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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?

58 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 57 Case Studies

59 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 58 Case 1

60 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice year-old male with extensive ART history dating back to 1995 Past ARVs included all NRTIs except ddC, all NNRTIs except DLV, and all PIs except FPV and full-dose RTV History of “buffalo hump” while taking IDV; removed with liposuction Former participant in the RESIST 1 trial ( ); ART regimen—TPV/r, TDF-FTC, EFV, ddI and ENV –HIV-1 RNA decreased from 510,000 to 5,200 copies/mL –CD4+ increased from 75 to 120 cells/mm 3 –Failed to achieve HIV-1 RNA < 50 copies/mL Discontinued ENF after 2.5 years due to lack of any available injection sites Experienced low-level viremia prior to discontinuing ENF Case 1: Patient History

61 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 60 Patient also a participant in the MOTIVATE 1 trial Randomized to placebo with OBR* of: SQV/RTV, TDF/FTC, ddI, EFV –IDV/RTV predicted to have full activity by resistance testing, but refused by patient due to prior history of lipodystrophy (buffalo hump) After eight weeks, VL 734,000 copies/mL (from 1,162,500 copies/mL), CD4+ 75 cells/mm 3 (7.8%) –< 0.5 log 10 decrease, thus considered a virologic failure Switched to open-label MVC 150 mg BID, IDV/RTV, TDF/FTC, ddI –Patient achieved HIV-1 RNA < 50 c/mL by week 24 and CD4+ cells increase to 155/mm 3 (22%); maintained for the next six months –At this time, patient develops bilateral hip pain, is diagnosed with advanced aseptic necrosis of the right hip joint and undergoes right total hip replacement surgery * Optimized Background Regimen Case 1: Patient History Continued

62 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 61 A. No B. Not Sure C. Yes Case 1: Would You Consider Changing the Patient’s Regimen at This Time?

63 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 62 Case 1: Case Progression You convince the patient to remain on his current regimen to maintain his HIV RNA < 50 copies/mL HIV-1 RNA increases to 580 copies/mL (repeat 1,280 copies/mL) (You suspect that patient’s confidence in his ART regimen has waned due to his hip surgery.) You determine that a change in regimen is indicated and order a phenotype and tropism assay

64 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 63 Case 1: Results of a Tropism Assay Tropism Result Copyright © Monogram Biosciences. Reprinted with permission.

65 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 64 Case 1: Results of Patient’s Resistance Test

66 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 65 Case 1: Should a Boosted PI Be Included in the Patient’s New Regimen? A.Yes B.No C.Not sure

67 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 66 Case 1: If You Included a PI, Which Would You Use? A.Atazanavir + ritonavir B.Darunavir + ritonavir C.Fosamprenavir + ritonavir D.Lopinavir/ritonavir E.Saquinavir + ritonavir F.Tipranavir + ritonavir G.No PIs

68 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 67 Case 1: Would You Switch the NRTI Component of the Patient’s Regimen? A. No B. Yes, I would drop ddI C. Yes, I would drop tenofovir/FTC D. Yes, I would not use NRTIs in his new regimen

69 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 68 Case 1: Would You Include Raltegravir in the Patient’s New Regimen? A. Yes B. No C. Not sure

70 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 69 Case 1: Would You Include Etravirine in the Patient’s New Regimen? A.Yes B.No C.Not sure

71 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 70 Case 1: Etravirine Resistance Information 2008 Update Clinical cut offs (CCOs) determined for phenotypic sensitivity Four additional etravirine RAMS identified (17 total) Weighted scoring system developed

72 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 71 Case 1: Response According to Phenotypic Etravirine CCOs Etravirine CCO Proportion of Patients With Viral Load < 50 Copies/mL (DUET Week 24), % (n) Decrease in log 10 Viral Load From Baseline (DUET Week 24), Mean (SE) < 371 (190/269)–2.67 (1.03) 3–1350 (37/74)–2.39 (1.21) > 1337 (22/60)–1.79 (1.42) Overall Placebo 36 (149/414)–1.51 (1.42) The highest responses occurred in patients with a fold change < 3 Virological responses were greater than placebo in patients with a fold change < 13 The highest responses occurred in patients with a fold change < 3 Virological responses were greater than placebo in patients with a fold change < 13

73 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice no mutation* L100I G190A V90I E138A Y181I M230L A98G Y181C K101E K101P K101H V179D V106I V179T Y181V G190S V179F Patients with confirmed VL <50 HIV-1 RNA copies/mL (%) *no detectable baseline NNRTI RAM from the list of 44; Dashed line indicates 75% of response in patients without NNRTI RAMs n= New 52 Effect of the Etravirine RAMs 2008 (17) on Virological Response

74 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 73

75 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 74 § § Y181I Y181V K101P L100I Y181C M230L E138A V106I G190S V179F V90I V179D K101E K101H A98G V179T G190A § V179F was never present as single Etravirine RAM (always with Y181C) Weight for Individual Mutations Weight for Individual Mutations Add Together Total Weighted Score Total Weighted Score Case 1: Weighting of 2008 Etravirine RAMs

76 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 75 Case 1: Relation Between the 2008 Etravirine Genotypic Score and the Virological Response (< 50 Copies/mL At Week 24)

77 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 76 Case 1: Would You Continue Maraviroc in the Patient’s New Regimen? A. Yes B. No C. Not sure

78 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 77 Case 1: Case Progression On his new regimen of MVC, DRV/r, ETV, RAL and TDF/FTC his HIV-1 RNA remains < 50 copies/mL and CD4+ cells slowly rise to 280 cells/mm 3 (28%) over the next eight months His left hip pain and MRI of it stabilize showing no further progression He continues to tolerate his ART regimen well

79 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 78 Case 2

80 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 79 Case 2: Patient History 45-year-old man Diagnosed with HIV-1 in 1994 when he presented with cutaneous Kaposi’s Sarcoma –CD4+ cell count: 360 cells/mm³ –HIV-1 RNA test not available in 1994 PMH: mild hypertension, controlled with diuretics FMH: diabetes, CVD

81 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 80 Case 2: Patient ARV History 1994: ZDV monotherapy –Discontinued six months later due to anemia and nausea ddI monotherapy –Tolerated for nine months, then developed pancreatitis Discontinued ARVs: KS quiescent, CD4+ cell count stable at 360 cells/mm³

82 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 81 Case 2: Patient History on HAART Regimens Starting in 1996, various regimens including –d4T + 3TC + SQV –d4T + 3TC + NFV –ABC + 3TC + EFV –d4T + 3TC + LPV/RTV –TDF + 3TC + LPV/RTV + FPV Intolerant to ZDV (anemia), ddI (pancreatitis), d4T (peripheral neuropathy), NFV (diarrhea), dual-boosted PIs (GI symptoms)

83 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 82 Case 2: Patient History on HAART Regimens (Continued) Reached HIV-1 RNA < 400 copies/mL but never < 50 copies/mL First genotypic assay (after d4T + 3TC + SQV) –RT gene: M41L, L74V, M184V, T215Y PR gene: L10I, L63P, L90M Second genotypic assay (after ABC + 3TC + EFV) –RT gene: M41L, L74V, K101P, K103N, Y181C, M184V, T215Y, K219R –PR gene: L10I, D30D/N, L63P, G73T, V77I, L90M CD4+ cell counts rose and fell, nadir: 240 cells/mm³

84 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 83 Case 2: Current History: 2008 Regimen: TDF + 3TC + LPV/RTV –HIV-1 RNA: 1,500-2,500 copies/mL –CD4+ cell count: cells/mm³ Hypertension poorly controlled with ACE inhibitor/diuretic + β-blocker Fasting glucose > 180 mg/dL Serum creatinine 1.9 mg/dL (baseline mg/dL) Patient wants to consider a new regimen

85 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 84 Case 2: Drug Resistance Test Results

86 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 85 Case 2: Viral Tropism Assay Tropism Result Copyright © Monogram Biosciences. Reprinted with permission.

87 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 86 Darunavir Resistance Mutations 11I, 32I, 33F, 47V, 50V, 54L/M, 74P, 76V, 84V, 89V Tipranavir Resistance Mutations 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V Case 2: Would You Use Darunavir or Tipranavir in the New Regimen? A.Yes, I would use darunavir + ritonavir B.Yes, I would use tipranavir + ritonavir C.Yes, I would use both D.No, I would not use either

88 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 87 Case 2: Would You Use NRTIs in This Regimen? Phenotype NRTIs: susceptible to TDF, ZDV, d4T NNRTIs: resistant to DLV, EFV, NVP PIs: partially susceptible to DRV A.Yes B.No

89 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 88 Case 2: How Many Additional Active Agents Does This Patient Need to Achieve HIV-1 RNA < 50 Copies/mL? A.1 B.2 C.3 D.Individualized for patient’s viral resistance

90 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 89 BENCHMRK-1 and -2 with virologic failures carried forward 5 PSSGSS ≥ 201 Overall Efficacy Data Patients With VL < 50 c/mL At Week 24 by PSS/GSS of OBT* (%) Raltegravir Placebo BENCHMRK 1&2: Response by Number of Active Agents in OBT (24 Weeks) Adapted from PN Kumar et al. EACS 2007; abstract P7.2/06.

91 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 90 DUET 1&2: Response by Number of Active Agents in OBT (24 Weeks) Anthony Mills and Christine Katlama et al. IAS 2007, abstract WESS204. Reprinted with permission.

92 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 91 MOTIVATE 1&2: Response by Number of Active Agents in OBT (24 Weeks) N= Number of Active Drugs in OBT Adapted from Mark Nelson et al. CROI 2007; abstract 104aLB. Adapted from Jacob Lalezari et al. CROI 2007; abstract 104bLB.

93 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 92 Case 2: Which Regimen Would You Choose? A.tenofovir/emtricitabine, darunavir + ritonavir, etravirine, maraviroc B.tenofovir/emtricitabine, darunavir + ritonavir, maraviroc, raltegravir C.tenofovir/emtricitabine, darunavir + ritonavir, etravirine, raltegravir D.tenofovir/emtricitabine, darunavir + ritonavir, etravirine, maraviroc, raltegravir E.Something else

94 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 93 Case 2: Evolution New regimen: TDF/FTC + DRV/RTV + ETR + MVC + RAL HIV-1 RNA at 6 weeks: < 50 copies/mL CD4+ cell count at 10 weeks: 420 cells/mm³ Serum creatinine ↑ to 2.7 mg/dL (from 1.9 mg/dL); 24-hour Cl Cr: 48 mL/min

95 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 94 Case 2: What Would You Do Now With the NRTI Portion of the Regimen? A.Continue TDF/FTC QD B.Continue TDF/FTC but decrease the dose to QOD C.Change TDF/FTC to ABC/3TC D.Discontinue TDF/FTC

96 The Body PRO CCR5 Antagonists and Tropism Testing in Clinical Practice 95 Case 2: Evolution Tenofovir discontinued due to concerns about decreased renal function New regimen: DRV/RTV + ETR + MVC + RAL HIV-1 RNA < 50 copies/mL CD4+ count ↑ to 550 cells/mm³ (from 420 cells/mm³) Serum creatinine  to 1.8 mg/dL (from 2.7 mg/dL); 24-hour Cl Cr: ↑ to 80 mL/min (from 24 mL/min)


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