Title: ABC107442 SHAPE Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation
1ABC107442 (SHAPE)Study of Hypersensitivity to
Abacavir and Pharmacogenetic Evaluation
- Michael Saag, Rukmini Balu, Elizabeth Phillips,
Philip Brachman, Claudia Martorell, William
Burman, Britt Stancil, Michael Mosteller, Cindy
Brothers, Paul Wannamaker, Arlene Hughes, Denise
Sutherland-Phillips, Simon Mallal and Mark
Shaefer for the SHAPE team - Presenting author
2Background
- Studies have observed variable sensitivity of
HLA-B5701 - Definition of abacavir hypersensitivity reaction
(ABC HSR) - nonspecificity of clinical phenotyping ?
- false positive clinical diagnosis
- Differences in white and nonwhite races
100
80
60
Sensitivity of HLA-B5701
40
20
0
Mallal
CNA30027
CNA30032
Mallal et al. Lancet 2002 Hughes et al.
Pharmacogenomics 2004
White
Black
3What is SHAPE?
- Retrospective case-control study
- To evaluate the sensitivity and specificity of
HLA-B5701 - Study design necessary because of low carriage
frequency of HLA-B5701 and low rates of ABC HSR
in Blacks - Addresses two important aspects of
pharmacogenetic research - Generalizability to White and Black races
- Supplement clinical definition of ABC HSR with
patch test (phenotype)
4Abacavir Skin Patch Testing
- Immune cell-mediated reaction
- Research tool used to identify
- patients with immune-mediated
- abacavir HSR
-
Schematic top view of skin patch
Adhesive surface
1 abacavir
Petrolatum control
10 abacavir
Excipient control
48 Hour
24 Hour
Phillips et al. AIDS 2002 and 2005 Phillips et
al. IAS 2007 Abstract MOPEB001
5SHAPE Study Design
6 7Demographic Characteristics for Cases
8Differential Clinical Symptoms of ABC HSR
100
96
91
80
73
66
64
64
60
58
55
Proportion of subjects
40
30
25
20
Constitutional (p0.02)
Fever (pRash (pNS)
GI (pNS)
Respiratory (pNS)
SPT-neg (n148)
SPT-Pos (n47)
9Symptom Categories for ABC HSR
100
91
80
62
60
32
40
20
9
3
3
0
1
2
3
SPT-pos (n47)
SPT-neg (n148)
Mantel-Haenszel Chi-square p-value 0.0004
10Days to Onset of ABC HSR
11Days to Onset of ABC HSR
12Primary EndpointSensitivity of HLA-B5701
Sensitivity of HLA-B5701 and 95 CI
White
Black
13Sensitivity and Specificity of HLA-B5701
100
Sensitivity/Specificity of HLA-B5701 and 95 CI
White
Black
OR White IC-HSR 1945 110-34352 CS-HSR
198-48 Black IC-HSR 900 30-21045
CS-HSR 174-164
14Context of SHAPE Results
100
78
80
57
48
60
Sensitivity of HLA-B5701
40
8
20
Mallal
CNA30027
CNA30032
CS-HSR
CS-HSR
CS-HSR
Mallal et al. Lancet 2002 Hughes et al
Pharmacogenomics 2004 Mallal et al. IAS, 2007,
abstract WESS101 Saag et al. IAS 2007, abstract
WEAB305 Phillips et al. IAS 2007 Abstract
MOPEB001
White
Black
15Screening Implications
Example shown is based upon PPV derived from
PREDICT-1 and SHAPE data.
16Screening Implications
Black n 100
White n 100
HLA-B5701 test
HLA-B5701 test
98 Negative
Appropriate to treat with ABC
2 Positive
94 Negative
6 Positive
Example shown is based upon PPV derived from
PREDICT-1 and SHAPE data.
17Screening Implications
Black n 100
White n 100
HLA-B5701 test
HLA-B5701 test
98 Negative
2 Positive
94 Negative
6 Positive
If treated with ABC
If treated with ABC
ABC HSR n 1
No ABC HSR n 1
ABC HSR n 4
No ABC HSR n 2
Example shown is based upon PPV derived from
PREDICT-1 and SHAPE data.
18Screening Implications
Black n 100
White n 100
HLA-B5701 test
HLA-B5701 test
98 Negative
Appropriate to treat with ABC
2 Positive
94 Negative
6 Positive
Do not treat with ABC
Do not treat with ABC
- Test 100 Black patients
- Treat 98 patients at low risk
- for ABC HSR
- Prevent 1 ABC HSR event
- Exclude ABC in 1 patient
- Test 100 White patients
- Treat 94 patients at low risk
- for ABC HSR
- Prevent 4 ABC HSR events
- Exclude ABC in 2 patients
Example shown is based upon PPV derived from
PREDICT-1 and SHAPE data.
19Conclusions
- Results in Whites consistent with the randomized
study PREDICT-1 (Abstract WESS101) that
demonstrated pre-therapy screening for HLA-B5701
significantly reduced both clinical and
immunologically confirmed ABC HSR. - Similar results seen in Blacks imply that
screening for HLA-B5701 is a broadly
generalizable approach for reducing ABC HSR
rates.
20Acknowledgments