and adverse aging-related syndromes Aging-related disease is driven by direct HIV biology, antiretroviral therapy effects, co-infection and burden of behavioral/clinical risk factors Priorities for clinical management include informed and tailored patient-centered, interdisciplinary care Understanding pathophysiologic pathways predisposing to non-aids disease and aging-related syndromes key to promoting healthy aging in HIV