A Clinical Trial of CCR5 Inhibition     in Treated HIV Infection: Highlighting Multidisciplinary T1 Research            fr...
SFGH CRC:A“Hub” for Multidisciplinary T1 Research                      Clinical Trials                      Hunt, Hatano, ...
HIV+ Patients Still Have a 10y Shorter Life         Expectancy than HIV- Controls                                         ...
Many morbidities associated with       aging also appear to be increased in               treated HIV disease   • Cardiova...
Many Chronic Diseases of Aging May BeDriven By Lifestyle Factors and ART Toxicity                ART               Toxicit...
Persistent Immune Activation andInflammation May Also Play Important Role        ART       Toxicity                       ...
An Important Clue from NatureSooty Mangabey                      Rhesus Macaque•Infect with SIV                    •Infect...
T Cell Activation Declines with ART            Hunt et al, JID, 2003 and 2008
But Remains Abnormally High During  ART-mediated Viral Suppresion           Hunt et al, JID, 2003 and 2008
CCR5 Inhibition:     A Potential Intervention to Reduce T Cell Activation• Maraviroc is a CCR5 inhibitor and the only curr...
Maraviroc Intensification Trial               Schematic   Randomize                                                      A...
CCR5 Expression is Much More Common     on T Cells in Rectal Mucosa
Baseline Characteristics                                                 Placebo           MaravirocCharacteristic        ...
Early Decline in Plasma HIV RNA Levels  by Single Copy Assay in Both Arms
Similar CD4 Count Increase in Both Arms     No evidence for difference in the rate of    CD4+ T cell recovery between arms...
CD8+ T Cell Activation DeclinedSignificantly in the Placebo Arm
While CD8+ T Cell Activation Tended to Increase in the Maraviroc Arm
Maraviroc Increases CD8 Activation      Compared to Placebo      P values represent difference between groups      in the ...
Maraviroc Prevents the Decline in CD4  Activation Compared to Placebo          P values represent difference between group...
No Change in Rectal T Cell Activation on PlaceboCD4+CD8+
But Maraviroc Causes a Nearly 2-fold increase in             Rectal T Cell ActivationCD4+CD8+
MVC intensification increases sCD14 levels                                                            Δ Wk 24-36          ...
Why does CCR5 inhibitionincrease T cell and monocyte      activation in vivo?
Ligand approaches CCR5         Binding and Signaling       Ligand-Receptor InternalizationLederman, JAMA, 2006• Maraviroc ...
>2-fold Increase in Plasma MIP-1β (CCR5 Ligand)     Levels During Maraviroc Intensification
MVC-mediated Increases in CCR5 ligands are associated with increases in sCD14                    Spearman’s rho:          ...
Brachial Artery Flow-Mediated Dilation                        Endothelial Stimulus:                        Reactive hypere...
Normal Brachial ArteryEndothelium-Dependent Vasomotion                      VasodilationBrachial Artery  Baseline        R...
Despite MVC-mediated Increases in T cell and Monocyte Activation, No difference in FMD                                    ...
Conclusions   Maraviroc intensification in HIV+ subjects with      incomplete ART-mediated CD4 recovery:• Causes a nearly ...
SFGH CRC:A“Hub” for Multidisciplinary T1 Research                      Clinical Trials                      Hunt, Hatano, ...
Acknowledgements            Clinical Trial Sites                     Lederman Laboratory (CWRU)   UCSF                  Ru...
Acknowledgements:                  SFGH CRCNURSING                 SPECIMEN PROCESSINGElizabeth Madruga, RN   Wendy StaubB...
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A Clinical Trial of CCR5 Inhibition in Treated HIV Infection: Highlighting Multidisciplinary Research

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A presentation by Peter W. Hunt, M.D., Assistant Professor in Residence at the University of California, San Francisco (UCSF), conducted at the San Francisco General Hospital (SFGH) and supported by CTSI's Clinical Research Services. Learn more about the service at http://ctsi.ucsf.edu/our-work/clinical-research-services

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  • Consistent with this hypothesis, maraviroc-treated patients experienced a significantly greater increase in sCD14 levels than placebo-treated subjects through week 24.
  • Will clean up this slide and try to crop away text.
  • Thesedata are consistent with the hypothesis that increasing CCR5 ligands during maraviroc intensification are causing monocyte/macrophage activation.
  • Despite these treatment-mediated increases in monocyte/macrophage activation, we observed no evidence for any clinically meaningful changes in vascular function –as assessed by FMD – at any timepoint. Specifically, we can confidently exclude harmful decreases in FMD of greater than 0.36% and beneficial increases of greater than 1.28%.
  • A Clinical Trial of CCR5 Inhibition in Treated HIV Infection: Highlighting Multidisciplinary Research

    1. 1. A Clinical Trial of CCR5 Inhibition in Treated HIV Infection: Highlighting Multidisciplinary T1 Research from the SFGH CRS Peter W. Hunt, M.D. Assistant Professor in Residence UCSF, SFGH HIV/AIDS Division
    2. 2. SFGH CRC:A“Hub” for Multidisciplinary T1 Research Clinical Trials Hunt, Hatano, Hsue, Deeks Cardiovascular SCOPE Cohort (FMD, IMT, etc) Deeks/Martin Hsue Lymph NodeGut Mucosal BiopsyBiospy Core HatanoSomsouk/Hunt SFGH Neurology (CSF Biomarkers) Specimen Bank CRC Price ASB Basic Laboratories McCune/Nixon Virology Core Lab Immunology Liegler Core Lab Sinclair Clinical Lab
    3. 3. HIV+ Patients Still Have a 10y Shorter Life Expectancy than HIV- Controls Survival from Age 25 Years N= 3,990 1 Probability of Survival 0.75 Population controls 0.5 Late HAART (2000–2005) 0.25 Early HAART (1997–1999) Pre-HAART 0 (1995–1996) 25 30 35 40 45 50 55 60 65 70 Age, yearsAdapted from Lohse N, et al. Ann Intern Med 2007;146:87–95 (See Also: ART-CC, Lancet, 2008; Lewden, JAIDS, 2007)
    4. 4. Many morbidities associated with aging also appear to be increased in treated HIV disease • Cardiovascular disease [1-3] • Cancer (non-AIDS) [4] • Bone fractures / osteoporosis [5,6] • Liver disease [7] • Kidney disease [8] • Cognitive decline [9] • Frailty [10]1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2; Hsue P, et al. Circulation. 2004;109:316-319. 3. Grinspoon SK,et al. Circulation. 2008;118:198-210. 4. Patel P, et al. Ann Int Med, 2008;148:728-736. 5. Triant V, et al. J Clin Endocrinol Metab.2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8.Choi A, et al. AIDS, 2009;23(16):2143-49. 9. McCutchan JA, et a. AIDS. 2007 ;21:1109-1117. 10. Desquilbet L, et al. J Gerontol ABiol Sci Med Sci. 2007;62:1279-1286
    5. 5. Many Chronic Diseases of Aging May BeDriven By Lifestyle Factors and ART Toxicity ART Toxicity Premature Aging Lifestyle (smoking, etc.) Deeks and Phillips, BMJ, 2009
    6. 6. Persistent Immune Activation andInflammation May Also Play Important Role ART Toxicity Premature Aging Lifestyle Persistent Inflammation Deeks and Phillips, BMJ, 2009
    7. 7. An Important Clue from NatureSooty Mangabey Rhesus Macaque•Infect with SIV •Infect with SIV•High Levels of Viral Replication •High Levels of Viral Replication•No AIDS, normal lifespan •AIDS and death•Minimal Immune Activation •Massive Immune Activation Silvestri, Immunity, 2003
    8. 8. T Cell Activation Declines with ART Hunt et al, JID, 2003 and 2008
    9. 9. But Remains Abnormally High During ART-mediated Viral Suppresion Hunt et al, JID, 2003 and 2008
    10. 10. CCR5 Inhibition: A Potential Intervention to Reduce T Cell Activation• Maraviroc is a CCR5 inhibitor and the only currently approved ARV drug that targets a host element.• In addition to blocking HIV entry, maraviroc blocks binding of natural CCR5 ligands. – Contribute to T cell and monocyte trafficking and activation• Potential immunologic benefit to blocking CCR5 supported by: – CCR5 ∆32 causes delayed HIV disease progression. – Natural hosts of non-pathogenic SIV have low CCR5 on central memory T cells and low T cell activation.• Hypothesis: Adding maraviroc to a suppressive regimen will decrease T cell activation in treated HIV infection
    11. 11. Maraviroc Intensification Trial Schematic Randomize ART alone (N=42) Add Maraviroc BID x 24 weeks x 12 weeks ART>1y VL<75 ART alone CD4<350 Add Placebo BID x 24 weeks x 12 weeksStudy Visits at Weeks: -2 0 1 2 4 6 8 12 16 20 22 24 28 36 T Cell Activation, biomarkers, Low-level Viremia (SCA), FMD (Cardiovascular) Clinical monitoring, CD4 count Flexible Sigmoidoscopy, Rectosigmoid Biopsy (UCSF only)
    12. 12. CCR5 Expression is Much More Common on T Cells in Rectal Mucosa
    13. 13. Baseline Characteristics Placebo MaravirocCharacteristic Median (IQR) Median (IQR) N=22 N=23Age, years 50 (43 to 57) 50 (46 to 56)Male Gender, No. (%) 20 (91) 23 (100)CD4 count, cells/mm3 202 (161 to 256) 206 (131 to 260)Plasma HIV RNA level, copies/ml <48 <48Duration of current ART regimen, months 31 (15 to 43) 30 (21 to 42)Hepatitis C Virus Antibody Positive, No. (%) 2 (14) 3 (20)
    14. 14. Early Decline in Plasma HIV RNA Levels by Single Copy Assay in Both Arms
    15. 15. Similar CD4 Count Increase in Both Arms No evidence for difference in the rate of CD4+ T cell recovery between arms, P=0.97
    16. 16. CD8+ T Cell Activation DeclinedSignificantly in the Placebo Arm
    17. 17. While CD8+ T Cell Activation Tended to Increase in the Maraviroc Arm
    18. 18. Maraviroc Increases CD8 Activation Compared to Placebo P values represent difference between groups in the change from baseline at each timepoint.
    19. 19. Maraviroc Prevents the Decline in CD4 Activation Compared to Placebo P values represent difference between groups in the change from baseline at each timepoint.
    20. 20. No Change in Rectal T Cell Activation on PlaceboCD4+CD8+
    21. 21. But Maraviroc Causes a Nearly 2-fold increase in Rectal T Cell ActivationCD4+CD8+
    22. 22. MVC intensification increases sCD14 levels Δ Wk 24-36 Δ Wk 0-4 Δ Wk 0-24 P=0.31 P=0.053 P=0.017 MVC arm had a mean 0.33 µg/mL greater increase in sCD14 from baseline to week 24 (95%CI: 0.06, 0.61, p=0.017)Interestingly, sCD14 levels tended to increase further after discontinuation of MVC.
    23. 23. Why does CCR5 inhibitionincrease T cell and monocyte activation in vivo?
    24. 24. Ligand approaches CCR5 Binding and Signaling Ligand-Receptor InternalizationLederman, JAMA, 2006• Maraviroc blocks internalization of receptor-ligand complexes leading to: • Increased CCR5 expression on cell surface • Increase in soluble ligands in plasma and tissues (Lin/Corbeau, AIDS, 2007; Nakata/Mitsuya, Antiviral Threrapy, 2010)• CCR5 ligands (MIP-1α, MIP-1β and RANTES) also bind other chemokine receptors (CCR1 on monocytes/neutrophils, CCR4/CCR4 on T cells) (Wolpe, J Exp Med, 1988; Fahey, JI, 1992)• Current Hypothesis: Activation of monocytes via CCR1 and T cells via CCR3/CCD4 might explain increased T cell and monocyte activation.
    25. 25. >2-fold Increase in Plasma MIP-1β (CCR5 Ligand) Levels During Maraviroc Intensification
    26. 26. MVC-mediated Increases in CCR5 ligands are associated with increases in sCD14 Spearman’s rho: 0.34, P=0.017
    27. 27. Brachial Artery Flow-Mediated Dilation Endothelial Stimulus: Reactive hyperemia after five minute cuff occlusion. Stimulates functioning endothelial cells to release NO. NO diffuses into vascular smooth muscle. Muscle relaxes. Control stimulus: Nitroglycerin, an endothelium-independent vasodilator Quantity measured: Diameter of artery, using B- mode ultrasound
    28. 28. Normal Brachial ArteryEndothelium-Dependent Vasomotion VasodilationBrachial Artery Baseline Reactive Hyperemia
    29. 29. Despite MVC-mediated Increases in T cell and Monocyte Activation, No difference in FMD Δ Wk 24-36 Δ Wk 0-24 Δ Wk 0-4 P=0.89 P=0.61 P=0.40 ART + Study Drug ART only Mean +0.46% greater week 24 change from baseline in MVC arm (95% CI: -0.36% to +1.28%, P=0.61)
    30. 30. Conclusions Maraviroc intensification in HIV+ subjects with incomplete ART-mediated CD4 recovery:• Causes a nearly 2-fold increase in T cell activation in GALT, and more modest increases in peripheral blood.• Also increases monocyte activation. – CCR5 ligand signaling through other chemokine receptors should be explored as a possible causal mechanism.• No clear effect on vascular function (by FMD) – Could decreased chemotaxis abrogate a negative effect of monocte and T cell activation?• The clinical implications of these findings are unclear. – CADIRIS, ANRS studies with clinical endpoints ongoing
    31. 31. SFGH CRC:A“Hub” for Multidisciplinary T1 Research Clinical Trials Hunt, Hatano, Hsue, Deeks Cardiovascular SCOPE Cohort (FMD, IMT, etc) Deeks/Martin Hsue Lymph NodeGut Mucosal BiopsyBiospy Core HatanoSomsouk/Hunt SFGH Neurology (CSF Biomarkers) Specimen Bank CRC Price ASB Basic Laboratories McCune/Nixon Virology Core Lab Immunology Liegler Core Lab Sinclair Clinical Lab
    32. 32. Acknowledgements Clinical Trial Sites Lederman Laboratory (CWRU) UCSF Rush/CORE Center Brian Clagett Nicholas Funderburg Lee Gilman Oluwatoyin Adeyemi Kathy Medvik Joy Madamba Julia Lee Melissa Krone Mieoak Bahk Karolinska Instituet Victor Dahl Jeffrey Martin Hamid Bouiri Sarah Palmer Steven Deeks Alan Landay UCSF/SFGH GI Division Ma Somsouk CWRU Stanford UCSF/SFGH Cardiology Division Benigno Rodriguez Debbie Slamowitz Priscilla Hsue Jane Baum Robert Shafer Amanda Schnell Michelle Gallagher Cindy Padilla UC Davis Mucosal Immunology Michael Banchy Martha Hamilton Timothy Hayes Michael Lederman Nancy Shulman Barbara ShacklettThis trial was supported by investigator-initiatedgrants from: Pfizer labs, Inc., and AMFAR
    33. 33. Acknowledgements: SFGH CRCNURSING SPECIMEN PROCESSINGElizabeth Madruga, RN Wendy StaubBernadette Tobin, RN Benny TongLorna Aquino, RN Fabiola CarrilloBeverly Schmidt, RN BIONUTRITIONNenette Dignadice, RN Viva TaiRosemarie Dario, LVN Jennifer CulpOscar Gomez Cruz, HA Marilou TarapeAntonio Everett, HA Marlene HomHector Vizoso, RN May YeeEileen Magnaye, RNBrenda Herrera, RN ADMINMelinda Rowan, RN Mark Jacobson, M.D. -Medical DirectorCory Groom, RN Eunice Stephens -Operations Director Gabriel Ortiz -Analyst
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