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Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection

Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection. Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division. Treating Immune Activation in HIV. What have we learned from recent unsuccessful attempts?

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Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection

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  1. Interventions to Reduce Inflammationand Immune Activationin Treated HIV Infection Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division

  2. Treating Immune Activation in HIV • What have we learned from recent unsuccessful attempts? • Mechanistic pathways of HIV pathogenesis inform therapeutic interventions. • Highlight ongoing and recently reported studies of novel interventions. • Importance of studying ART-suppressed patients • A way forward

  3. What have we learned from recent unsuccessful attempts to decrease immune activation?

  4. IL-2 Increases CD4 Counts in Treated Patients IL-2 also decreases HLA-DR and CD38 expression (Kovacs, NEJM, 1995) Abrams et al, NEJM, 2009

  5. However, IL-2 Had No Effect on AIDS/Death P=0.47 P=0.55 Abrams et al, NEJM, 2009

  6. Why Didn’t IL-2 Work? Suppression of Healthy T Cell Responses Preferential Expansion of Tregs Bad for Health IL-2 Increased CD4 Count Good for Health

  7. Maraviroc Intensification Increases CD8 Activation Compared to Placebo Hunt, CROI, 2011, Abstract 153LB

  8. >2-fold Increase in Plasma CCR5 Ligand Levels During Maraviroc Intensification • Due to prevention of ligand-receptor complex internalization by CCR5+ cells (Lin/Corbeau, AIDS, 2007; Nakata, Antiviral Threrapy, 2010) • RANTES/MIP-1a may activate monocytes/macrophages and neutrophils via CCR1

  9. What Have We Learned? • Immune system is complicated! • Multiple parallel and competing pathways, feedback loops • Primary effects assessed in vitro may fail to capture important competing secondary effects in vivo • Need for carefully designed placebo-controlled trials, follow up studies to elucidate these mechanisms • May need to improve more than surrogate inflammatory markers to advance to clinical endpoint trials (i.e., FMD, BMD, etc).

  10. What specific mechanisms should we intervene upon?

  11. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  12. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  13. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  14. Anti-LPS antibodies have no effect on CD4 recovery: CORAL HIBC= hyperimmune bovine colostrum Enriched in anti-LPS antibodies Raltegravir HIBC + n=18 placebo HIBC + n=18 HIV+ On cART CD4<350 cells/ul ∆CD4<50 past 12 months Raltegravir placebo + n=18 placebo placebo + RESULTS No effect on CD4 recovery No effect on LPS, sCD14, T cell activation n=18 Slide courtesy of Sharon Lewin Bykawaga et al, J Infect Dis 2011 (in press)

  15. Microbial Translocation:Cause or Consequence of Immune Activation in Treated HIV Infection? • Observational studies linking MT to immune activation cannot prove causality • Causality can only be formally addressed in clinical trials • DC/Macrophage activation can cause IDO induction, ↓Th17, and microbial translocation • Ongoing/Planned studies assessing blocking microbial translocation directly • Rifaximin(ACTG) • Sevalamer (ACTG)

  16. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  17. Chloroquine Might Reduce CD8 Activationin Untreated HIV+ Patients Chloroquine Placebo • No apparent effect on plasma HIV RNA Levels (though some missing data) • Possible early decrease in plasma LPS • Probable mechanism: TLR inhibition (3,4,7,8,9) Murray, JV, 2010

  18. Hydroxychloroquine Did Not Reduce CD8 Activation in Untreated HIV+ Patients Viral Load %CD38+HLA-DR+ CD8s Plasma HIV RNA Level (log10 copies/ml) Why did viral load increase with HCQ? And why didn’t CD8 activation increase with the increase in VL? Paton, IAS 2011, MOPE269

  19. Impact of Innate Immune ResponseUntreated HIV Disease IL-6, TNFα↑ TF expression, D-dimer ↑ T cell turnover/exhaustion ↑ LN fibrosis ↑ Direct Antiviral Effects Adjuvant to HIV-specific T cells The Bad: Immune Activation ↑ The Good: HIV replication ↓ Immune Activation ↓

  20. Impact of Innate Immune ResponseDuring ART-mediated VL Suppression Antiviral Effects Irrelevant IL-6, TNFα↑ TF expression, D-dimer ↑ T cell turnover/exhaustion LN fibrosis The Good: None VL already suppressed by drugs The Bad Immune Activation ↑

  21. HCQ Decreases Immune Activation in ART-suppressed Immunologic Non-responders %CD38+ Memory CD8s %CD69+ CD14+ Monocytes Piconi, Blood, 2011

  22. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  23. Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation in HIV+ Patients with CD4<350 despite ART -4.4% HIV- Median • Cytopenias may limit long-term usefulness. • Need new, safer CMV agents! Hunt et al, JID, 2011

  24. HIV-Mediated Immune Activation and Aging HIV-1 Infection Immunodeficiency TLR 7,8 Nef, gp120 Bacterial Translocation Viral Reactivation (eg, CMV) Innate Immune Activation (MØ/DC) Cytokine Secretion (eg, IL-6, TNFL) Increased Cell Turnover and Lymphoid Fibrosis Increased TF Expression and clotting Immune Exhaustion CAD/Stroke, Thrombosis “Inflam-Aging” (eg, atherosclerosis, osteoporosis) Malignancy, Infections Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

  25. Atorvostatin Decreases T Cell Activation in Untreated HIV Infection • 24 untreated patients, X-over design • Significant reduction in HLA-DR on CD8s during atorvostatin Tx • No effect on plasma HIV RNA levels • Studies ongoing in ART-suppressed patients Atorvostatin 80mg Placebo Ganesan, J Infect Dis, 2011

  26. COX-2 Inhibition Decreases T Cell Activation in Untreated HIV Infection • 27 untreated patients, 12 weeks celecoxib vs. placebo. • Significant reduction in CD38 on CD8s during celecoxib Tx • No effect on plasma HIV RNA levels • CAD toxicity a potential problem with celecoxib • ASA? Mesalamine? CD38 Molecules/cell Celecoxib Placebo Pettersen, JV, 2011

  27. Other Strategies to block Monocyte/Macrophage Activation? • Combined CCR5/CCR2 blockade? • CCR5 inhibition increased immune activation, likely indirectly through MØ activation • CCR2 (MCP-1 receptor) blockade might overcome this effect? • IDO inhibitors? • Prevent proliferative defects and allow for restoration of Th17 cells • Might interrupt vicious circle of microbial translocation and innate immune activation

  28. Immunosuppressive Therapies • TNFα inhibitors IL-6 inhibitors • CTLA-4 analogs IL-23/IL-12 inhibitors • Steroids Cyclosporine • Methotrexate Decreased Immune Activation Suppression of Healthy Immune Reponses The Good The Bad

  29. A Way Forward… • Target proximal causes of monocyte activation • Small pilot trials to establish proof of principal • “Immunologic Non-Responders” have higher immune activation and are at highest risk for disease • Studying treated patients allows cleaner biologic inferences • Need to thoroughly evaluate mechanistic pathways in vivo • Advance promising agents to mid-range trials with surrogate markers of end-organ disease • Liver, renal, bone (BMD), cardiovascular (FMD) • Advance promising/safe/scalable interventions to clinical endpoint trials

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