Transcript Response to Vicriviroc (VCV) in HIV

Response to Vicriviroc in HIV-Infected TreatmentExperienced 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
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
120
Detection (%)
100
80
60
40
Original
Standard
Enhanced
Enhanced
20
0
0.001
0.01
0.1 0.3
1
10
100
% X4 clone
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
ACTG 5211 Study Design
Placebo
VCV 5 mg qd
SCREENING:
R5 tropism by
the original
Trofile assay
VCV 10 mg qd
VCV 15 mg qd
failing ART regimen
STUDY
SCREEN
(stopped early)
STUDY DAY
ENTRY 14
optimized ART regimen
WEEK
24
WEEK
48
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
Coreceptor Tropism by the Original and
Enhanced Trofile
Original Trofile
Screen
R5
R5
R5
Entry
DM
R5
R5
Enhanced Trofile
On study
DM/X4
DM/X4
R5
DM at Screen (n, %)
7/12, 58%
9/18, 50%
9/84, 11%
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
Change in log10 HIV-1 RNA
Change in Viral Load among VCV Recipients at
Day 14 by Co-receptor Tropism (Enhanced Trofile)
2
0
-2
-4
-6
DM Screen
R5 Screen
DM Entry
R5 Screen
R5 Entry
n
15
5
64
Mean
-0.09
-0.66
-1.15
Adjusted p value*
<0.0001
0.37
Reference
*From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors
Change in log10 HIV-1 RNA
Change in Viral Load among VCV Recipients at
Week 24 by Co-receptor Tropism (Enhanced Trofile)
2
0
-2
-4
-6
DM Screen
R5 Screen
DM Entry
R5 Screen
R5 Entry
n
14
5
58
Mean
-0.57
-1.20
-1.95
Adjusted p value*
0.0001
0.10
Reference
*From a regression model adjusted for baseline log10 HIV-1 RNA and study stratification factors
Change in CD4 Cell Count
Change in CD4 Counts among VCV Recipients at
Week 24 by Co-receptor Tropism (Enhanced Trofile)
500
400
300
200
100
0
-100
n
Mean
14
R5 Screen
DM Entry
5
45
75
140
Median (Q1, Q3)
32 (-1, 68)
68 (68, 125)
86 (40, 192)
Adjusted p value*
0.22
0.70
Reference
DM Screen
R5 Screen
R5 Entry
58
*From a regression model adjusted for baseline CD4 count and study stratification factors
Viral Load Reduction in Subjects with R5 Virus at
Screen by the original & Enhanced Trofile Assays
Change in Viral Load
(log10 HIV-1 RNA)
0
-0.5
-1
-1.5
Original
-2
Enhanced
15
10
5
Placebo
15
Week 24
10
5
0.5
Placebo
Day 14
Prop. Achiving Treshold
Proportion of VCV Recipients with R5 Virus
Achieving Defined HIV-1 RNA Levels at Week 24
Original
0.8
Trofile (ES)
Enhanced
0.6
0.4
0.2
0
≥ 1.0 log10
log10
>1.0
Reduction
Reduction
<400
<400
cp/mL
cp/mL
<50<50
cp/mL
cp/mL
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 Krambrink
Michael 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 Owens
Field Rep: Valery Hughes
Team Investigators:
Timothy Wilkin
Robert Gross
Scott Hammer
Andrew Zolopa
Martin Hirsch
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