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Inflammation biomarkers in HIV infection

Inflammation biomarkers in HIV infection. Laurence WEISS. Predictive biomarkers in HIV infection. Reflect The extent of immune deficiency The level of HIV replication and of HIV reservoir The level of chronic immune activation/inflammation

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Inflammation biomarkers in HIV infection

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  1. Inflammation biomarkers in HIV infection Laurence WEISS

  2. Predictive biomarkers in HIV infection Reflect The extent of immune deficiency The level of HIV replication and of HIV reservoir The level of chronic immune activation/inflammation The strength and quality of HIV-specific immune responses Type of biomarkers Virologic, immunologic, activation/inflammatory and genetic biomarkers (HLA, CCR5, KIR) Predictive biomarkers for HIV progression in untreated and/or treated patients Predictive biomarkers for the occurrence of co morbidities in patients with ART-mediated viral suppression

  3. Predictive biomarkers in HIV infection Reflect The extent of immune deficiency The level of HIV replication and of HIV reservoir The level of chronic immune activation/inflammation The strength and quality of HIV-specific immune responses Type of biomarkers Virologic, immunologic, activation/inflammatory and genetic biomarkers (HLA, CCR5, KIR) Surrogate markers for HIV progression in untreated and/or treated patients Surrogate markers for the occurrence of co morbidities in patients with ART-mediated viral suppression

  4. - Membrane expression of the activation markers HLA-DR (MHC class II), CD38, CD25, CD70 - Intranuclear expression of Ki-67 (cell cycle) T-cell activation markers in the chronic phase of HIV infection Healthydonor Survival > 18 M Survival < 6 M CD4 CD38 T-cell activation is associated with mortality CD8 HLA-DR Giorgi, JID 99 Leng et al, J.AIDS 2001 Hazenberg et al, AIDS 2003

  5. C-Reactive Protein IL-6 Haptoglobin a1-glycoprotein acid TISSUE TISSUE COAGULATION COAGULATION PROINFLAMMATORY CYTOKINE NETWORK PROINFLAMMATORY CYTOKINE NETWORK FACTOR FACTOR  D-dimer  D-dimer HIV Other viruses (CMV, HCV...) Bacterial products (LPS…) Innate immunity Mono/M,DC, NK cell activation Adaptative immunity • sCD14 • sCD163 • sCD14 • sCD163 T-cell activation T-cell activation INFLAMMATION • APP 0 1 2 3 4 5 6

  6. Inflammation Innate Immunity

  7. C-Reactive Protein IL-6 Haptoglobin a1-glycoprotein acid TISSUE TISSUE COAGULATION COAGULATION PROINFLAMMATORY CYTOKINE NETWORK PROINFLAMMATORY CYTOKINE NETWORK FACTOR FACTOR  D-dimer  D-dimer HIV Other viruses (CMV, HCV...) Bacterial products (LPS…) Innate immunity Mono/M,DC, NK cell activation Adaptative immunity • sCD14 • sCD163 • sCD14 • sCD163 • sCD14 • sCD163 … T-cell activation T-cell activation T-cell activation INFLAMMATION • APP 0 1 2 3 4 5 6

  8. Soluble activation biomarkers β2- microglobulin, neopterin hsCRP: acute phase protein IL-6, IL-1RA, sTNFR: Cytokines and CR of innate immunity D dimer: marker of procoagulant activity sCD14: acute phase protein, monocyte activation sCD163: secreted by activated monocytes/macrophages ICAM, VCAM: endothelialactivation/dysfunction IP-10: chimiokine produced in response to IFN Fahey, NEJM 1990, Kuller, PloS Med 2008, Sandler, JID 2011, Burdo, JID 2011

  9. Predictive biomarkers in primary HIV infection

  10. Immune activation set point during early HIV infection: predictive of subsequent CD4 T-cell changes independently of viral load CD8 T-cell activation set point 68 recently HIV-infected adults before ART proportion with CD4 > 350 CD38-MFI on CD8 T cells Time (weeks) Time to a CD4 T-cell count less than 350 cells/mm3 Deeks, Blood 2004

  11. The early level of double negative CD4-CD8- T cells predicts the level of T-cell activation at set point DN T cells produce anti-inflammatory cytokines R=-0.76 p=0.004 R=-0.60 p=0.035 •  DN T cells might play a role in the control of the harmful systemic immune activation Petitjean, Chevalier et al, AIDS 2012

  12. An innate immune setpoint ? IL-1RA sCD14 % CD38+HLA-DR+ CD8 T cells at M6 % CD38+HLA-DR+ CD8 T cells at M6 % CD38+HLA-DR+ CD8 T cells atM6 plasma sCD14 (ng/mL) plasma IL-1RA (log pg/mL) plasma IL-1RA at baseline (log pg/mL) log Th17/Treg ratio at baseline plasma sCD14 at baseline (ng/mL) Innate immune activation set point Baseline M6 Baseline M6 plasma 16S rDNA (copies/µL) Chronic HIV (untreated) Sepsis (S. aureus) Acute HIV baseline Acute HIV M6 n=27 n=25 n=20 n=10 Chevalier, Plos Path 2013

  13. Predictive biomarkers in untreated chronic infection

  14. T-cell activation, predictive marker of AIDS progression independent of VL Proportion of CD70+CD4+ T cells > median (—) < median (- - -) Giorgi, JAIDS 1998 Hatzenberg , AIDS 2003

  15. Relationship between T-cell activation and HIV reservoir • The proportion of HLA-DR+ CD38+/ CD8+ T cells before TI predicts the increase in total HIV-DNA levels between baseline and M12 of TI (ANRS 116 SALTO) (r= 0.552; p = 0.004) • Weiss, PlosOne 2010 • Positive relationship between total HIV-DNA and CD8 and CD4 T-cell activation at 12 months of TI See poster Weiss et alMOPDA0106

  16. Predictive values of soluble biomarkers in cohort studiesC Reactive Protein Level: associated with AIDS - free survival N= 513 patients randomly selected from the MACS population Median CD4: 532 (IQR 342;721) Median HIV-RNA: 18450 (IQR 5359; 63741) 62% AIDS event 2709 person-years of follow-up Lau, Arch Intern Med 2006

  17. Fibrinogen and CRP, independent predictors of mortality in the FRAM study • 922 HIV-infected participants > 85% on cART (past or present) • 70% with history of AIDS •  50% HIV-RNA BLD • 20% HCV+ • 5-year mortality risk Tien, JAIDS 2010

  18. Biomarker levels associated with progression in RCT SMART • All-cause mortality: higher for patients with CD4> 350 randomly assigned to CD4-guided interruption of ART (DC) than continuous ART (VS) • Most common causes of death: non AIDS-malignancy, CVD • Case control study (85 cases and 170 matched controls); a study to compare DC and VS participants for biomarker changes (249 DC and 250 VS) • Baseline IL-6, hsCRP and D-dimerassociated with all cause mortality • Higher BL IL-6, D-dimer and hsCRP: related to CVD • IL-6 and D-dimer↗ at 1 mo in the DC group. Increases related to HIV-RNA levels • BL or latest IL-6 or hsCRP: predictive of OI • Elevated pre-ART levels of hsCRP, IL-6 and D-dimer: strongly associated with early mortality after ART initiation Ledwaba, PlosOne 2012 • Other markers associated with disease progression (case control ACTG 384 and 5015) : sTNFR-1, sCD27 and sCD40L Kalayjian,JID 2010 KullerPlos Medicine 2008 Rodger JID 2008 DuprezPlosOne 2012 PHIDISA (South Africa trial)

  19. Predictive inflammatory biomarkers in HIV controllers IP10 and sCD163 levels predict subsequent CD4 counts Lambotte, IAS 2014, MoAA0102

  20. Predictive biomarkers in patients with chronic infection and ART-mediated viral suppression Residual immune activation and inflammation under ART

  21. Persistence of residual chronic T-cell activation in ART-treated patients n = 30 HIV+ with CV < 75 c/mL Hunt, JID, 2003 Hunt, JID 2008

  22. Despite long-term viral suppression, soluble inflammatory biomarkers remain higher in patients compared to the general population % Diff. from General Population (MESA) Neuhaus JID 2010

  23. Inflammation withongoing viral replication Inflammation under ART Inflammation HIV- controls MonocytespDCsInnate Immunity NK Adaptative immunity

  24. Plasma levels of sCD14: independent predictor of mortality in the SMART study • Nested case-control study in SMART • 74 deaths + 120 CV events + 100 AIDS events (20 NA) / N= 5472 • 2 controls/case • Most patients under ART with VL < 400 cp/mL • Baseline plasma sCD14, IFABP, LPS, EndoCAB SCD14: marker of monocyte activation (acute phase protein) not necessarily indicative of microbial translocation Sandler, JID 2011

  25. Can we improve prediction of mortality by adding inflammatory biomarkers? • Veterans Aging Cohort Study: 1 302 veterans under ART; 70% with VL <500 c/mL; 154 deaths • RI= age/CD4/VL • VACS index= RI + Hb/ FIB4 index age, transa, platelets /HCV/eGFR: better prediction of mortality than any biomarker or than RI (p< 0.001) • VACS+ inflammatory biomarkers (IL-6, D-dimer, sCD14) Justice CID 2012

  26. Cardio- Vascular Diseases Cognitive disorders CHRONIC VIRAL INFECTIONS (HIV) CANCER Inflammation Osteoporosis

  27. Cardiovascular comorbidities In HIV infection : Alteration in biomarkers known or potentially associated with CVD in non-HIV infected individuals HDL cholesterol depletion Chronic inflammation ( CRP,  IL-6,  sCD14) Endothelial activation/dysfunction ( VCAM, ICAM) Activation of coagulation ( D-dimer) Atherosclerotic plaque Only partially normalized during sucessfull ART

  28. Association of soluble CD163 with arterial inflammation Hypothesis: Arterial inflammation > HIV+ pts compared with non-HIVFRS-matched controls Correlated to mono/Mф activation (CD163) 81 participants. 27 HIV pts under ART (CD4 nadir  100) FDG-PET (activated Mф : high metabolic rate) FDG uptake Lack of association between aortic FDG uptake and CRP or D-dimer in the HIV+ population Subramanian JAMA 2012

  29. Soluble markers of inflammation & coagulation, but not T-Cell activation, predict non-AIDS defining events during suppressive ART Case-control study of ALLRT subjects (ACTG studies) (ART-naïve at BL and ART-suppressed during FU) Cases : non-AIDS death, MI, stroke, non-AIDS cancer, or serious non-AIDS bacterial infection Controls (2 - 3/case) Greater CD4 change at yr 1 associated with a decreased risk for non-AIDS event (OR per 100 cells increase= 0.81, p= 0.007) High T-cell activation: not consistently associated with a non-AIDS-related event Higher IL-6,sCD14, sTNFR-I, sTNFR-II, and D-dimer prior to ART independently associated with non AIDS events Tenorio CROI 2013

  30. Case-control study of ALLRT subjects (ACTG studies) (ART-naïve at BL and ART-suppressed during FU) Cases : non-accidental non-AIDS death, MI, stroke, non-AIDS cancer, or serious non-AIDS bacterial infection Controls (2 - 3/case) Greater CD4 change at yr 1 associated with a decreased risk of non-AIDS event (OR per 100 cells increase= 0.81, p= 0.007) High T-cell activation: not consistently associated with a non-AIDS-related event Higher IL-6,sCD14, sTNFR-I, sTNFR-II, and D-dimer prior to ART independently associated with non AIDS event Soluble markers of inflammation & coagulation, but not T-Cell activation, predict non-AIDS defining events during suppressive ART Tenorio CROI 2013

  31. Persistent • Inflammation • under ART • CRP, IL-6, IL-1RA, sCD14, sTNFR • D-dimer • Fg Suboptimal CD4 T-cell gains Immune senescence Comorbidities (Accelerated atherosclerosis, arterial inflammation, cognitive disorders, chronic renal disease, osteoporosis: « Inflam-Aging » , cancers) ↗ Risk of mortality

  32. Summary Levels of immune activation (T-cell activation and inflammation) predict HIV disease progression in untreated patients with primary and chronic infection Soluble biomarkers of inflammation and coagulation, but not T-cell activation, predict non-AIDS defining events during suppressive ART Unresolved issues Value of these biomarkers to improve CV risk prediction in the HIV-infected population ? Significance: just an association or role in pathogenesis ? Help to identify cellular pathways important in the pathogenesis of HIV disease Interventions that target these pathways (e.g. IL-6) and/or the mechanisms involved in low levels of chronic activation/inflammation (e. g. ongoing low-level viral replication, MT, coinfections..) are warranted (or already in progress) with the ultimate goal to decrease the incidence of non-AIDS related morbidity in HIV-infected patients on virally suppressive ART

  33. Remerciements Hôpital Européen G. Pompidou Christophe Piketty Maria Manea Erika Bourzam Hôpital Saint-Antoine Pierre-Marie Girard Pauline Campa Nelly Desplanques Hôpital Tenon Laurence Slama Gilles Pialoux INSERM U 1018 Laurence Meyer Christiane Deveau FerielTibaoui Mathieu Chevalier Gaël Petitjean Céline Didier Daniel Scott-Algara Françoise Barré-Sinoussi CHU Carémeau Nîmes Jean-Philippe Lavigne Catherine Dunyach …and all the physicians that included patients EA 3620 Christine Rouzioux U943 Dominique Costagliola Lambert Assoumou the ANRS 116 SALTO study group All the patients included in the studies

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