CROI Update: What's New with HIV Associated Immune Activation

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Maile A. Karris, MD, of the UC San Diego AntiViral Research Center, presents "CROI Update: What's New with HIV Associated Immune Activation"

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CROI Update: What's New with HIV Associated Immune Activation

  1. 1. The UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.AIDS CLINICAL ROUNDS
  2. 2. Maile Karris, MDCheck out Sharon Lewin’s CROI 2013 webcast “ART andInflammation: Implications for the Approach to Care in 2013”Original presentation:Tuesday March 5Update from CROI 2013: HIV andImmune Activation
  3. 3. What we will cover today HIV Immune ActivationWhy does it matter?Can we do anything about it?What about ART choices?
  4. 4. HIV Immune Activation? HIV is characterized not only by immunodeficiencybut also by generalized persistent immune activation Adaptive immunity (T cells, B cells) Innate immunity (APCs, NKs) Coagulation cascade
  5. 5. Why does it matter? HIV infected persons experience more non-AIDSassociated events than HIV negative peers Even after adjustments for age,ART exposure and traditionalrisk factors
  6. 6.  The main contributor to this observed increase riskof non-AIDS events is thought to be persistentimmune activation
  7. 7. Soluble Markers of Inflammation & Coagulation,but not T-Cell Activation, Predict Non-AIDS-Defining Events During Suppressive ARTTenorioA, Zheng E, Bosch R, Deeks S, Rodriguez B, Krishnan S, Hunt P,Wilson C, Leerman M,LandayA andACTGDefine the associations between IA with NAE- accounting for ART and traditional RF Case-control study of ALLRT cohort ART naïve + HIV-1 RNA < 400 c/mL at week 48 ofART+ Maintained HIV RNA < 400 c/mL 143 Cases and 315 Controls Evaluated multiple markers of IA T cell, and soluble markers 790
  8. 8.  Higher IL-6, sCD14, sTNFr-I, sRNFR-II, and D-dimer wereassociated with non-AIDS related morbidity or death Associations were present prior to ART and persisted despiteART Independent of traditional risk factors Controls had higher median CD4+ T cell change one year onART than cases A greater CD4+T cell change at one year was associated withdecreased risk for non-AIDS related outcomeAssociation of biomarkers and odds of SNAEBASELINE ONE-YEAR PRE-EVENT
  9. 9. Combined Effect of IL-6 and D-dimer on therisk of Serious Non-AIDS ConditionsGrund B, Baker J, Deeks S,Wolfson J,Wentworth D, Cozzi-Lepri A, Cohen C, Phillips A,Lundgren J, Neaton JEstimate the joint associations of IL-6 and D-dimer with the risk of composite outcome ofSNA/death in treated suppressed pts The predictive utility of using IL-6 and/or D-dimeras a markers for future candidate drugs Data from ESPRIT, SILCAAT, SMARTSESSION 10 ORAL ABSTRACTS #60
  10. 10.  206 persons experienced SNA/death 36% cancer 26% CVD 8% hepatic 3% renal 27% death/ot
  11. 11.  The IL-6 & d-dimer score could be used tocompare drugs with different mechanisms ofaction (targeting IL-6, d-dimer, or both) for theirpotential to reduce SNA/death
  12. 12. Monocyte Activation but not T cell ActivationPredicts Progession of Coronary Artery Calciumin a Contemporary HIV Cohort (SUN)Baker JIdentify cellular phenotypes reflecting IA thatpredict accelerated coronary atherosclerosis SUN study – prospective observational cohortNaïve to ART or solely exposed to combination ART Measured changes in CAC scores ImmunophenotypedT cells and monocytesSESSION 10 ORAL ABSTRACTS #66LB
  13. 13.  Short time progression in Coronary atherosclerosis waspredicted by higher frequence of CD16+ monocytes No associations present between CD4 or CD8T ellphenotypes or immune depletion (total CD4T cell count) Suggest ongoing innate IA may be a proximal mechanism andsubsequently possible therapeutic target in the pathogenesisof HIV-related CAD
  14. 14. The Impact of Age on the Prognostic Capacity ofCD8+ T-cell Activation during Suppressive ARTLok J, Hunt P, Collier A, Benson C,Witt M, LuqueA, Deeks S, Bosh R.Evaluate the impact of age, CD4 and CD8T-cellactivation on AIDS and NAE duringsuppressive ART 1025ART naïve who were had HIV RNA < 200 cp/mL at1 yr ofART CD8+T cell activation (% CD38+HLA-DR+), CD4counts, and age as predictors of NAE or AIDS 2-5 yearsfromART793
  15. 15.  94 subjects had events in years 2-5 12AIDS defining 82 nonAIDS defining = 13% probability
  16. 16.  Older HIV infected persons are at significantly icnreasedrisk of clinical events compared to younger subjects
  17. 17. What Causes HIV IA?ImmuneActivationLow levelHIVreplicationMicrobialTranslocationCo-infection withother viruses- Incomplete drugpenetration intocompartments- Suboptimal HAART- Intermittent activation oflatently infectedT cellsReplication induced by- HIV- Immunosuppression- Cytokines-Loss of GALT CD4T cells-Local cytokine release damages gut epithelials-Collagen deposition
  18. 18. What can we do about it? Treating immune activation Immunosuppressive drugs Ongoing HIV Replication - treatmentintensification Co-infections – treatment of co-infections Microbial translocation Drugs that specifically impact known biomarkersassociated with NAE (d-dimer, IL-6, sCD14 etc)
  19. 19. Statin Use in HIV Known to reduce CV and plaque regression Decreased inflammation (CRP) Decreased pro-inflammatory monocyte subsets inanimal models Significantly beneficial survival ratio in personson statins with HIV (longitudinal cohort study) But statins haveAE
  20. 20. The Effect of Statins on Immune Activation andInflammation in HIV-Infected Subjects on ARTMcComsey G, JiangY, Debanne S, Clagett B, Robinson J, Labbato D, Storer N, Lederman M,Funderburg N.To assess the effect of 24 weeks of statin onsystemic and vascular inflammation and inmonocyte and lymphocyte IA in HIV + on ART 146 participants enrolled in a RCCT of rosuvastatin StableART with HIV-1 RNA < 1,000 copies/mL CD8+CD38+HLA-DR+ > 19% or hsCRP > 2 mg/L LDL < 130 mg/dL Measured soluble IA markers, vascular inflammation,monocyte and lymphocyte activation markers 186LB
  21. 21. Changes in the proportion of CD14dim16+TF+ and in levels of sCD14and lipoprotein associated phospholipase A2CD14dimcd16+TF+sCD14+Lp-PLA2
  22. 22. Impact of Statin Exposure on Mortality and Non-AIDS Complications in HIV Patients on HAARTDrechsler H, Zhang S, Maalouf N, Cutrell J,Tebas P, Bedimo R.Evaluate the impact of cumulative exposure ofstatins on death or NAE in a clinical cohort VA Clinical Case Registry to find persons on HAART< 14 days (1995-2009) Analyzed all persons on HAART (n = 25,884) and thosewho were suppressed within 18 weeks (n = 15,936) Looked at occurrence of death, CVA, MI, malignancy,fragility fractures765
  23. 23.  Cumulativeexposure tostatins wasassociated with asignficantreduction in all-cause mortalityin virologicallysuppressedpersons The effect sizewas larger withexposure toatorvastatin androsuvastatin
  24. 24. Does ART matter? ART regimens historically evaluated on theirability to suppress viremia and CD4+ T-cellrecovery ART regimens are also evaluated by theirtoxicities So are certain ART regimens “better” atdecreasing HIV associated IA?
  25. 25. cART-Induced Immunological Function Restorationis Independent of the cART Regimen and is notCorrelated with the Extent of CD4 GainsRallon N,Torres B, Diaz Al,Alos L, Martinez E, LeonA, Gatell J, SorianoV, Garcia F, Benito J.Assess the impact of LPV/r vs EFV on parametersof immune function in a RCCT 50 naïve participants randomized to LPV/r or EFVwithTDF/FTC , 22 underwent evaluation of immuneparameters Evaluated persons at baseline and week 48 for CD4 andCD8 subsets, activation, recent thymic emigration,senescence, exhaustion and apoptosis310
  26. 26.  The use of either LPV/r or EFV did not alter levels ofcellular IA It is unclear if the differential changes that wereobserved are of clinical significance
  27. 27. Early Changes in Adhesion Molecules Expressionand Endothelial Function in Patients InitiatingART with Atazanavir or LopinavirBanderaA,Trabattoni D, Squillace N, MuscatelloA, Calascibetta F, MaolbertiA, Giannattasio C,MarcandalliV, Clerici M, Gori A.Does treatment with ATZ versus KALdifferentially impact immune or metabolicparameters Prospective randomized study of 30 naïve participants 200 < CD4 < 500/uL No CVD,OI or tx with immunomodulant agents Evaluated clinical, lipid, and immune parameters andindices of endothelial structure, function and arterialstiffness 752
  28. 28.  No difference between study arms was observed forChanges in proportions ofT cell subsetsDecreases in cell surface activation markers onTcells and monocytes Did observe that persons on atazanavir demonstrated a“particularly strong” increase in the expression ofCD11a on CD4+T-cells
  29. 29.  ART with either atazanavir or lopinavir did notimpact intima mediat thickness, or pulse wavevelocity by week 24 However there was a trend to decreased arterialdiameter in the atazanavir arm compared tolopinavir
  30. 30. Soluble CD14 Declines in Virologically SuppressedWomen Switching from PI or NNRTI to Raltegravir:The Women, Integrase and Fat Accumulation Trial794Lake J, McComsey G, HulganT,Wanke C, MangiliA,Walmsley S, Boger M, Stramotas S, Currier J.Describe changes in markers of microbialtranslocation and monocyte activation duringART regimen switches 48 week study HIV women who switch to RAL atweek 0 or week 24 with central adiposity HIVVL < 50 copies/mL On NNTRI or PI based regimen Evaluated sCD14, sCD164,TNFRII, I-FABP,TNF-a
  31. 31.  Switch toRaltegravir wasaccompanied bysignificant decreasesin sCD14
  32. 32.  Other changes observed include significant increases inexpression ofTNF-alpha andTNFRII
  33. 33. Conclusions on HIV IA Why does it matter? SNAE are associated with abnormalities in innateimmune markers Steps are being made to attempt to come up with amarker or score that in the future may assistclinicians in identifying which of their patients areat most risk for SNAE As our patients are living longer, we need to bemore vigilant about prevention of known riskfactors for SNAE
  34. 34. Conclusions on HIV IA Can we do anything about it?Support is growing for the use of statins in ourpopulation but the recommendation is not thereyetStay tuned for CROI 2014 and beyond
  35. 35. Conclusions on HIV IA What aboutART choices?ART choices may impact IA, but moreextensive studies are necessary
  36. 36. CROI 2013 PODCASTS MONDAY- Themed Discussion 16: Statin Use and HIV: How Sweet Is It?- Oral Abstracts Session 19: CVD and other Non-AIDS EventsEpidemiology and Pathogenesis TUESDAY- Symposia: Opportunities andThreats toART Success WEDNESDAY-Themed Discussion 49: Inflammatory Biomarkers,Microparticles and Clinical Outcomes

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