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

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

5.  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: Clin Inf Dis 2010;50:1387-1396

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

7.  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.  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.  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. SLIDE to COME

11.  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. SLIDE to COME

13.  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.  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) OutcomeAdjusted HRP value Progression to ADE or death1.52.0035 Progression to new ADE1.50.0087 HIV-1 RNA <500 copies/mL1.23<.05 Grabar S. AIDS. 2004;18(15):2029-2038. HR, hazard ratio; yoa, years of age. ADE, AIDS-defining event; BL, baseline;

15.  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 Parameter % With Abnormality All patients18-39 years40-49 years≥50 yearsP value TC or LDL26.621.026.434.0.04 Glucose9.76.011.414.4<.001 Creatinine5.23.25.88.3NR Silverberg MJ. Arch Intern Med. 2007;167(7):684-691. TC, total cholesterol; LDL, low-density lipoprotein

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

17.  Monthly CD4 T-cell count increases significantly lower in patients ≥50 years of age Grabar S. AIDS. 2004;18(15):2029-2038. Mean CD4 T-Cell Count Increase/Month, cells/mm 3 Within First 6 Months of ART a After 6 Months of ART a Age <50 years Age ≥50 years Age <50 years Age ≥50 years BL HIV-1 RNA <5 log 10 copies/mL 17.314.111.19.8 BL HIV-1 RNA ≥5 log 10 copies/mL 42.936.917.915.6 a P<.0001 for <50 yoa vs ≥50 yoa in all subgroups. yoa, years of age

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

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

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

23. Friis-Møller N, et al. AIDS. 2003;17:1179-1193. Prevalence of Cardiac Risk Factors at Baseline in the D:A:D Study Family History of CHD Previous History of CHD Current Smoking BMI > 30 mg/m 2 HTNDiabetes Mellitus ↑ Total Cholesterol ↑ TG 0 10 20 30 40 50 60 Percentage of Cohort With Risk Factor at Baseline  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 11.7 4.8 7.2 2.8 1.5 56.2 32.3 21.1

24. D:A:D: Risk Factors for CHD in an HIV-Infected Population 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. Relative Rate of MI (95% CI) WorseBetter 0.10.51510 RR: 1.86 (1.31-2.65) Diabetes mellitus (yes vs no) RR: 1.30 (0.99-1.72) Hypertension (yes vs no) Family history Previous CVD Male sex Age per 5 yrs older Smoking RR: 1.40 (0.96-2.05) RR: 2.92 (2.04-4.18) RR: 2.13 (1.29-3.52) RR: 4.64 (3.22–6.69) RR: 1.32 (1.23-1.41) Friis-Møller, et al. N Engl J Med. 2007;326:1723-1735.

25. Risk Score Results Age505030505050505050 SexMFMMMMMMM Total cholesterol, mg/dl 280280280230 200280280280280 HDL cholesterol, mg/dL 444444444435444444 SmokerNoNoNoNoNoNoNoYesYes SBP, mm Hg 125125125125125125150125150 On antihypertensive meds NoNoNoNoNoNoNoNoNo Risk score 9%3%1%6%5% 11 % 22 % 27% 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.  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. Clin Inf Dis 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 ARTRR 95% CI P value Exposure to ART 1.261.12–1.41<.001 Age (per 5 years) 1.38 1.26 – 1.50 <.001 History of smoking 2.17 1.30 – 3.62.007 Previous history of CVD 5.813.51–9.72<.001 Male sex 1.99 1.04 – 3.79.04 DAD Study Group. New Engl J Med. 2003;349(21):1993-2003. None <11-22-33-4 >4 0 1 2 3 4 5 6 7 8 Incidence per 1000 PY Exposure (yr) No. of events No. of PY 3 5714 9 4140 14 4801 22 5847 31 7220 47 8477

28. DAD Study Group. New Engl J Med. 2007;356(17):1723-1735. 8.0 4.0 2.0 1.0 0.5 Adjusted Relative Rate Exposure (Years) 0<11 - 22 - 33 - 44 - 55 - 6> 6 PINNRTI

29. PIsNNRTIs 1.2 1.13 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 RR per year 95% CI Lundgren J, et al. 16 th CROI; 2009; Montreal. Abstract 44LB. Cumulative Exposure to Each Drug

30. 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 * Lundgren J, et al. 16 th CROI; 2009; Montreal. Abstract 44LB. Recent Exposure*Cumulative Exposure Overall 580 MIs in 33,308 patients (178,835 PY of observation) Recent use=current or within last 6 months. **Not shown (low number of patient currently on ddC)

31. No further adjustment b Adjusted also for: Latest CD4 count Latest VL Latest lipids Latest blood pressure Diabetes Fat loss/gain Latest glucose 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. Adjusted Relative Rate (95% CI) Relative Rate of MI Associated With Recent a ABC Use 1.90 0.5 1 1.5 2 2.5 3 D:A:D Study Group. Lancet. 2008;371:1417-1426. Predicted 10-year CHD risk Recent ABC No recent ABC 35 30 25 20 15 10 5 0 OverallLowModerateHighNot known Rates of MI for Recent a Use of ABC by Predicted 10-year CHD Risk

32. C-Reactive Protein Concentration (mg/liter) <0.550.56 – 1.141.15 – 2.10 >2.11 Relative Risk of MI Ridker et al. N Engl J Med 1997;336:973-979

33. 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) Adjusted for other biomarkers AND traditional CVD Risk Factors 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) Ridker et al. N Engl J Med 2000;342:836-843

34. BiomarkerHIV+ Group N=32 Median (IQR) HIV- Group N=29 Median (IQR) P Value hsCRP μg/mL1.94 (0.82-5.84)1.46 (0.68-5.04)0.49 IL-6 pg/mL1.79 (1.32-5.35)1.26(0.72-2.14)0.01 sICAM-1 ng/mL312(251-488)225(168-279)<0.01 D-dimer μg/mL0.39(0.19-0.67)0.19(0.13-0.38)0.02 Baker et al. J Inf Dis 2010;201:285-292

35. Virologic Suppression (VS) Continuous ART throughout follow-up Drug Conservation (DC) ART stopped/deferred until CD4+ 350 cells/mm 3 HIV-1-infected patients with CD4+ cell count > 350 cells/mm 3

36. No. of Patients With EventsParameterRR (95% CI) Severe complications114 1.5 CVD, liver, or renal deaths Nonfatal CVD events 31 63 1.4 1.5 Nonfatal hepatic events Nonfatal renal events 14 7 1.4 2.5 1.010.00.1Favors TIFavors CT Risk of Complications 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) El-Sadr W, et al. N Engl J Med. 2006;355:2283-2296.

37. Kuller L et al. PLoS 2008;10:1496-150 BiomarkerOR(4 th /1 st quartile) P-valueOR(4 th /1 st quartile) P- value Hs-CRP2.00.053.10.02 IL-68.3<0.000112.4<0.0001 Amyloid A2.20.073.10.05 D-dimer12.4<0.000141.2<0.0001 UnadjustedAdjusted* ‡ * 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

38. Duprez ACC 2009 BiomarkerOR(95% CI)P-value Hs-CRP2.1 (1.3-3.5)0.005 IL-63.3 (1.9-6.0)<0.0001 D-Dimer2.5 (1.4-4.3)0.002 Adjusted ‡

39.  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 HIV- Controls HIV+ Patients BaselineBaseline 3 months of ART sICAM-1* ‡ 144 ±12 ng/mL 296 ±24 ng/mL 248 ±12ng/mL hsCRP* 6665 ±2063 ng/mL 28,060 ±5530 ng/mL 14,708 ±2358 ng/mL sVCAM-1 † 876 ±39 ng/mL 957 ±40 ng/mL 766 ±33 ng/mL E-selectin † 15.8 ±1.2 ng/mL 17.9 ±1.1 ng/mL 15.1 ±0.8 ng/mL *P 0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15th CROI. 2008; abstract #953.

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

41.  Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade *DC pts on ART at BL with HIV RNA ≤400 c/mL μg/mL ≤400401– 10,000 10,000– 50,000 >50,000 0 0.1 0.2 0.3 0 0.04 0.11 0.28 Month 1 HIV RNA (c/mL) Change in D-Dimer* (BL to 1 mo) P=0.0005 for trend Kuller L, et al. PLoS 2008;10:1496-1508

42. ≤ 400401-10,00010,000-50,000>50,000 Month 1 HIV RNA Level (copies/mL) ∆ IL-6 (pg/mL) P<0.0001 for trend ∆ HDL (μmol/L) * DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL ∆ IL-6 ∆ HDL P=0.0003 for trend SMART/INSIGHT: Duprez et al, CROI, 2009 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4

43.  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 HIV- ControlsHIV+ Patients Baseline 3 months of ART sICAM-1* ‡ 144 ±12 ng/mL296 ±24 ng/mL248 ±12ng/mL hsCRP* 6665 ±2063 ng/mL28,060 ±5530 ng/mL14,708 ±2358 ng/mL sVCAM-1 † 876 ±39 ng/mL957 ±40 ng/mL766 ±33 ng/mL E-selectin † 15.8 ±1.2 ng/mL17.9 ±1.1 ng/mL15.1 ±0.8 ng/mL *P 0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15th CROI. 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 Median Change in FMD From Baseline, % LPV/NRTIEFV/NRTIEFV/LPV 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Overall Week 4Week 24 * * * † *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 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.  Aspirin  Angiotensin-converting enzyme inhibitors  Eicosapentaenoic acid  Dexamethasone  Anti-cytokine monoclonal antibodies  Statins

47.  Blocking HMG-CoA reductase 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. Aterioscler Thromb Vasc Biol. 2001;21:1327-1332 Kleemann R et al. Circulation 2003;108:1368-1374

53.  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

54. Multiple studies have found increased prevalence of osteoporosis and osteopenia in HIV-infected persons compared with uninfected persons Meta-analytical review of studies – 67% HIV infected persons had reduced BMD (OR 6.4) – 15% HIV+ had osteoporosis (OR 3.7) Brown et al AIDS 2006;20:2165-2174

55. Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502. WomenMen Fracture Prevalence Higher in HIV Fracture Prevalence/100 Persons 0.5 1.0 1.5 2.0 2.5 3.0 0 HIV Non-HIV P=0.002 P=0.01 P=0.53 P=0.01 AnyVertebralHipWrist Fracture Prevalence/100 Persons 0.5 1.0 1.5 2.0 2.5 3.0 0 HIV Non-HIV P<0.0001 P=0.001 AnyVertebralHipWrist Population: 8,525 HIV+ and 2,208792 HIV- Patients with fracture: 245 HIV+ and 39,073 HIV- Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV-

56. Effects of HIV on Bone Metabolism  HIV-1 p55 gag and gp120 ◦ Significantly decrease calcium deposition in vitro 1 ◦ Reduce RUNX-2 activity in vitro 1  gp120 increases PPARγ activity 1  gp120 (100 ng/ml) induces RANKL 2 1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12):1521-1529. 2. Fakruddin JM et al. J Biol Chem. 2003;278:48251-48258. RUNX-2 (Runt-related transcription factor-s) promotes osteoblast differentiation. PPARγ (Peroxisome proliferator-activated receptor gamma) promotes adipogenesis. RANKL (Receptor Activator for Nuclear Factor κ B Ligand), activates osteoclasts.

57. Changes in Hip Bone Mineral Density with Antiretroviral Therapy Intermittent (Fracture 0.03/100 PY) Continuous (Fracture 0.13/100 PY) n = 109 86 51 9 n = 95 75 47 15 Est. diff.: 1.3 1.7 1.0 2.5 P values:.002.005.27.21 Gallant et al. JAMA 2004, 292:191.Grund B et al. ICAAC/IDSA 2008. Abstract 2312a. d4T + 3TC + EFV TDF + 3TC + EFV n=301 267 246 226 205 185 181 n=299 261 234 221 209 193 185 -4 -3 -2 0 1 0134 Years Change From Baseline (%) 2 Gilead 903 Study SMART Study -8 -6 -2 0 4 8 2 6 Baseline24487296120144 Weeks P=0.06 -4 Change From Baseline (%)

58. Association of Osteoporosis with Antiretroviral Therapy Brown TT et al. AIDS. 2006, 22:2168. Antiretroviral Therapy OverallProtease Inhibitor Therapy Odds ratio0.01100 Study Amiel (2004) Bruera (2003) Garcia (2001) Knobel (2001) Knishi (2005) Mededdu (2004) Vescini (2003) Overall (95%CI) Odds ratio (95%CI) 2.41 (0.77, 7.58) 4.81 (0.60, 38.74) 1.60 (0.13, 19.84) 2.68 (0.70, 10.33) 0.84 (0.03, 22.43) 11.00 (0.65, 187.76) 0.54 (0.05, 5.68) 2.38 (1.20, 4.75) Odds ratio (95%CI) 0.61 (0.21, 1.72) 11.09 (0.57, 217.66) 1.18 (0.37, 3.78) 0.71 (0.11, 4.51) 1.57 (0.05, 43.79) 1.97 (0.47, 8.27) 2.63 (1.13, 7.03) 1.89 (0.23, 15.81) 3.25 (2.08, 9.83) 1.83 (0.35, 9.62) 1.24 (0.34, 4.52) 0.77 (0.15, 2.34) 1.57 (1.05, 2.34) Study Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Mededdu (2004) Mondy (2003) Nolan (2001) Tebas (2000) Vescini (2003) Yiu (2005) Overall (95%CI) Caveat: Few studies adjusted for age or duration of infection

59. 25-OH Vitamin D Deficiency Prevalent in HIV-Infection 1.Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14. 2.Seminari E et al. HIV Med. 2005;6:145-150. 3.Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):537-539. 47% Boston outpatient HIV clinic (n=57) 1 – Low Vitamin D intake in 31% < 50 years and 76% 51-70 years – Low calcium intake in in 37% < 50 years and 71% 51-70 years 81% Italian HIV treatment-experienced patients (n=48) 2 86% in Spanish cohort of men (n=30) 3 – Mean 25,OH Vitamin D level 14.3 ng/ml in healthy controls vs.11.4 ng/ml (p=0.044)

60. Inflammatory markerQ1Q2Q3Q4 CRP13.513.716.517.4 IL-614.215.613.017.5 TNF  12.515.114.620.8 † IL-2sR10.913.815.925.4 § IL-6sR12.013.617.622.3 ‡ § TNF sRI14.010.514.826.7 ‡ § TNF sRII8.615.917.922.3 Cauley JA et al. J Bone Miner Res. 2007;22:1091. Inflammatory Biomarkers Associated With Bone Fracture † P<.05 from trend test. ‡ P<.01 from trend test. § P<.001 from trend test. Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory

61. Cauley JA et al. J Bone Miner Res. 2007;22:1092. Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers* Years 0 4 8 12 16 20 % With Non-spine Fracture 081234657 2 6 10 14 18 2+ 0 or 1 P = 0.0093 (log rank test) *CRP, IL-6, TNFα

62.  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

63. PYFU, person-years of follow-up Monforte A. AIDS. 2008;22(16):2143-2153. ADM, AIDS-defining malignancies (n=112) nADM, non-AIDS-defining malignancies (n=193) Event Rate 1,000 PYFU Age Group <3030-3435-3940-4445-4950-5455-5960-6465-69 0 2 20 18 16 14 12 10 8 6 4 ADM, n=112 nADM, n=193

64.  Retrospective database analysis of 19,280 HIV-infected patients; 202,313 HIV-uninfected patients Silverberg M, et al. CROI 2010. Abstract 28. Table reproduced with permission. Adjusted HR*HIV Infected CD4+ Cell Count, cells/mm 3 < 200201-499≥ 500P Value Any infection related12.8 † 5.9 † 3.2 † <.001 Anal164.2 † 83.1 † 34.2 † <.001 Hodgkin’s lymphoma55.0 † 11.0 † 11.6 † <.001 Oral/pharyngeal3.1 † 1.9 ‡ 0.8.030 Any infection unrelated1.8 † 1.21.1.002 Lung2.1 ‡ 1.01.2.083 Colorectal2.2 ‡ 1.00.9.050 *Adjusted for age, sex, smoking, overweight, alcohol/drug abuse, viral hepatitis; reference = uninfected cohort. † P <.001 relative to uninfected. ‡ P <.05 relative to uninfected.

65.  Temporal trends in US cohort - incidence of anal cancer (/100,000 PYs) ◦ 19 (1992-95), 48.3 (1996-99), 78.2 (2000-2003)  Impact of ART on risk of malignant transformation ◦ ART was not associated with altered risk of cytological progression or regression  Oral HPV infection in HIV may enhance smoking induced risk of oropharyngeal cancer  Anal HPV infection may increase risk of HIV transmission Patel et al, Ann Intern Med 2008; Paramsothy et al, Obstet and Gynecol 2009; Chin-Hong et al, AIDS 2009; Gillison, Curr Opin Oncol 2009.

66.  Risk of AIDS-related cancers decreased due to benefit of ART ◦ Except HPV-induced genital cancers  HIV-infected population is aging ◦ Risk of fatal non-AIDS-defining cancers increases 47% per 5 year older age (i.e. >2-fold increase over a 10 year period Secondary cancers - may further increase the 47% estimate 1  Immunodeficiency  Chronic pro-oncogenic viral infections  e.g. HPV, EBV, viral hepatitis  Other cancers (and associated therapy hereof)  e.g. bladder cancer after prostate cancer 2 ; leukemia after NHL 3  ART ? 1 D:A:D study group, AIDS 2008 2 Shirodkar et al, Curr Opin Urol 2009 3 Mudie et al, J Clin Oncol 2006

67. For 20 / 28 cancers examined there was significantly increased incidence in both groups – strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung 2.72.2 Leukaemia 3.22.4 Kidney 1.56.8 Oesophagus 1.63.1 Stomach 1.92.0 Meta-analysis: 444,172 people with HIV, 31,977 transplant patients Grulich et al, Lancet 2007.