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CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational grants from Faculty: W. David Hardy, M.D. Director,

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Presentation on theme: "CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational grants from Faculty: W. David Hardy, M.D. Director,"— Presentation transcript:

1 CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational grants from Faculty: W. David Hardy, M.D. Director, Division of Infectious Diseases Cedars-Sinai Medical Center; Los Angeles, California W. David Hardy, M.D. Copyright © 2008 Body Health Resources Corporation. All rights reserved. The Body PRO Presents: This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.

2 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 1 Faculty for This Activity W. David Hardy, M.D. W. David Hardy, M.D., is an associate professor of medicine-in-residence at the David Geffen School of Medicine, University of California, Los Angeles (UCLA). He gained his medical degree from the Baylor College of Medicine in Houston, Texas, in 1981, completed a residency in internal medicine at Harbor-UCLA Medical Center in Torrance, California in 1984 and a clinical fellowship in infectious diseases and immunology in 1986 at UCLA School of Medicine. Later in his career he also completed a postdoctoral fellowship in basic retrovirology in 2002, also at the UCLA School of Medicine. Dr. Hardy has conducted clinical trials with several antiretroviral agents beginning in He is a member of numerous professional societies including the American Academy of HIV Medicine, for whom he serves as a member of the National Board of Directors and Chairman of the California/Hawaii Chapter. Disclosures Dr. Hardy has received grants or research support from Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer and Tibotec. He has served as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Monogram, Pfizer and Tibotec. He has received fees for non-CME services from Gilead Sciences, Pfizer and Tibotec. He owns stock in Merck.

3 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 2 Retrovirus Life Cycle Coreceptor, CD4 Binding Inhibitors maraviroc vicriviroc TNX 355 Reverse Transcriptase Inhibitors Protease Inhibitors Maturation Inhibitor bevirimat Integrase Inhibitors raltegravir elvitegravir Fusion Inhibitors enfuvirtide zidovudinenevirapine didanosinedelavirdine zalcitabineefavirenz stavudinelamivudine emtricitabineabacavir tenofoviretravirine rilpivirine saquinavirindinavir ritonavir nelfinavir fosamprenavirlopinavir atazanavirtipranavir darunavir

4 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 3 HIV Entry Inhibitors Adapted from Moore JP, PNAS 2003;100:

5 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 4 Targets Involved in HIV Entry Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

6 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 5 Structure of the HIV-1 Envelope Glycoprotein Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

7 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 6 Binding of the gp120 Subunit to CD4 Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

8 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 7 Conformational Change Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

9 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 8 gp120 Binds to the Coreceptor, CCR5 Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

10 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 9 Conformational Changes in the gp41 Subunit Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

11 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 10 Fusion of the Viral and Cell Membranes Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

12 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 11 HIV Natural History and Tropism Expression

13 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 12 CCR5 Function and Genetics CCR5 is a receptor for C-C chemokines (chemo-attractive cytokines) –Expressed on immune effector cells and antigen presenting cells –Molecules that bind to CCR5 include MIP-1 , MIP-1 , and RANTES Activation of CCR5 on T cells by chemokines leads to: –T-cell migration to the site of inflammation –Immune response to various antigens CCR5, together with CD4, are the primary receptors utilized by HIV for viral entry Galvani AP et al. Proc Natl Acad Sci U S A. 2003;100: McNicholl JM et al. Emerg Infect Dis. 1997;3: Stephens JC et al. Am J Hum Genet. 1998;62:

14 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 13 Mixed or Dual-Tropic Viruses Use CCR5 and/or CXCR4 (in vitro) Graeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission.

15 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 14 Coreceptor Usage of HIV-1 Variants X4 R5 CXCR4 CCR5 CD4 T-cell lines Primary lymphocytesMonocyte/macrophages CD4 Naive CD4 memory CD4 Copyright © Pfizer Inc. All rights reserved.

16 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 15 Global Prevalence of CCR5  32 Allele Galvani AP et al. PNAS. 2003;100: McNicholl JM et al. Emerg Infect Dis. 1997;3: Stephens JC et al. Am J Hum Genet. 1998;62: ~14% ~6% Rare 10%- 15% Rare ~10% Rare 5%-14% of Caucasians of European descent carry CCR5  32 (1% are CCR5  32 homozygous) The origin of the CCR5 D32 allele has been traced to European geography ~1,000 years ago Possible selection by pandemic pathogen, likely smallpox or bubonic plague

17 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 16  CCR5 Wild Type and CCR5  32 CCR5 wild type   CCR5  32 wt/wt wt/  32  32/  32 NormalHeterozygotesHomozygotes Click on slide for animation. Liu R et al. Cell. 1996;86: Huang Y et al. Nat Med. 1996;2: Samson M et al. Nature. 1996;382: Michael NL et al. Nat Med. 1997;3: Dean M et al. Science. 1996;273: Eugen-Olsen J et al. AIDS. 1997;11: Normal CCR5 exp Progression of HIV Normal immune fx* Decreased CCR5 exp Delayed prog. to AIDS/death Normal immune fx* No CCR5 exp Rare infection with X4 Normal immune fx* *fx = function

18 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 17  Patients Heterozygous for CCR5  32 Have Slower Progression to AIDS and Death Adapted from de Roda Husman A-M, et al. Ann Intern Med. 1997;127:

19 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 18 The Tropism Assay

20 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 19 Why is a Tropism Test Required? CCR5 antagonists block entry of HIV that uses CCR5 only, no effect on HIV that uses CXCR4 Presence of X4 HIV has been associated with more rapid CD4 decline and disease progression The effect a CCR5 antagonist will have in patients with R5/X4 HIV is unknown Regulatory agencies likely to require tropism assay prior to use of a CCR5 antagonist Copyright © Pfizer Inc. All rights reserved. Reprinted with permission.

21 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 20 The Monogram Tropism Assay HIV-1 Expression Vector (pHIVluc  U3) Envelope Expression Vector (pHIVenv) P A+ HIV envelope a/bc/d Indicator Gene U5 gag pol Luciferas e P R  env P R A+ gp120 gp41 Copyright © Monogram Biosciences. Reprinted with permission.

22 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 21 HIV Entry Cell Assay Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:

23 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 22 HIV Entry Cell Assay: R5 HIV Only Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:

24 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 23 HIV Entry Cell Assay: X4 HIV Only Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:

25 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 24 HIV Entry Cell Assay: R5/X4 Tropic HIV Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:

26 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 25 Demonstration of R5 Virus Light Generated CCR5 Use R5 Virus No Light Generated No CXCR4 Use Not an X4 Virus Virus Click on slide for animation. Copyright © Monogram Biosciences. Reprinted with permission. CCR5 CXCR4

27 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 26 Demonstration of Dual Virus Light is generated on both CCR5 and CXCR4 cell lines. This is a DUAL virus. Virus CCR5 CXCR4 Click on slide for animation. Copyright © Monogram Biosciences. Reprinted with permission.

28 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 27 This population shows CCR5 AND CXCR4 co-receptor use. This is a mixed population. Demonstration of Mixed Virus Population CCR5 CXCR4 Click on slide for animation. Copyright © Monogram Biosciences. Reprinted with permission.

29 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 28 What Is This Population? Most of these viruses are R5: Strong luciferase activity Some are X4: Lower level luciferase activity CXCR4 CCR5 Click on slide for animation. Copyright © Monogram Biosciences. Reprinted with permission.

30 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 29 Comparison of Original Tropism to Enhanced Sensitivity Tropism Test Standard Tropism Assay (August 2007 – June 2008) Enhanced Tropism Assay (June 2008 – Present) Sensitivity 100% if X4-using HIV > 10% of viral population 83% if X4-using HIV > 5% of viral population 100% if X4-using HIV > 0.3% of viral population Plasma Volume Required3 mL Shipping RequirementDry ice Viral Load Requirement> 1,000 copies/mL Turnaround Time~ 2 weeks Copyright © Monogram Biosciences. Reprinted with permission.

31 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 30 Coreceptor Tropism: Epidemiological Data

32 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 31 Percentage of HIV Coreceptor Usage Study/SourcePopulationNR5X4R5/X4 Homer cohort 1 Naive97982%< 1%18% C & W cohort 2 Naive40281%< 1%19% Demarest 3 Naive29988%0%12% Study Naïve142885%< 1%15% TORO 1/2 6 Experienced61262%4%34% ViroLogic 5 Experienced> %2%50% ACTG Experienced39149%4%47% MOTIVATE 1/2 8 Experienced256056%3%41% 1 Brumme ZL et al. J Infect Dis. 2005;192: Moyle GJ et al. J Infect Dis. 2005;191: Demarest J et al. ICAAC 2004; abstract H Waters L et al. ICAAC 2006; abstract H Whitcomb JM et al. CROI 2003; abstract Paxinos EE et al. ICAAC 2002; abstract Wilkin T et al. CROI 2006; abstract Coakley E et al. International Workshop on Targeting HIV Entry 2006; abstract 8. This table may not include all available reported data; majority of data are generated in the developed world (subtype B)

33 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 32 Prevalence of X4 Phenotype by Baseline CD4+ Count Adapted from Brumme ZL et al. J Infect Dis. 2005:192; Baseline CD4 Coreceptor use was determined in 1191 patients starting HAART Patients with D/M virus had a poorer clinical profile than patients with R5 virus –Median CD4+ T-cell count of 110 versus 290 cells/mm 3 (P<.0001) –HIV RNA of 175,000 versus 120,000 copies/mL (P=.0006) The following were associated with the prevalence of D/M-tropic virus: –Low baseline CD4+ T-cell count –High baseline HIV RNA –CCR5-Δ32 deletion heterozygous patients –Basic mutations at gp120-V3 codons 11 or < ≥ 500 Percentage of Patients R5 D/M

34 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 33 Tropism in Naive Patients: Impact on CD4+ Decline and Response to Treatment Graeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission. 402 treatment-naive subjects had tropism tested –326 R5 –73 D/M –3 X4 340 started HAART by August 2006 –229 R5 –60 D/M –51 excluded from analysis

35 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 34 CD4+ Decline Before HAART Graeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission. DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CI

36 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 35 Time to Viral Suppression Graeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission. Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART

37 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 36 Tropism Does Not Affect Response to HAART Graeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission. R5 Tropic R5/X4 Tropic P Value CD4+ T-Cell Count Rise at 12 Months, Cells/mm 3 (95% CI) 185 ( ) 182 ( ).812 CD4+ T-Cell Count Rise at 24 Months, Cells/mm 3 (95% CI) 247 ( ) 292 ( ).482 Patients With VL < 50 Copies/mL at 12 Months, n (%) 168 (73.4)47 (78.3).509 Patients With VL < 50 Copies/mL at 24 Months, n (%) 166 (72.4)41 (68.3).67 CI = confidence interval

38 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 37 Clinical Trials

39 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 38 MOTIVATE 1&2: Trial Design David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

40 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 39 MOTIVATE 1&2: Demographics and Baseline Characteristics David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

41 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 40 MOTIVATE 1&2: Mean Change in HIV-1 RNA* From Baseline to Week 48 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

42 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 41 MOTIVATE 1&2: Percentage of Patients With Undetectable HIV-1 RNA David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

43 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 42 MOTIVATE 1&2: Mean Change in CD4+ Cell Count From Baseline to Week 48 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. CD4+ cell count increases up to 48 weeks were more favorable in both the maraviroc groups than the placebo group The mean change from baseline in CD4+ cell count* was: +61 cells/mm 3 in the placebo + OBT +116 cells/mm 3 in maraviroc QD + OBT +124 cells/mm 3 in the maraviroc BID + OBT group * Last observation carried forward approach used to impute missing values

44 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 43 MOTIVATE 1&2: Patients With HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48) David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

45 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 44 MOTIVATE 1&2: Safety Analyses Unadjusted For Duration of Exposure David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

46 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 45 MOTIVATE 1&2: Maximum Liver Function Test Values Over 48 Weeks Without Regard To Baseline David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

47 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 46 MOTIVATE 1&2: Percentage of Adverse Events Occurring in ≥ 5% of Patients in Any Group, Unadjusted for Treatment Exposure David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

48 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 47 VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.

49 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 48 VICTOR-E1: Virologic Efficacy of Vicriviroc vs. Placebo at Week 48 No clinically significant differences in adverse events between VCV arms and placebo Mean Change in HIV-1 RNA From BL (log 10 copies/mL) VCV 30 mg n = 39 0 VCV 20 mg n = 40 Placebo n = Difference: P =.0028 Difference: P = Patients With HIV-RNA-1 < 50 copies/mL (%) VCV 30 mg n = 22 0 VCV 20 mg n = 21 Placebo n = 5 Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.

50 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 49 MERIT: Maraviroc vs. Efavirenz in Treatment-Naive Patients Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission. Antiretroviral-naive patients infected with CCR5-tropic HIV-1 and HIV-1 RNA  2000 copies/mL (N = 740) MVC 300 mg twice daily + ZDV/3TC (n = 360) EFV 600 mg once daily + ZDV/3TC (n = 361) Week 48 primary endpoint Stratified by HIV-1 RNA < or  100,000 copies/mL and by Northern or Southern Hemisphere MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16) Week 96  Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI

51 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 50 MERIT: Patients With Viral Load < 400 and < 50 Copies/mL by Week 48 (ITT) Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission. VL < 400 copies/mLVL < 50 copies/mL Patients, % Time (weeks) % 73.1% 69.3% 65.3% EFV (n = 361)MVC (n = 360)  MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)  CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm 3 )

52 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 51 MERIT: Patients With Viral Load < 50 Copies/mL by Baseline Viral Load Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission Patients, % BL VL < 100,000 Copies/mL BL VL ≥ 100,000 Copies/mL n = MVCEFV  EFV patients more likely to discontinue due to AE –Overall : 25.2% –AE: 13.6% –Efficacy: 4.2%  MVC patients more likely to discontinue due to lack of efficacy –Overall: 26.9% –AE: 4.2% –Efficacy: 11.9%

53 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 52 MERIT: Week 48 Safety Analyses All Causalities and SeveritiesEFV + CBV N=361 MVC + CBV N=360 Patients With Adverse Events 340 (94.2)331 (91.9) Patients With Grade 3 AEs, n (%) 66 (18.3)51 (14.2) Patients With Grade 4 AEs, n (%) 24 (6.6)22 (6.1) Patients With SAEs, n (%) † 46 (12.7)41 (11.3) Patients With Category C events, n (%) 12 (3.3)6 (1.7) Malignancies 16 (4.4)10 (2.8) Deaths † *, n (%) 11 AEs = adverse events; SAEs = serious adverse events †Based on all data through 21 June 2007 *Deaths reported up to 28 days after stopping study drug; one additional death on EFV within 28 days, date of death not captured in database Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

54 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 53 MERIT: Viral Suppression at Week 48 by Baseline Tropism n = Patients With VL < 50 c/mL at Week 48 (%) EFV MVC Tropism at Screening (Overall) Tropism at Baseline (R5) Tropism at Baseline (D/M) Change in detected HIV-1 tropism from R5 at screening to D/M at BL and potentially adherence may explain some treatment failures on MVC –3.5% of patients experienced change in detected tropism between screening and BL –50.0% of patients with R5 virus at BL and without confirmed X4 at failure had plasma MVC concentrations below limit of detection Tropism changes more common in patients with lower mean CD4+ cell count at screening as well as with clade B or other/undetermined HIV-1 subtype vs clade C Jayvany Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.

55 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 54 MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48 Edwin DeJesus et al. CROI 2008; abstract 929. Reprinted with permission.

56 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 55 Questions

57 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 56 Main Discussion Questions Does the use of CCR5 antagonists prevent the immune system from mounting an effective defense against West Nile virus infection and its complications? Is the new enhanced tropism test sensitive enough to more accurately identify patients who may have some X4-tropic virus? Is there going to be a second clinical trial of maraviroc in treatment- naive patients that uses the more sensitive assay? Who is the best patient to use a CCR5 antagonist?


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