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Z Su, JD Reeves, A Krambrink, E Coakley, M Hughes, C Flexner, T Wilkin, P Skolnik, W Greaves, D Kuritzkes, R Gulick, A

Response to Vicriviroc in HIV-Infected Treatment-Experienced Subjects using an Enhanced Version of the Trofile HIV Co-receptor Tropism Assay: Reanalysis of ACTG 5211 Results . Z Su, JD Reeves, A Krambrink, E Coakley, M Hughes, C Flexner, T Wilkin, P Skolnik, W Greaves, D Kuritzkes, R Gulick,

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Z Su, JD Reeves, A Krambrink, E Coakley, M Hughes, C Flexner, T Wilkin, P Skolnik, W Greaves, D Kuritzkes, R Gulick, A

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  1. Response to Vicriviroc in HIV-Infected Treatment-Experienced Subjects using an Enhanced Version of the Trofile HIV Co-receptor Tropism Assay: Reanalysis of ACTG 5211 Results Z Su, JD Reeves, A Krambrink, E Coakley, M Hughes, C Flexner, T Wilkin, P Skolnik, W Greaves, D Kuritzkes, R Gulick, ACTG 5211 Team

  2. Objective • To assess whether the enhanced Trofile assay is an improved screening tool compared to the original Trofile assay for the selection of patients who may benefit from CCR5 antagonist therapy.

  3. Sensitivity - X4 Minor Variant Detection Original Enhanced 0.3 • Enhanced Trofile detected 0.3% CXCR4-tropic (X4) variants with 100% sensitivity (from assay validation experiments of 288 samples). Trinh et al. XVII International HIV Drug Resistance Workshop, Abstract 118, 2008

  4. ACTG 5211 Study Design Placebo SCREENING: R5 tropism by the original Trofile assay VCV 5 mg qd (stopped early) VCV 10 mg qd VCV 15 mg qd failing ART regimen optimized ART regimen WEEK 24 WEEK 48 STUDY SCREEN STUDY ENTRY DAY 14 • 118 subjects enrolled • Stratified by: enfuvirtide use, CD4 ≤50 or >50 cells/µL • All regimens included 100-800 mg RTV Gulick et al., JID 2007; 196: 304-312

  5. Coreceptor Tropism by the Original and Enhanced Trofile 25/114 • Enhanced Trofile reclassified 25 individuals with R5 virus at screen • 15/25 were VCV recipients • 12/15 had early detection of X4 virus on study (before week 8) by original Trofile

  6. Change in Viral Load among VCV Recipients at Day 14 by Co-receptor Tropism (Enhanced Trofile) 2 0 -2 -4 -6 Change in log10 HIV-1 RNA DM Screen R5 Screen DM Entry R5 Screen R5 Entry *From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors

  7. Change in Viral Load among VCV Recipients at Week 24 by Co-receptor Tropism (Enhanced Trofile) 2 0 -2 -4 -6 Change in log10 HIV-1 RNA R5 Screen R5 Entry DM Screen R5 Screen DM Entry *From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors

  8. Change in CD4 Counts among VCV Recipients at Week 24 by Co-receptor Tropism (Enhanced Trofile) 500 400 300 200 100 0 -100 Change in CD4 Cell Count DM Screen R5 Screen DM Entry R5 Screen R5 Entry *From a regression model adjusted for baseline CD4 count and study stratification factors

  9. Viral Load Reduction in Subjects with R5 Virus at Screen by the original & Enhanced Trofile Assays Day 14 Week 24 0.5 Placebo Placebo 15 10 15 10 5 5 0 -0.5 Change in Viral Load (log10 HIV-1 RNA) -1 -1.5 Original -2 Enhanced

  10. Proportion of VCV Recipients with R5 Virus Achieving Defined HIV-1 RNA Levels at Week 24 Trofile (ES) ≥ 1.0 log10 <400 <50 Reduction cp/mL cp/mL

  11. Summary • Screen tropism results from the enhanced Trofile were predictive of early detection of CXCR4-use in ACTG 5211 VCV recipients • Greater viral load reduction was observed at Day 14 and Week 24 in subjects with R5 virus at screen and entry compared to DM at screen by the enhanced Trofile • There were trends for improved virologic responses at Day 14 and Week 24 in VCV recipients with R5 virus at screen by the enhanced Trofile compared to original analysis according to the original Trofile

  12. Conclusions • Enhanced Trofile showed improved ability to predict antiretroviral responses to VCV • Enhanced Trofile is an improved screening tool for determining patient eligibility for CCR5 antagonist therapy

  13. Acknowledgements (1) • Monogram Biosciences • Jackie Reeves • Eoin Coakley • Dong Han • Wei Huang • Linda Kiss • Jeff Larson • Neil Parkin • Chris Petropoulos • Lan Trinh • Jeannette Whitcomb • Terri Wrin • Monogram Biosciences Clinical Reference Laboratory • ACTG 5211 Team • Chair: Trip Gulick • Co-Chair: • Dan Kuritzkes • Charles Flexner • Statisticians: • Zhaohui Su • Amy Krambrink • Michael Hughes • Pharmaceutical Rep: • Wayne Greaves • Eoin Coakley • Immunologist: Paul Skolnik • Neurologist: David Clifford

  14. Acknowledgements (2) • DAIDS Pharmacist: Ana Martinez • Laboratory Tech: Antoine Simmons • Lab Data Coordinator: • Mary Dobson • Howard Gutzman • Community Rep: Jim Smith • Participating ACTG sites, • ACTG/NIAID/NIH, and • patient volunteers • ACTG 5211 Team (Cont) • DAIDS Clincal Rep: • Carla Pettinelli • Catherine Godfrey • Clinical Trials Specialist: • Beatrice Kallungal • Data Manager: Susan Owens • Field Rep: Valery Hughes • Team Investigators: • Timothy Wilkin • Robert Gross • Scott Hammer • Andrew Zolopa • Martin Hirsch

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