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Long-Term Consequences of Immune Activation and ART

Long-Term Consequences of Immune Activation and ART. William G Powderly, MD, Moderator Sally L. Hodder, MD Jens Lundgren, MD. Faculty Disclosures. William G. Powderly, MD Consulting fees : Boehringer Ingelheim Other : Member of DSMB : Tibotec Sally L. Hodder, MD

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Long-Term Consequences of Immune Activation and ART

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  1. Long-Term Consequences of Immune Activation and ART William G Powderly, MD, Moderator Sally L. Hodder, MD Jens Lundgren, MD

  2. Faculty Disclosures William G. Powderly, MD Consulting fees: Boehringer Ingelheim Other: Member of DSMB: Tibotec Sally L. Hodder, MD Consulting fees: Gilead Sciences Jens Lundgren, MD Consulting fees, contracted research: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, Tibotec

  3. Long-Term Consequences of Immune Activation and ART William G. Powderly, MD Dean of Medicine Head, University College Dublin School of Medicine and Medical Science Dublin, Ireland

  4. Immune Activation in HIV • Chronic untreated 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, although often incompletely • Markers of inflammation elevated in untreated HIV infection • Only partially reversed with effective ART

  5. Mechanism of Immune Activation • Partially a direct effect of HIV • Decrease in markers of inflammation and immune activation during ART • Likely to be indirect effects also • Most activated T cells are not HIV specific • Markers of inflammation do not return to normal with sustained effective ART suppression • Other putative mechanisms of persistent immune activation have been postulated • Microbial translocation • Irreversible damage to lymphoid infrastructure, • Irreversible thymic dysfunction • Increased prevalence of coinfections (eg, CMV) • Persistent low-level HIV replication

  6. Significance of Immune Activation • Constant T-cell proliferation and death in uncontrolled HIV may result in eventual immunologic exhaustion • Even with treatment, persistent immune activation may lead to immune senescence and premature aging of the immune system • Full immune recovery (with reversal of activation) may not be seen with effective ART, especially in patients with low CD4+ T-cell count nadir (<200 cells/mm³) prior to treatment • Is there a relationship between persistent immune activation, immune senescence and diseases associated with aging?

  7. Long-Term Consequences of Immune Activation and ART Jens D. Lundgren, MD, DMSc Professor, Faculty of Health SciencesUniversity of Copenhagen Head, Centre for Viral Diseases/KMA, Rigshospitalet Head, Copenhagen HIV Programme, Denmark

  8. Discussion Questions Related to CVD What is the evidence that HIV infection is associated with an increased risk of cardiovascular disease? What are the possible causes of this increased risk? Is immune activation a possible cause?

  9. Principal factors affecting risk of CVD in HIV HIV + Traditional risk factors + + ART

  10. Risk of Major CVD Events* by Treatment Arm Relative hazard: 1.57 (1.00 – 2.46) p = 0.05 DC VS % With a Major CVD Event DC = Drug Conservation VS = Viral Suppression Years from randomization No. at risk DC 2752 1306 713 379 10 VS 2720 1292 696 377 10 * Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure SMART/CVD: Phillips et al, AVT 2008

  11. Change in Log IL-6 (pg/mL) and HDL Cholesterol Concentration (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

  12. Some PI: progressive risk with cumulative exposure Start ABC Stop ABC Time-Course for Association Between ARV Drug Exposure and Risk of MI MI risk

  13. Rates of MI For Recent* Use of Abacavir by Predicted 10-Year CHD Risk No recent abacavir Recent abacavir 35 30 25 20 15 10 5 0 Rate (per 1000 PY) Overall Low Moderate High Not known Predicted 10-year CHD risk * Recent = still using or stopped within last 6 months D:A:D study: Sabin et al, Lancet, 2008

  14. Long-Term Consequences of Immune Activation and ART Sally L. Hodder, MDProfessor of MedicineNew Jersey Medical SchoolUniversity of Medicine and Dentistry of New JerseyNewark, NJ

  15. Discussion Questions Are HIV-infected patients at a greater risk for bone disease? Is HIV- associated bone disease related to virus or to treatment?

  16. Bone Mineral Density in HIV-Infected Persons • 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

  17. Fracture Prevalence Higher in HIV Patients • 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- Women Men 3.0 3.0 P=0.002 P<0.0001 HIVNon-HIV HIVNon-HIV 2.5 2.5 2.0 2.0 Fracture Prevalence/100 Persons Fracture Prevalence/100 Persons P=0.01 P=0.001 1.5 1.5 P=0.01 P<0.0001 1.0 1.0 P=0.001 P=0.53 0.5 0.5 0 0 Any Vertebral Hip Wrist Any Vertebral Hip Wrist Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502.

  18. Changes in Hip Bone Mineral Density with Antiretroviral Therapy d4T + 3TC + EFV TDF + 3TC + EFV Gilead 903 Study SMART Study Intermittent (Fracture 0.03/100 PY) 8 Continuous (Fracture 0.13/100 PY) 1 6 0 4 -1 2 Change From Baseline (%) -2 0 -3 -2 P=0.06 -4 -6 0 1 2 3 4 Years -8 Baseline 24 48 72 96 120 144 n = 109 86 51 9 n = 95 75 47 15 Weeks n=301 267 246 226 205 185 181 n=299 261 234 221 209 193 185 Est. diff.: 1.3 1.7 1.0 2.5P values: .002 .005 .27 .21 Gallant et al. JAMA 2004, 292:191. Grund B et al. ICAAC/IDSA 2008. Abstract 2312a.

  19. Association of Osteoporosis with Antiretroviral Therapy Antiretroviral Therapy Overall Protease Inhibitor Therapy 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) 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) 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) 0.01 Odds ratio 100 0.01 Odds ratio 100 Caveat: Few studies adjusted for age or duration of infection Brown TT et al. AIDS. 2006, 22:2168.

  20. Effects of HIV on Bone Metabolism HIV-1 p55 gag and gp120 Significantly decrease calcium deposition in vitro1 Reduce RUNX-2 activity in vitro1 gp120 increases PPARγ activity1 gp120 (100 ng/ml) induces RANKL2 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. 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.

  21. 25-OH Vitamin D Deficiency Prevalent in HIV-Infection • 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) • Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14. • Seminari E et al. HIV Med. 2005;6:145-150. • Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):537-539.

  22. Inflammatory Biomarkers Associated With Bone Fracture Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory † P<.05 from trend test. ‡ P<.01 from trend test. § P<.001 from trend test. Cauley JA et al. J Bone Miner Res. 2007;22:1091.

  23. Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers* *CRP, IL-6, TNFα 20 18 16 2+ 14 12 0 or 1 10 % With Non-spine Fracture 8 6 4 P = 0.0093 (log rank test) 2 0 0 1 2 3 4 5 6 7 8 Years Cauley JA et al. J Bone Miner Res. 2007;22:1092.

  24. Long-Term Consequences of Immune Activation and ART Jens D. Lundgren, MD, DMSc Professor, Faculty of Health SciencesUniversity of Copenhagen Head, Centre for Viral Diseases/KMA, Rigshospitalet Head, Copenhagen HIV Programme, Denmark

  25. Discussion Questions Are there important long-term CNS consequences of HIV in adequately treated patients? Is CNS penetration of antiviral drugs important?

  26. HIV-1 Infection and the CNS Mean Incidence HIV Dementia MACS Cohort 1990-1998 Mean Incidence HIV Dementia MACS Cohort 1990-1998 • HIV-Associated Neurocognitive Disorder • Asymptomatic neurocognitive impairment • Minor neurocognitive disorder • Dementia Number/1000 person years Antinori A et al. Neurology. 2007;69:1789-1799 Sacktor N et al. Neurology. 2001;56:257-260

  27. Does CNS Antiretroviral Agent Penetration Matter? N=31 (24 ART naïve) CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV 0.5 0.4 0.3 Proportion of Subjects With Detectable CSF Viral Load Proportion of Subjects With Detectable CSF Viral Load 0.2 0.1 0 ≤0.5(n=38) 1(n=128) ≥3.5(n=25) 1.5(n=100) 2(n=100) 2.5(n=63) 3(n=13) CPE Score CPE Score Letendre S et al. Arch Neurol. 2008;65(1):65-70.

  28. Does CSF HIV RNA Affect Neurocognitive Function? 1.0 0.5 Reduction in GDS at Follow-up 0.0 2=6.25 P=.01 -0.5 N=14 N=17 Not Suppressed Suppressed CSF HIV RNA Suppression at Follow-up Letendre S et al. Ann Neurol. 2004;56:419.

  29. ART Affects CNS Immune Activation Off Failure Success HIV– Blood CD8 Activation CSF CD8 Activation 100 100 80 80 60 60 % Bld CD8 CD38+DR+ 40 40 % CSFCD8 CD38+DR+ 20 20 0 0 Off Failure Success HIV– Off Failure Success HIV– Sinclair E et al. JAIDS. 2008;47:548.

  30. Long-Term Consequences of Immune Activation and ART Jens D. Lundgren, MD, DMSc Professor, Faculty of Health SciencesUniversity of Copenhagen Head, Centre for Viral Diseases/KMA, Rigshospitalet Head, Copenhagen HIV Programme, Denmark

  31. Discussion Question Related to Cancers Will we see more cancers in HIV infected patients in the next 10 years?

  32. AIDS and Non-AIDS Defining Cancers in Baltimore Cohort Long et al, AIDS 2008

  33. Incidence of non-AIDS defining cancers in HIV-infected and uninfected persons in VA Bedimo et al, JAIDS 2009.

  34. Why Will Incidence of Cancers Increase in the Next 10 Years • 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% estimate1 • Immunodeficiency • Chronic pro-oncogenic viral infections • e.g. HPV, EBV, viral hepatitis • Other cancers (and associated therapy hereof) • e.g. bladder cancer after prostate cancer2; leukemia after NHL3 • 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

  35. HIV and Risk of Non-AIDS Malignancies Meta-analysis: 444,172 people with HIV, 31,977 transplant patients 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 2.7 2.2 Leukaemia 3.2 2.4 Kidney 1.5 6.8 Oesophagus 1.6 3.1 Stomach 1.9 2.0 Grulich et al, Lancet 2007.

  36. HPV Cancers and HIV Transmission • 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.

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