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. DisclosuresDr. 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.
12 CCR5 Function and Genetics CCR5 is a receptor for C-C chemokines (chemo-attractive cytokines)Expressed on immune effector cells and antigen presenting cellsMolecules that bind to CCR5 include MIP-1, MIP-1, and RANTESActivation of CCR5 on T cells by chemokines leads to:T-cell migration to the site of inflammationImmune response to various antigensCCR5, together with CD4, are the primary receptors utilized by HIV for viral entryGalvani 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:
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 Global Prevalence of CCR5 D32 Allele ~14%~6%Rare10%-15%~10%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 agoPossible selection by pandemic pathogen, likely smallpox or bubonic plagueGalvani 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:
16 CCR5 Wild Type and CCR5 32 Normal Heterozygotes Homozygotes wt/wtwt/3232/32Normal CCR5 expProgression of HIVNormal immune fx*Decreased CCR5 expDelayed prog. to AIDS/deathNormal immune fx*No CCR5 expRare infection with X4Normal immune fx**fx = functionClick 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:
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:
31 Percentage of HIV Coreceptor Usage Study/SourcePopulationNR5X4R5/X4Homer cohort1Naive97982%< 1%18%C & W cohort240281%19%Demarest329988%0%12%Study 10264Naïve142885%15%TORO 1/26Experienced61262%4%34%ViroLogic5> 200048%2%50%ACTG 5211739149%47%MOTIVATE 1/28256056%3%41%This table may not include all available reported data; majority of data are generated in the developed world (subtype B)1Brumme 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 2040.7Wilkin T et al. CROI 2006; abstract Coakley E et al. International Workshop on Targeting HIV Entry 2006; abstract 8.
32 Prevalence of X4 Phenotype by Baseline CD4+ Count 10092.8Coreceptor use was determined in 1191 patients starting HAARTPatients with D/M virus had a poorer clinical profile than patients with R5 virusMedian CD4+ T-cell count of 110 versus 290 cells/mm3 (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 countHigh baseline HIV RNACCR5-Δ32 deletion heterozygous patientsBasic mutations at gp120-V3 codons 11 or 258054.460R5Percentage of PatientsD/M4045.6207.2< 2525-4950-99≥ 500Baseline CD4Adapted from Brumme ZL et al. J Infect Dis. 2005:192;466-74
33 Tropism in Naive Patients: Impact on CD4+ Decline and Response to Treatment 402 treatment-naive subjects had tropism tested326 R573 D/M3 X4340 started HAART by August 2006229 R560 D/M51 excluded from analysisGraeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission.
34 CD4+ Decline Before HAART DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CIGraeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission.
35 Time to Viral Suppression Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAARTGraeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission.
36 Tropism Does Not Affect Response to HAART R5 TropicR5/X4 TropicP ValueCD4+ T-Cell Count Rise at 12 Months, Cells/mm3 (95% CI)185 ( )182 ( ).812CD4+ T-Cell Count Rise at 24 Months, Cells/mm3 (95% CI)247 ( )292 ( ).482Patients With VL < 50 Copies/mL at 12 Months, n (%)168 (73.4)47 (78.3).509Patients With VL < 50 Copies/mL at 24 Months, n (%)166 (72.4)41 (68.3).67CI = confidence intervalGraeme Moyle et al. ICAAC 2006; abstract H Reprinted with permission.
38 MOTIVATE 1&2: Trial Design David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
39 MOTIVATE 1&2: Demographics and Baseline Characteristics David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
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.
41 MOTIVATE 1&2: Percentage of Patients With Undetectable HIV-1 RNA David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
42 MOTIVATE 1&2: Mean Change in CD4+ Cell Count From Baseline to Week 48 CD4+ cell count increases up to 48 weeks were more favorable in both the maraviroc groups than the placebo groupThe mean change from baseline in CD4+ cell count* was:+61 cells/mm3 in the placebo + OBT+116 cells/mm3 in maraviroc QD + OBT+124 cells/mm3 in the maraviroc BID + OBT group* Last observation carried forward approach used to impute missing valuesDavid Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
43 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. 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.
44 MOTIVATE 1&2: Safety Analyses Unadjusted For Duration of Exposure David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
45 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. MOTIVATE 1&2: Maximum Liver Function Test Values Over 48 Weeks Without Regard To BaselineDavid Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
46 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. MOTIVATE 1&2: Percentage of Adverse Events Occurring in ≥ 5% of Patients in Any Group, Unadjusted for Treatment ExposureDavid Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
47 VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.
48 VICTOR-E1: Virologic Efficacy of Vicriviroc vs. Placebo at Week 48 VCV 30 mg n = 39VCV 20 mg n = 40Placebo n = 35100Patients With HIV-RNA-1 < 50 copies/mL (%)Mean Change in HIV-1 RNA From BL (log10 copies/mL)90-0.280-0.470-0.6566053-0.8-0.7950-1.040-1.230-1.42014-1.610-1.8-1.77-1.75Difference: P = .0028-2.0Difference: P = .0017VCV 30 mg n = 22VCV 20 mg n = 21Placebo n = 5No clinically significant differences in adverse events between VCV arms and placeboBarry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.
49 MERIT: Maraviroc vs. Efavirenz in Treatment-Naive Patients Stratified by HIV-1 RNA < or 100,000 copies/mL and by Northern or Southern HemisphereWeek 48 primary endpointWeek 96MVC 300 mg twice daily + ZDV/3TC(n = 360)Antiretroviral-naive patients infected with CCR5-tropic HIV-1 and HIV-1 RNA 2000 copies/mL(N = 740)EFV 600 mg once daily + ZDV/3TC(n = 361)MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16)Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CIMichael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
50 MERIT: Patients With Viral Load < 400 and < 50 Copies/mL by Week 48 (ITT) EFV (n = 361)MVC (n = 360)100VL < 400 copies/mL100VL < 50 copies/mL73.1%808069.3%6070.6%6065.3%Patients, %Patients, %4040202024816243240482481624324048Time (weeks)Time (weeks)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/mm3)Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
51 MERIT: Patients With Viral Load < 50 Copies/mL by Baseline Viral Load EFV patients more likely to discontinue due to AEOverall : 25.2%AE: 13.6%Efficacy: 4.2%MVC patients more likely to discontinue due to lack of efficacyOverall: 26.9%AE: 4.2%Efficacy: 11.9%EFVMVC100908071.669.67066.659.660Patients, %5040302010n =211204150156BL VL < 100,000 Copies/mLBL VL ≥ 100,000 Copies/mLMichael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
52 MERIT: Week 48 Safety Analyses All Causalities and SeveritiesEFV + CBV N=361MVC + CBV N=360Patients With Adverse Events340 (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)Malignancies16 (4.4)10 (2.8)Deaths†*, n (%)1AEs = 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 databaseMichael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
53 MERIT: Viral Suppression at Week 48 by Baseline Tropism 20307010405060809010069.354.67.1n =111468.0339331Patients With VL < 50 c/mL at Week 48 (%)EFVMVC65.3Tropism at Screening (Overall)361360Tropism 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 MVC3.5% of patients experienced change in detected tropism between screening and BL50.0% 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 CJayvany Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.
54 MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48 Edwin DeJesus et al. CROI 2008; abstract 929. Reprinted with permission.
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?