1. HIV and Aging Kathleen K Casey, MD Director, AIDS Ambulatory Care Center Jersey Shore University Medical Center

2. 2 % of Patients 50 and Older Estimated Percentage of Persons Living with HIV/AIDS Who Are 50 and Older by Year, 2001-2007 a Year a For years 2001-2003, data are based on 33 states and US-dependent areas with confidential name-based HIV infection reporting, CDC HIV/AIDS Surveillance Report, 2005. For years 2004-2007, data are based on 34 states and 5 US-dependent areas with confidential name- based HIV infection reporting, CDC HIV/AIDS Surveillance Report, 2007. Gay Men’s Health Crisis. Growing Older With the Epidemic: HIV and Aging. 2010.

3. Concurrent HIV/AIDS Among Persons Diagnosed with HIV in the United States in 2006, by Age Group 3 Persons Newly Diagnosed with HIV, % HIV only (non-AIDS)Concurrent HIV/AIDS 12 20 24 38 44 49 55 76 62 56 51 45 30 20 10 0 40 50 60 70 80 90 100 0-1213-1920-2930-3940-4950-5960+ Age Group at Diagnosis a AIDS diagnosis within one year of HIV diagnosis. Gay Men’s Health Crisis. Growing Older With the Epidemic: HIV and Aging. 2010. 88 80

4. How Are We Finding Our Patients Over 50? Hospitalized patients with opportunistic infections Screening of patients with malignancy Partner Testing STD clinic visits Dialysis Screening Dementia screening Rarely through routine primary care assessment and routine testing despite CDC recommendations!

5. Older patients are more likely than younger patients to present late for HIV diagnosis and care 1 Physicians are less likely to discuss HIV/AIDS and related risk factors with older patients 2 Asymptomatic older HIV-infected individuals are less likely to seek out testing and medical care 3 Symptomatic older HIV-infected individuals are more likely to attribute HIV-related symptoms to other illnesses or to the normal aging process 3 5 1 Cuzin L et al. Clin Infect Dis. 2007;45:654-657. 2 Skiest DJ et al. Arch Fam Med. 1997;6:289-294. 3 Siegel K et al. AIDS Care. 1999;11:525-535.

6. Physicians reported that 69.7% of their patients older than 50 years rarely or never asked them questions about HIV or AIDS 60.8% of respondents reported rarely or never discussing HIV or AIDS with their patients aged >50 years, while 40% reported rarely or never asking their patients aged >50 years about possible HIV risk factors 67.5% of respondents reported rarely or never discussing behaviors that may reduce HIV risk in their patients older than 50 years, while only 6.8% of the physicians rarely or never discussed risk factors in their patients younger than 30 years Family practitioners were more likely than internists to rarely or never ask patients aged >50 years about HIV risk factors (54.9% vs 28.9%, P=.007) 6 Skiest DJ et al. Arch Fam Med. 1997;6:289-294.

7. Study explored how symptom interpretations influence the initiation of HIV testing and medical care among adults aged ≥50 years through patient interviews N=78 patients living with HIV (58 men, 20 women) 19 patients aged ≥60 32 African American, 15 Puerto Rican, 31 non-Hispanic whites 51% identified as completely/mostly heterosexual, 42% as completely/mostly homosexual 47 (60%) diagnosed with AIDS, 9 (12%) symptomatic HIV disease, 22 (28%) asymptomatic HIV infection Mean CD4 cell count at first interview: 400 cells/mm 3 (SD=311, range 32-1500 cells/mm 3 ) 91% reported other chronic health conditions: heart disease (27%), respiratory problems (36%), arthritis (36%), and other illnesses (41%) Presence or absence of putative symptoms of AIDS most often led to patients’ HIV testing Attributing symptoms to other illnesses (eg, hypertension, normal aging, menopause) was a common reason for delaying HIV testing Some patients delayed or refused to seek medical care even after being diagnosed as HIV+ because they did not feel ill and/or misattributed their symptoms to other illnesses 7 Siegel K et al. AIDS Care. 1999;11:525-535.

8. How well do older patients do with HIV treatment?

9. 9 Achieving HIV RNA <500 Copies/mL at 12 Months Experiencing HIV RNA Rebound Within 2 Years a P =.009; b P =.01. Adjusted for age only. Hazard Ratio (95% CI) 18-39 1.00 (Reference) 40-49≥50 Age at Baseline (years) 0.81 b (0.69-0.96) 0.88 (0.73-1.06) CI, confidence interval. Silverberg MJ et al. Arch Intern Med. 2007;167:684-691. 18-3940-49≥50 Age at Baseline (years) 1.00 (Reference) 0.97 (0.88-1.06) 1.15 a (1.04-1.27) Hazard Ratio (95% CI)

10. Patients 50 years and older have higher risk of clinical progression but improved virologic response compared with younger patients Prospective cohort study of 3015 treatment-naive patients initiating ART 50 years and older: n=401 Younger than 50 years: n=2614 Median follow-up: 31.5 months At baseline, older patients more likely to have ADE (P =.0001) Lower CD4 T-cell count (P =.0002) Higher HIV-1 RNA level (P =.0001) 10 OutcomeAdjusted HRP Value Progression to ADE or death1.52.0035 Progression to new ADE1.50.0087 HIV-1 RNA <500 copies/mL1.23<.05 ADE, AIDS-defining event; HR, hazard ratio. Grabar S. AIDS. 2004;18:2029-2038.

11. 11 Rates per 1000 Person-years Death AIDS-defining Illnesses (hospitalizations) 28.8 47.4 a 8.4 7.5 PCP, pneumocystis pneumonia. Silverberg MJ et al. Arch Intern Med. 2007;167:684-691. PCP Candidiasis AIDS Dementia Wasting Syndrome AIDS Diagnoses 28.5 36.4 b 2.3 5.9 a 1.6 5.9 a 2.3 7.2 a a P ≤.001 and b P=.01 vs <50 years. Age (years) <50 (n=4094) ≥50 (n=997) Kaiser Permanente of Northern California chart review study of all members who initiated ART from 1995-2004 (N=5090)  18 years and older; starting 3 or more anti-retrovirals in combination; median follow-up: 3.8 years

12. 12 18 - 39 Years40 - 49 Years≥50 Years Parametern (%) OR (95% CI)n (%)OR (95%) TC and LDL a 310 (21.0)311 (26.4)1.31 (0.84- 2.06) 241 (34.0) 1.66 (1.02 - 2.70) Glucose b 917 (6.0)713 (11.4)1.92 (1.17- 3.15) 486 (14.4) 2.85 (1.71 - 4.75) Creatinine c 1265 (3.2)1021 (5.8)1.06 (0.53- 2.12) 625 (8.3)2.03 (1.03 - 4.00) Silverberg MJ. Arch Intern Med. 2007;167:684-691. LDL, low-density lipoprotein; NR, not reported; OR, odds ratio; TC, total cholesterol. a Abnormal cutoff defined as ≥240 mg/dL for total cholesterol and ≥ 160 mg/dL for LDL cholesterol. b Abnormal cutoff defined as 161 mg/dL (random), 126 mg/dL (fasting) and 54 mg/dL (low). c Abnormal cutoff defined as ≥1.8 mg/dL for men and ≥1.65 mg/dL for women. Analysis of Patients Who Developed at Least Grade 2 Laboratory Abnormality After ART Initiation

13. Assessed deaths in 13 HIV-1 cohorts composed of 39,727 persons (5293 patients 50 years and older) Of 1876 deaths, definitive cause in 85% Non-AIDS–related deaths in 50.5%: 13 Antiretroviral Therapy Cohort Collaboration (ART-CC). Clin Infect Dis. 2010;50:1387-1396. Infection Non-AIDS 16.3% CVD 15.7% Malignancy 23.5% Violence Sub Abuse 15.4% Liver-related 14.1% Other 9.0% Respiratory 3.1% Renal 3.0%

14. Among 2857 HIV-infected patients participating in ALLRT study 1 : At baseline, 16% of patients had abnormal levels of urine protein as measured by ratio of spot urine (P/Cr ≥0.2) Older age was significantly associated with P/Cr ≥0.2 Per 10 years: OR 1.21 (95% CI, 1.10-1.33; P <.001) In the EuroSIDA cohort, the rate of chronic renal failure a at baseline ranged from 3.5% to 4.7% depending on the method of GFR calculation 2 By multivariate analysis, age was a strong predictor of chronic renal failure at baseline OR 5.47, 95% CI, 4.4-6.72; P <.0001 2 14 a GFR <60 mL/min/1.73 m 2. GFR, glomerular filtration rate. 1 Gupta SK, et al. Antivir Ther. 2009;14:543-549. 2 Mocroft A. AIDS. 2007;21:1119-1127.

15. Multiple studies have found increased prevalence of osteoporosis and osteopenia in persons with HIV compared with uninfected persons 2 Meta-analysis of studies 2 67% persons with HIV had reduced BMD (OR 6.4) 15% persons with HIV had osteoporosis (OR 3.7) 15 1 Aaron JE et al. Clin Orthop Relat Res. 1987;215:260-271. 2 Brown TT et al. AIDS. 2006;20:2165-2174. BMD Loss with Age in the General Population, by Sex 1 Mean ± SE Change in Bone a Volume,% Age (years) 40506070 10 15 20 25 30 Female Male n=15 n=14 n=13 n=19 n=14 n=26 n=15 n=18 n=29 n=21

16. 8525 HIV+ and 2,208,792 HIV- Patients from 1996-2008 Men a Clinical care data registry from the Partners HealthCare System, which consists primarily of Brigham and Women’s Hospital and Massachusetts General Hospital. Triant VA et al. J Clin Endocrinol Metab. 2008;93:3499-3504. P =.002 (overall comparison) P <.0001 (overall comparison) Women 16 Frequency per 100 Persons

17. In a cross-sectional analysis of 202 patients with HIV enrolled in the Hawaii Aging with HIV Cohort (n=103 patients 50 years and older): HIV-associated dementia was more frequent in adults aged 50 years and older vs those aged 20-39 years OR 2.13, 95% CI, 1.02-4.44 After adjusting for education, race, drug use, ART status, viral load, CD4 count, and Beck Depression Inventory score, risk of HIV-associated dementia was even higher among older patients OR 3.26, 95% CI, 1.32-8.07 17 Valcour VG et al. Neurology. 2004;63:822-827.

18. Cancer Type Cancer Diagnosis (Mean Age  SD) P Value HIV+ a HIV- b Anal/rectal SCC 51.65  8.6657.53  15.93.0001 Hodgkin lymphoma 39.66  7.8041.42  17.87.685 Non-Hodgkin lymphoma 41.54  9.2065.56  16.17.0001 Cervical 41.94  5.2951.20  17.87.053 Liver 40.94  6.3965.36  14.86.0001 Head and neck 50.67  11.5867.11  13.44.0001 Lung 51.65  8.6668.81  12.52.0001 Breast 44.92  12.0060.57  10.25.0001 Prostate 53.46  12.7271.48  15.98.0001 Nguyen ML et al. 18th IAC; Vienna; 2010. Abstract WEAB0105. 18 ADM, AIDS-defining malignancy; NADM, non-AIDS—defining malignancy; SCC, squamous cell carcinoma. a N=8300 patients seen at the Infectious Diseases Ponce de Leon Center during 2000-2007 (516 cancer cases). b Data gathered from 17 registries of the Surveillance, Epidemiology and End Results (SEER) database.

19. 19 Adapted from Grunfeld C et al. Circulation. 2008;118:e20-e28. Insulin resistance ↑ Glucose Dyslipidemia: ↑ TG ↓ HDL ↑ FFA ↑ Small, dense LDL ↕↔ LDL CVD Inflammation Body composition: Lipoatrophy Lipohypertrophy ART, antiretroviral therapy; ARV, antiretroviral; FFA, free fatty acids; HDL, high-density lipoprotein; HTN, hypertension; LDL, low- density lipoprotein; TG, triglycerides. Predisposing factors: Genetics, smoking, sedentary lifestyle, diet, obesity, HTN, renal disease HIV infection ART, including specific ARVs

20. 20 b b b Adapted from Triant VA et al. Clin Endocrinol Metab. 2007;92:2506-2512. a Cohort population: all patients aged 18-84 years who presented on at least two occasions to one of two Boston health care facilities, Brigham and Women’s Hospital (BWH) or Massachusetts General Hospital (MGH) between 1996 and 2004. b P <.0001 for comparison between proportions in HIV+ and HIV- cohorts by Χ 2. Patients, % Percentage of Subjects with CV Risk Factors by ICD Code ICD, International Classification of Disease(s).

21. 21 Triant VA et al. J Clin Endocrinol Metab. 2007;92:2506-2512. AMI Rates by Age Group 0 20 40 60 80 100 18-3435-4445-5455-6465-74 Events per 1000 P-Y Age Group (years) HIV+ (n = 3851)HIV- (n = 1,044,589) AMI, acute myocardial infarction; P-Y, patient-year. a Clinical care data registry from the Partners HealthCare System, which consists primarily of Brigham and Women’s Hospital and Massachusetts General Hospital; identified patients who presented at least twice from 1996-2004.

22. Framingham Cardiovascular Risk Assessment Tool Age Gender Total cholesterol HDL Smoking status Systolic blood pressure Family history of CAD Medication used to control blood pressure

23. BMI, body mass index; CHD, coronary heart disease; D:A:D, data collection on adverse events of anti-HIV drugs. Adapted from Friis-Møller N et al. AIDS. 2003;17:1179-1193. Large observational cohort of HIV+ patients followed longitudinally (N = 17,852) 15,537 (87%) with previous ART exposure; 2315 (13%) ARV-naive 23 Percentage of Cohort with Risk Factor at Baseline Family History of CHD Previous CVD Current Smoking BMI >30 mg/m 2 HTNDiabetes Mellitus ↑Total Cholesterol ↑TG

24. HIV+ treatment-naïve patients with undetectable VLs (HIV controllers) had a higher mean carotid IMT than the HIV- participants, even after controlling for traditional risk factors HIV controllers had a trend toward higher median cIMT than untreated HIV noncontrollers 24 Hsue P et al. AIDS. 2009;23:1059-1067. cIMT, carotid intima media thickness (a validated measure of atherosclerosis); IMT, intima media thickness; VL, viral load. n = 93 n = 33n = 96 Mean IMT (mm) Mean Carotid IMT (mm) 2.0 1.0 0.0 2.5 1.5 0.5 1.0 0.0 2.0 1.5 0.5 P <.001 HIV-HIV+ ART- VL <75 HIV+ ART- VL >75 CD4 >500 HIV-HIV+ Elite Controllers P <.001 P =.13 a All study participants with HIV were recruited from the UCSF SCOPE Cohort, which contains a large group of rare individuals who were recruited on the basis of their ability to control HIV replication in the absence of therapy. HIV- participants were selected mainly from those answering advertisements to participate in research studies who were similar in age and sex to participants with HIV.

25. Prospective observational cohort study of patients with HIV Analysis included patients receiving care from 2002-2009; N=2005 (148 incident CV events) Median age: 42 years Categorized patients according to the NCEP 10-year CVR score criteria (10-yr CVR) Analyzed incidence and rates of CVD during observation period and calculated the relative attributable risks of various traditional and HIV risk factors to incident CVD 25 CV, cardiovascular; CVR, cardiovascular risk; HDL-C, high-density lipoprotein-cholesterol; HTN, hypertension; NCEP, National Cholesterol Education Program. Lichtenstein KA et al. Clin Infect Dis. 2010;51:435-447. Attributable Risk, % Relative Contribution of Risk Factors to Incident CVD

26. D:A:D Study Group. N Engl J Med. 2007;356:1723-1735. 0 <11-22-33-44-55-66-7>7 Incidence per 1000 Person-Years 0 10 9 8 7 6 5 3 2 1 4 Total Number of events:161720416162514730345 Number of person-years: 11,81 5 7105 902 7 12,09814,892 14,39 4 11,351 793 5 585394,469 MI, myocardial infarction. 26 Exposure (years) MI Incidence

27. Metabolic Syndrome Hypertension Hypergylcemia Central obesity Hypercholesterolemia

28. 28 BP, blood pressure; MS, metabolic syndrome; WC, waist circumference. Bonfanti PB et al. J Acquir Immune Defic Syndr. 2007;45:426-431. Prevalence of MS Components in HIV+ Patients and HIV- Controls P <.0001 NS Subjects, %

29. Patients with fat redistribution had significantly increased 10-year CHD risk compared with matched controls Patients without fat redistribution did not have increased 10-year CHD risk compared with matched controls 7.4 3.3 P =.002 P =.27 10-year CHD-risk Estimate (%) 0 6 7 8 9 10 Framingham Offspring Study controls HIV+ patients with fat redistribution 4.1 5.3 1 2 3 4 5 HIV+ patients without fat redistribution Patient Population (n = 91)(n = 90)(n = 30)(n = 273) Adapted from Hadigan C et al. Clin Infect Dis. 2003;36:909-916. 29 a Study included 91 consecutive HIV+ subjects (65 men and 26 women) who reported recent changes in body fat distribution who were prospectively evaluated from December 1998 through November 1999 at the Clinical Research Center of the Massachusetts Institute of Technology.

30. Lipodystrophy (fat redistribution) reported in large numbers of patients with HIV 1 Proportion of affected patients is greater in those receiving certain ARVs Prevalence rates of lipodystrophy vary between 11% and 83% in cross-sectional studies Lipodystrophy may be a clinical symptom of insulin resistance, diabetes, and increased CV risk 1 Lipodystrophy may be associated with decreased quality of life and poorer ART adherence in affected patients 2 30 1 Khunnawat C et al. Am J Cardiol. 2008;102:635-642. 2 Nachega JB et al. Curr HIV/AIDS Rep. 2009;6:121-129.

31. Lichenstein et al. CID 2010; 51(4):435-447 Looked at MI, non-embolic or hemorrhagic stroke, CAD, angina and peripheral arterial disease Assessed the association of latest CD4 count and the CV event CD4 <350 had a hazard ratio of 1.58 Traditional CV risk factors and a CD4 count <500 were associated with a greater risk than any cumulative risk of any ARV class or individual drug

32. Remaining Questions: Is there truly a risk of increased incidence of MI in HIV infection that can be separated from background demographics? If there is an increased risk, what is it about HIV or immune dysfunction that drives the risk? Do potential ART related toxicities influence the incidence of MI?

33. Freiberg,MS et al JAMA Intern Med March 2013 Looked at MI only in men 2003 to 2009 82,459 participants with 33.2% being HIV positive They were matched not only by traditional risk factors but by similar demographic and geographic backgrounds They determined that the HIV population carried about a 50% increase in risk for MI and that the Framingham risk assessment was likely to underestimate the true risk in the HIV population

34. Observed rates Best estimate of predicted rate 0 1 2 3 4 5 6 7 8 No<1 year 1-2 years 2-3 years 3-4 years 4+ years Duration of ART Rates Per 1000 Person-years Schambelan M et al. Circulation. 2008;1182:e48-e53. 34

35. All patients should be assessed for CVD risk Those with 2 risk factors should be further evaluated and managed according to the HIVMA and NCEP guidelines All patients should be encouraged to stop smoking regardless of CVD risk, and HTN and diabetes mellitus should be managed as appropriate A fasting glucose level and a fasting lipid profile should be obtained from all patients upon initiation of care and every 6-12 months thereafter Consider testing 1-3 months after starting or modifying ART Hemoglobin A1c level should be obtained every 6 months in patients with diabetes mellitus 35 HIVMA, HIV Medicine Association; IDSA, Infectious Disease Society of America. Aberg JA et al. Clin Infect Dis. 2009;49:651-681.

36. Why Is There an Increased Risk for Myocardial Infarction? Is it the dyslipidemia mainly characterized by a low HDL and increased triglyceridemia? Is it the chronic inflammation associated with years of viral replication before the disease is treated? Is it due to an altered immune response that persists despite viral control? Do our current anti-retroviral medications contribute in ways we have not yet appreciated? Do the interventions we employ to decrease risk in HIV negative people work in HIV infected people? What about women?

37. IRR (95% CI) vs never smoked: MI: 3.73 (2.46, 5.64); CHD: 2.93 (2.07, 4.14); CVD: 2.32 (1.69, 3.18) within the first year of smoking cessation MI: 2.07 (1.19, 3.63); CHD: 1.83 (1.16, 2.89); CVD: 1.49 (0.99, 2.24) after >3 years of smoking cessation 37 IRR of MI and Smoking Status IRR of CVD and Smoking Status IRR, incident rate ratio. Petoumenos K et al. HIV Med. 2011;12:412-421. 0.5 2.5 5 IRR 0.5 2.5 5 IRR Never smoked Previous smoker Current smoker <1 year 1-2 years 2-3 years >3 years Stopped smoking during follow-up:

38. 38 Silverberg M et al. Ann Intern Med. 2009;150:301-313. Results are based on linear regression with adjustment for age, sex, year, lipid-lowering therapy class, months of follow-up, baseline LDL cholesterol and TG levels, number of coronary disease risk factors, past coronary disease or diabetes diagnoses, and hepatitis B or C infection. Model for any statin use is also adjusted for dose-equivalents of different individual statins and concomitant use of other lipid- lowering therapy classes. Adjusted Percentage Changes in LDL-C and TG Levels Within 12 Months of Lipid-lowering Therapy Change in LDL-C Level, % Change in TG Level, % HIV-infected patients (n = 616) HIV-uninfected patients (n = 5451) HIV-infected patients (n = 213) HIV-uninfected patients (n = 1490) -10 -30 0 -20 -40 -10 -30 0 -20 -40 -50 -60 -70 Any Lipid- lowering Therapy Any Statin -25.6 (P =.001) -28.3 (reference) -19.9 (reference) -19.2 (P =.38) HIV+ HIV- -52.1 (reference) -41.2 (P <.001) LDL-C, low-density lipoprotein cholesterol. a A retrospective cohort study to compare the effectiveness and safety of lipid-lowering therapy in patients with and without HIV infection in an integrated health care delivery system (1996-2005). N = 829 HIV+ patients and 6941 HIV- patients HIV infection beginning lipid- lowering therapy for elevated LDL-C or TG levels.

39. HIV infection itself affects endothelial function Baseline FMD: 3.68% FMD improved during ART: At Week 4: +0.74% (P ≤.01) At Week 24: +1.48 (P <.001) No significant differences between treatment arms No consistent significant correlations between changes in FMD and changes in any lipids or glycemic parameter Improvement in FMD significantly correlated with decrease in HIV-1 RNA at Week 24 No relationship with baseline VL 39 Torriani F et al. J Am Coll Cardiol. 2008;12;52:569-576. -5 -0 5 10 Change in FMD from Baseline to Week 24, % All SubjectsPI- sparing NNRTI- sparing NRTI- sparing FMD, brachial-artery flow-mediated dilation; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. a The ACTG (AIDS Clinical Trials Group) study 5152s is a substudy of ACTG 5142, a prospective, multicenter, randomized, clinical trial that investigated time to virologic failure in ART‐naive subjects randomly assigned to receive 1 of 3 ART‐sparing regimens (N = 82).

40. 40 Currier J et al. Circulation. 2008;118:e29-e35. Increasing CV RiskDecreasing CV Risk Dyslipidemia, insulin resistance, body habitus changes associated with HIV itself and certain components of ART Control of viral replication with ART improves endothelial function High rates of other CV risk factors, in particular smoking Current ARV regimens have more favorable effects on metabolic parameters and morphological changes than earlier regimens Prolongation of survival: older patients are intrinsically at greater CV risk ART reduces inflammatory markers and immune activation HIV providers more aggressive about modification of ART or initiation of lipid-lowering therapies

41. 41 HBV, hepatitis B virus; HCV, hepatitis C virus; CMV, cytomegalovirus. Deeks SG. Topics HIV Med. 2009;17:118-123. Residual viral replication Persistent virus expression (in lymph nodes) Loss of immunoregulatory cells Collagen deposition Microbial translocation High pathogen load (CMV, HBV, HCV) Thymic dysfunction Suboptimal CD4 gains Residual inflammation Hypercoagulation Non-AIDS—related events and premature mortality

42. Outcome Measures Age >70 years, HIV- HIV+, Untreate d Long-term (5-10 years) Treated HIV+ Low CD4/CD8 ratioYes Unknown Low naïve/memory ratioYes Possible Low T-cell proliferative potential Yes Possible (low CD4 nadir) Expanded CMV-specific CD8 cells Yes Expanded CD28-CD8+ T cells Yes Unknown Expanded CD57+ T cellsYes Unknown Reduced T-cell repertoireYes Possible Deeks SG. Annu Rev Med. 2011;62:141-155. 42

43. 43 Outcome Measures Age >70 years, HIV- HIV+, Untreate d Long-term (5-10 years) Treated HIV+ Increased IL-6Yes Possible Increased T-cell activation UnclearYesPossible Reduced thymus function Yes Unknown Low IL-2, high IFN-γ (CD8+ T cells) Yes Unknown Reduced response to vaccines Yes Possible (CD4 nadir) Reduced T-cell telomere lengths YesYes (CD8)Controversial Deeks SG. Annu Rev Med. 2011;62:141-155.

44. 44 Untreated HIV Infection CMV replication HIV replication Loss of immuno- regulatory cells Thymic dysfunction and loss of regenerative potential Loss of gut mucosal integrity and microbial translocation ART Decreased but persistent (1) defects in T-cell regenerative potential; (2) loss of immunoregulatory function; (3) CMV and other co-pathogen levels; (4) and microbial translocation Chronic inflammation T-cell maturationT-cell dysfunctionProgenitor-cell exhaustion Immunosenescence and clinical disease Deeks SG. Annu Rev Med. 2011;62:141-155.

45. CV risk factors, including metabolic disorders, and CVD are highly prevalent in patients with HIV Etiology of CVD and metabolic complications is multifactorial Traditional risk factors HIV infection ART Clinicians caring for patients with HIV should be cognizant of the increased risk of CVD and metabolic disorders in this patient population and manage them appropriately 45

46. The number of HIV-infected persons 50 years and older is increasing Morbidity associated with normal aging may be enhanced by HIV infection and/or ART Clinicians should be aware of the challenges associated with management of an older patient with HIV Older patients may present with more advanced HIV disease Immunologic response in aging patients is less robust than in younger patients Primary health care considerations in patients with HIV should include screening and management of age-related comorbidities 46