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

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

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.

Sensitivity - X4 Minor Variant Detection

Enhanced Trofile detected 0.3% CXCR4-tropic (X4) variants with 100% sensitivity (from assay validation experiments of 288 samples).

0

20

40

60

80

100

120

0.001 0.01 0.1 1 10 100

% X4 clone

De

tec

tio

n (

%)

StandardEnhanced

0.3

Trinh et al. XVII International HIV Drug Resistance Workshop, Abstract 118, 2008

OriginalEnhanced

118 subjects enrolled

Stratified by: enfuvirtide use, CD4 ≤50 or >50 cells/µL

All regimens included 100-800 mg RTVGulick et al., JID 2007; 196: 304-312

ACTG 5211 Study Design

PlaceboPlacebo

VCV 5 mg qdVCV 5 mg qd

VCV 10 mg qdVCV 10 mg qd

VCV 15 mg qdVCV 15 mg qd

(stopped early)

STUDY ENTRY

DAY 14

WEEK 24

WEEK 48

optimized ART regimenfailing ART regimen

STUDY SCREEN

SCREENING: R5 tropism by the original Trofile assay

Coreceptor Tropism by the Original and Enhanced Trofile

25/114

Enhanced Trofile reclassified 25 individuals with R5 virus at screen15/25 were VCV recipients

12/15 had early detection of X4 virus on study (before week 8) by original Trofile

Original Trofile Enhanced Trofile

Screen Entry On study DM at Screen (n, %)

R5 DM DM/X4 7/12, 58%

R5 R5 DM/X4 9/18, 50%

R5 R5 R5 9/84, 11%

Change in Viral Load among VCV Recipients at Day 14 by Co-receptor Tropism (Enhanced Trofile)

*From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors

2

0

-2

-4

-6Ch

ang

e in

lo

g10

HIV

-1 R

NA

DM Screen R5 ScreenR5 Entry

R5 ScreenDM Entry

n 15 5 64

Mean -0.09 -0.66 -1.15

Adjusted p value* <0.0001 0.37 Reference

Change in Viral Load among VCV Recipients at Week 24 by Co-receptor Tropism (Enhanced Trofile)

*From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors

DM Screen R5 ScreenR5 Entry

R5 ScreenDM Entry

2

0

-2

-4

-6Ch

ang

e in

lo

g10

HIV

-1 R

NA

n 14 5 58

Mean -0.57 -1.20 -1.95

Adjusted p value* 0.0001 0.10 Reference

Change in CD4 Counts among VCV Recipients at Week 24 by Co-receptor Tropism (Enhanced Trofile)

*From a regression model adjusted for baseline CD4 count and study stratification factors

DM Screen R5 ScreenR5 Entry

R5 ScreenDM Entry

500

400

300

200

100

0

-100Ch

ang

e in

CD

4 C

ell

Co

un

t

n 14 5 58

Mean 45 75 140

Median (Q1, Q3) 32 (-1, 68) 68 (68, 125) 86 (40, 192)

Adjusted p value* 0.22 0.70 Reference

Viral Load Reduction in Subjects with R5 Virus at Screen by the original & Enhanced Trofile Assays

-2

-1.5

-1

-0.5

0

0.5P

lace

bo

5 10 15 Pla

cebo

5 10 15

Day 14 Week 24

Ch

ang

e in

Vir

al L

oad

(lo

g10

HIV

-1 R

NA

)

Original

Enhanced

Proportion of VCV Recipients with R5 Virus Achieving Defined HIV-1 RNA Levels at Week 24

≥ 1.0 log10 <400 <50Reduction cp/mL cp/mL

Trofile (ES)

0

0.2

0.4

0.6

0.8

>1.0 log10Reduction

<400 cp/mL <50 cp/mL

Pro

p. A

chiv

ing

Tre

sh

old

Original

Enhanced

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

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

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 KrambrinkMichael Hughes

Pharmaceutical Rep: Wayne Greaves Eoin Coakley

Immunologist: Paul Skolnik Neurologist: David Clifford

Acknowledgements (2)

ACTG 5211 Team (Cont)

DAIDS Clincal Rep: Carla Pettinelli Catherine Godfrey

Clinical Trials Specialist: Beatrice Kallungal

Data Manager: Susan OwensField Rep: Valery Hughes Team Investigators:

Timothy Wilkin Robert GrossScott Hammer Andrew Zolopa Martin Hirsch

DAIDS Pharmacist: Ana Martinez Laboratory Tech: Antoine SimmonsLab Data Coordinator:

Mary DobsonHoward Gutzman

Community Rep: Jim Smith

Participating ACTG sites,ACTG/NIAID/NIH, andpatient volunteers