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HIV AND AGING

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  1. HIV AND AGING Sally L. Hodder M.D. Professor of Medicine New Jersey Medical School – UMDNJ Newark, New Jersey

  2. Learning Objectives At the conclusion of this presentation, participants should be able to: • Appreciate occurrence of immune activation and relevance to aging • Describe differences in response to antiretroviral therapy in older compared with younger HIV-infected persons • Characterize selected age-related comorbidites in HIV-infected persons and appreciate implications for preventive care

  3. OFF-Label Disclosure This presentation will include discussion of the following investigational uses of products • Statins to decrease immune activation

  4. HIV Cases Among Persons >50 Years of Age Percentage of Reported HIV Cases Occurring in Persons >50 Years Year CDC. HIV/AIDS Surveillance Report, 2005; Smith G. US Senate Special Committee on Aging. Serial no. 109-7; May 12, 2005. 

  5. Causes of Death In HIV-1 HAART Treated Persons 1996-2006 • Assessed deaths in 13 HIV-1 cohorts comprising 39,727 persons • Of 1876 deaths, definitive cause in 85% • Non-AIDS related deaths in 50.5% • Of those: ClinInfDis 2010;50:1387-1396

  6. Death Rates in Persons Living With AIDS New York City 1999-2004 Age-Adjusted Mortality Rates per 10,000 PLWA PLWA CVD includes chronic ischemic heart disease, acute MI, hypertension related deaths Sackoff J et al. Ann Intern Med. 2006;145:397-406. 

  7. Overview • HIV infection and immune activation • Relevance to aging • Possible importance of CMV • Responses to antiretroviral therapy • Immunologic • Virologic • Implications • Age-related co-morbidities • Cardiovascular Disease • Osteoporosis • Malignancy

  8. Overview • HIV infection and immune activation • Relevance to aging • Possible importance of CMV • Responses to antiretroviral therapy • Immunologic • Virologic • Implications • Age-related co-morbidities • Cardiovascular Disease • Osteoporosis • Malignancy

  9. Immune Activation in HIV • HIV infection is associated with immune activation • In established infection, ≤50% of peripheral CD8+ T cells appear to be activated, compared with <10% in HIV-uninfected persons • Similar trends in the CD4+ T-cell population • Frequency of activated T cells predicts disease progression, independent of HIV-1 RNA • Antiretroviral therapy reduces HIV-associated T-cell activation, though often incompletely

  10. Model of Immunosenesence and Aging SLIDE to COME

  11. CMV Increases CD8+ Activation • Prospective trial of valganciclovir (VAL) in CMV seropositive HIV-1 infected persons on HAART • 100% with suppressed CMV DNA at 8 and 12 weeks • VAL arm (n=14) with significant (p=0.01) decrease in CD8+ cell activation • Decreased 4.1% (constituted 20% reduction) • hsCRP decreased significantly in VAL arm (p=0.014), however, no significant difference between arms • CMV and possibly other viruses appear to be determinant of CD8+ activation Hunt et al. CROI 2010, San Francisco. Abrstract 380

  12. Model of Immunosenesence and Aging SLIDE to COME

  13. Overview • HIV infection and immune activation • Relevance to aging • Possible importance of CMV • Responses to antiretroviral therapy • Immunologic • Virologic • Implications • Age-related co-morbidities • Cardiovascular Disease • Osteoporosis • Malignancy

  14. Higher Risk of Clinical Progression in Patients ≥50 Years of Age • Patients ≥50 years have higher risk of clinical progression but improved virologic response compared with younger patients • Prospective cohort study of 3015 treatment-naive patients initiating ART • Aged ≥ 50 years: n=401 • Aged < 50 years: n=2614 • Median follow-up: 31.5 months • At BL, older patients more likely to have • AIDS-defining event (P=.0001) • Lower CD4 T-cell count (P=.0002) • Higher HIV-1 RNA level (P=.0001) ADE, AIDS-defining event; BL, baseline; Grabar S. AIDS. 2004;18(15):2029-2038. HR, hazard ratio; yoa, years of age.

  15. Antiretroviral Tolerability Decreases With Age • Kaiser Permanente of Northern California chart review study of all members who initiated ART from 1995-2004 (N=5090) • ≥18 years of age • Starting ≥3 antiretrovirals in combination • Laboratory test results available for year before and year after ART initiation • Excluded patients with laboratory test result abnormality in year before ART • Analysis of patients who developed grade 2-4 abnormality while on ART • Median follow-up: 3.8 years TC, total cholesterol; LDL, low-density lipoprotein Silverberg MJ. Arch Intern Med. 2007;167(7):684-691.

  16. Older Patients More Likely to Achieve HIV-1 RNA <500 Copies/mL 1.3 1.2 1.07 1.15 1.15 1.1 1.03 1.0 0.97 0.97 HR (95% CI) 0.97 0.9 0.95 0.8 Age ≥50 yearsAge 40-49 years 0.7 0.6 Age + adherence Age + Charlson comorbidity Age All predictors Model: CI, confidence interval; HR, hazard ratio; yoa, years of age Silverberg MJ. Arch Intern Med. 2007;167(7):684-691. Kaiser Permanente study compared patients 40-49 yoa and ≥50 yoa to patients 18-39 yoa Patients >50 yoa more likely to achieve HIV-1 RNA <500 copies/mLvs patients 18-39 yoa, even when adjusting for comorbidities Adherence major advantage for older patients

  17. Immunologic Response Slower in Patients Aged 50 Years or Older • Monthly CD4 T-cell count increases significantly lower in patients ≥50 years of age aP<.0001 for <50 yoa vs ≥50 yoa in all subgroups. yoa, years of age Grabar S. AIDS. 2004;18(15):2029-2038.

  18. Overview • HIV infection and immune activation • Relevance to aging • Possible importance of CMV • Responses to antiretroviral therapy • Immunologic • Virologic • Implications • Age-related co-morbidities • Cardiovascular Disease • Osteoporosis • Malignancy

  19. Cardiovascular Disease • CVD is presently the #1 cause of death in the US and worldwide • An estimated 80.7 million (1 in 3) Americans have 1 or more types of CVD • Approximately 38 million of those patients are ≥ 60 years of age • CVD accounted for 36.3% of all deaths in the US as of 2004 Rosamond W, et al. Circulation. 2008;117(4):e25-e146.

  20. CVD Disease Mortality Trends for Males and Females United States: 1979-2005 Source: NCHS and NHLBI. Note:No comparability ratios were applied

  21. CVD Prevalence in adults > 20 Years by Age and Sex (NHANES: 2005-2006) These data include coronary heart disease, heart failure, stroke and hypertension Source: NCHS and NHLBI

  22. Age-adjusted Death Rates Selected Diagnoses in Women Source: NCHS and NHLBI.

  23. Prevalence of Cardiac Risk Factors at Baseline in the D:A:D Study • Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468) • 18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive 60 56.2 50 40 32.3 Percentage of Cohort With Risk Factor at Baseline 30 21.1 20 11.7 7.2 10 4.8 2.8 1.5 0 Family Historyof CHD PreviousHistory of CHD CurrentSmoking BMI> 30 mg/m2 HTN DiabetesMellitus ↑ TotalCholesterol ↑ TG Friis-Møller N, et al. AIDS. 2003;17:1179-1193.

  24. D:A:D: Risk Factors for CHD in an HIV-Infected Population Better Worse RR: 1.32 (1.23-1.41) Age per 5 yrs older RR: 2.13 (1.29-3.52) Male sex RR: 4.64 (3.22–6.69) Previous CVD RR: 2.92 (2.04-4.18) Smoking Family history RR: 1.40 (0.96-2.05) RR: 1.86 (1.31-2.65) Diabetes mellitus (yes vs no) RR: 1.30 (0.99-1.72) Hypertension (yes vs no) 0.1 0.5 1 5 10 Relative Rate of MI (95% CI) Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family hx CVD, smoking, previous CVD event, TC, HDL, HTN, DM. Friis-Møller, et al. N Engl J Med. 2007;326:1723-1735.

  25. Predicting MI Risk Using Framingham Equation National Cholesterol Education Program. Available at: http://hin.nhlbi.nih.gov/atpiii/calculator.asp. Accessed November 16, 2007.

  26. Framingham Predicted CHD Risk • High Risk (> 25% over 10 years or DM) • HIV+ men: 17% • HIV+ women: 12% • Persons with income <$10,000 were more than twice as likely to have moderate/high CHD risk • In CPCRA First Study, Blacks had greater risk for cardiovascular disease • Unadjusted HR = 3.83 (1.28-11.5) • HR (after adjustment) = 2.64 (1.04-6.67) Kaplan RC. ClinInfDis 2007; 45:1074-1081 Tedaldi EM. JAIDS 2008;47: 441-448.

  27. 126 patients had an MI during 36,199 PY Incidence of MI According to the Duration of Exposure to ART 8 7 6 5 4 3 2 1 0 D:A:D 2003: Use of ART Increases MI Risk Incidence per 1000 PY <1 1-2 2-3 3-4 >4 None Exposure (yr) No. of events 3 9 14 22 31 47 No. of PY 5714 4140 4801 5847 7220 8477 DAD Study Group. New Engl J Med. 2003;349(21):1993-2003.

  28. D:A:D 2007: ART Class and MI Risk 8.0 4.0 2.0 1.0 0.5 PI NNRTI Adjusted Relative Rate 0 <1 1 - 2 2 - 3 3 - 4 4 - 5 5 - 6 > 6 Exposure (Years) DAD Study Group. New Engl J Med. 2007;356(17):1723-1735.

  29. DAD 2009: PI and NNRTI Risk of MI Cumulative Exposure to Each Drug PIs NNRTIs 1.2 1.13 RR per year 95% CI 1 0.9 IDV NFV LPV/r SQV NVP EFV #PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 #MI: 298 197 150 221 228 221 Lundgren J, et al. 16th CROI; 2009; Montreal. Abstract 44LB.

  30. D:A:D 2009: NRTIs and Risk of MI • Overall 580 MIs in 33,308 patients (178,835 PY of observation) Recent Exposure* Cumulative Exposure 1.9 1.5 1.2 1 0.8 0.6 RR 95% CI ** ZDV ddI ddC d4T 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 #MI: 523 331 148 405 554 221 139 Recent use=current or within last 6 months. **Not shown (low number of patient currently on ddC) Lundgren J, et al. 16th CROI; 2009; Montreal. Abstract 44LB.

  31. D:A:D 2008: Recent ABC Use Is Associated With Increased Risk of MI Rates of MI for Recenta Use of ABC by Predicted 10-year CHD Risk Relative Rate of MI Associated With Recenta ABC Use 1.90 • No further adjustmentb • Adjusted also for: • Latest CD4 count • Latest VL • Latest lipids • Latest blood pressure • Diabetes • Fat loss/gain • Latest glucose 35 30 25 20 15 10 5 0 No recent ABC Recent ABC Overall Low Moderate High Not known 0.5 1 1.5 2 2.5 3 Adjusted Relative Rate (95% CI) Predicted 10-year CHD risk a. Still using or stopped within last 6 months. b. All data depicted also adjusted for demographic factors, calendar year, cohort, CV risk factors unlikely to be modified strongly by ART use, and cumulative exposure to other ARVs. D:A:D Study Group. Lancet. 2008;371:1417-1426.

  32. hsCRP and MI Risk in Healthy Men Relative Risk of MI <0.55 0.56 – 1.14 1.15 – 2.10 >2.11 C-Reactive Protein Concentration (mg/liter) Ridker et al. N Engl J Med 1997;336:973-979

  33. Adjusted for other biomarkers AND traditional CVD Risk Factors Adjusted Relative Risk of CV Events by Increase of 1 Quartile in Biomarker Marker RR(95% CI) hsCRP 1.5(1.1-2.1) SAA 1.1(0.8-1.6) sICAM-1 1.1(0.8-1.4) IL-6 0.8(0.6-1.1) Chol:HDL 1.4(1.1-1.9) Adjusted for other biomarkers Marker RR(95% CI) hsCRP 1.4(1.1-1.9) SAA 1.1(0.8-1.4) sICAM-1 1.1(0.9-1.4) IL-6 0.9(0.7-1.2) Chol:HDL 1.4(1.1-1.7) Ridker et al. N Engl J Med 2000;342:836-843

  34. Biomarker Levels in Untreated HIV-Infected and Uninfected Persons Baker et al. J InfDis 2010;201:285-292

  35. Virologic Suppression (VS) Continuous ART throughout follow-up SMART Trial Study Design HIV-1-infected patients with CD4+ cell count > 350 cells/mm3 Drug Conservation (DC) ART stopped/deferred until CD4+ < 250 cells/mm3 then episodic ART to increase CD4+to > 350 cells/mm3

  36. SMART: HIV Progression With Continuous HAART vs Interruption • CD4-guided drug conservation strategy associated with significantly greater disease progression or death compared with continuous viral suppression: RR: 2.5 (95% CI: 1.8-3.6; P < .001) Parameter No. of Patients With Events RR (95% CI) 1.5 Severe complications 114 1.4 CVD, liver, or renal deaths 31 1.5 Risk of Complications Nonfatal CVD events 63 1.4 Nonfatal hepatic events 14 2.5 Nonfatal renal events 7 0.1 Favors TI 1.0 Favors CT 10.0 El-Sadr W, et al. N Engl J Med. 2006;355:2283-2296.

  37. Baseline Biomarkers and All Cause Mortality Unadjusted Adjusted* * Adjusted for age, race, ART, HIV RNA level, CD4+ cell count, smoking, BMI, prior CVD, diabetes, antihypertensive and/or lipid lowering agent use, total/HDL cholesterol, Hepatitis B or C coinfection Kuller L et al. PLoS 2008;10:1496-150

  38. Levels of Biomarkers Associated with Cardiovascular Disease in SMART Adjusted Duprez ACC 2009

  39. Increased Levels of Circulating Endothelial Activation Markers in Patients With HIV • Circulating markers of inflammation and endothelial activation were significantly elevated in treatment-naïve HIV+ patients compared with healthy HIV- controls • Initiation of ART in HIV+ patients reduced or normalized the levels of the majority of these markers after 3 months, an effect that remained at 12 months *P<0.001, HIV+ patients vs HIV- controls; †P<0.001, HIV+ patients baseline vs 3 months ART; ‡P>0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15thCROI. 2008; abstract #953.

  40. hsCRP Levels and HAART P=0.0207 for trend hsCRP concentration (μg/mL) Henry K et al. AIDS 2004;18:2435-2437

  41. SMART Study: D Dimer • Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade Change in D-Dimer* (BL to 1 mo) P=0.0005 for trend 0.3 0.28 0.2 μg/mL 0.11 0.1 0.04 0 0 ≤400 401–10,000 10,000–50,000 >50,000 Month 1 HIV RNA (c/mL) *DC pts on ART at BL with HIV RNA ≤400 c/mL Kuller L, et al. PLoS 2008;10:1496-1508

  42. Change in Log IL-6 (pg/mL) and HDL (μmol/L) from Baseline to 1 Month* ∆ IL-6 0.4 0.4 P=0.0003 for trend ∆HDL 0.3 0.3 0.2 0.2 0.1 0.1 ∆ IL-6 (pg/mL) ∆ HDL (μmol/L) 0 0 -0.1 -0.1 -0.2 -0.2 P<0.0001 for trend -0.3 -0.3 ≤ 400 401-10,000 10,000-50,000 >50,000 -0.4 -0.4 Month 1 HIV RNA Level (copies/mL) * DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL SMART/INSIGHT: Duprez et al, CROI, 2009

  43. Increased Levels of Circulating Markers of Endothelial Activation in Patients With HIV • Circulating inflammatory markers were significantly elevated in treatment-naïve HIV+ patients compared with healthy HIV- controls • Initiation of antiretroviral therapy in HIV+ patients reduced levels of the majority of these markers after 3 months; effect remained at 12 months *P<0.001, HIV+ patients vs HIV- controls; †P<0.001, HIV+ patients baseline vs 3 months ART; ‡P>0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15thCROI. 2008; abstract #953.

  44. A5152s: VL Decrease Associated With Improved Endothelial Function HIV infection itself affected endothelial function Baseline FMD: 3.7% FMD improved during HAART No consistent correlations between changes in FMD and changes in any lipids or glycemic parameter Improvement in FMD significantly associated with decrease in VL at Week 24 No relationship with baseline VL 3.5 Week 4 Week 24 † 3.0 2.5 2.0 Median Change in FMD From Baseline, % 1.5 * * * 1.0 0.5 0 Overall LPV/NRTI EFV/NRTI EFV/LPV *P < .01 compared with baseline. †P < .01 compared with baseline and within group. Torriani F, et al. Lipodystrophy Workshop 2007. Abstract O-18. Torriani F, et al. IAS 2007. Abstract WEAB302.

  45. Abnormal Endothelial Function and hsCRP in HIV-infected Persons • Abnormal endothelial function is strong risk factor for cardiovascular disease (CVD) • Endothelial function impaired in virologically suppressed HIV-1 infected persons (3.5%) compared with HIV-uninfected controls (5.3%) • Higher hsCRP levels associated with impaired flow mediated dilation in HIV-infected persons on ART with suppressed HIV RNA viral loads (p=0.03) • Age more predictive of abnormal flow mediated dilation in HIV-uninfected controls (p=0.004) Hsue et a .lCROI 2010; San Fracisco. Abstract 708.

  46. Possible “Treatment” for Elevated Biomarkers • Aspirin • Angiotensin-converting enzyme inhibitors • Eicosapentaenoic acid • Dexamethasone • Anti-cytokine monoclonal antibodies • Statins

  47. Why Should Statins Affect Biomarker Levels and Should we Care? • Blocking HMG-CoAreductase reduces mevalonate, a precursor to geranylpyrophosphate and farnesylpyrophosphate, necessary to turn on IL-6 gene • IL-6 stimulatesrs CRP in human hepatocytes • Animal models have shown that statins decrease LPS induced IL-6, CRP, and TNF-α Diomede L et al. AteriosclerThrombVasc Biol. 2001;21:1327-1332 Kleemann R et al. Circulation 2003;108:1368-1374