Transcript HLA Testing: A Single Centre Experience Laura Waters, Andrea Gritz, Desmond Maitland, Brian Gazzard & Mark Nelson. Research Fellow PKR/SSR St.

HLA Testing: A Single
Centre Experience
Laura Waters, Andrea Gritz, Desmond Maitland,
Brian Gazzard & Mark Nelson.
Research Fellow PKR/SSR
St. Stephen’s Centre
Chelsea & Westminster Hospital, London
Introduction
• Guidelines recommend 3 fixed dose NRTI
combinations for initial therapy:
- Tenofovir + emtricitabine
- Abacavir* + lamivudine
- Zidovudine + lamivudine
• Combivir® less attractive due to twice daily
dosing and probable association with
lipoatrophy
*ABC
Introduction
• Adverse events are a common cause of
treatment discontinuation1,2
• ABC HSR occurs in 5-8% individuals3,4
• Strong association between ABC HSR and
HLA B*5701 positivity5,6
• Prospective testing has reduced ABC HSR
in two cohorts7,8
1. Monforte et al 2000; 2. O’Brien et al 2003; 3. European SPC; 4. US SPC; 5. Mallal et al 2002;
6. Hetherington et al 2002; 7. Rauch et al 2006; 8. Reeves et al 2006.
Fall in early ABC discontinuation
with genetic screening
Proportion of ABC-naïve patients
discontinuing ABC within 6 weeks
0.20
Before
After
genetic screening genetic screening
0.15
Possible ABCrelated symptoms
0.10
Definite ABC HSR
#
2 patients results not
reviewed prior to therapy
$ 1 patient with informed
choice/incomplete haplotype
0.05
0.0
1998/1999
n=68
Rauch A et al 2006.
#$
2000/2001
n=131
#
2002/2003 2004–7/2005
n=102
n=49
*p<0.05
Clinician assessed HSR pre
and post-B*5701
350
Number of subjects
300
p = 0.001
250
200
150
total
6.2% (4.1-9.4%)
HSR
100
0.5% (0.1-3.0%)
50
0
Pre B*5701
Reeves I et al. ADRL 2006
Post B*5701
Aims
• To describe the frequency of the HLA
B*5701 allele in our clinic cohort
• To assess the rate of ABC discontinuation
with prospective HLA testing
• To compare ABC HSR rates before and
after the introduction of routine HLA
B*5701 screening
Methods
• HLA screening was introduced in August 2005
for:
- all treatment-naïve subjects commencing therapy
- treatment-experienced patients considering a switch to
ABC
• ABC avoided if B*5701 positive
• All individuals undergoing HLA testing between
1/8/05 and 1/7/06 were reviewed
Methods
• Data collected:
- gender, ethnicity
- treatment history
- adverse events
• Detailed case note review of all subjects
discontinuing ABC
• Suspected ABC HSR rate with prospective
B*5701 screening compared with historical
ABC HSR rate (1/8/04 – 1/8/05)
Statistical Methods
• ABC HSR rates before and after the use of
prospective HLA B*5701 testing:
Chi-squared test with Yates’ correction
• ABC HSR rates between groups:
Chi-squared test with Yates’ correction or
Fisher’s exact test
Results
• 739 HLA B*5701 tests performed:
- 735 successful
- 4 test failures
• 54/735 tested HLA B*5701 positive = 7.3%
• 11/111 females HLA B*5701 positive = 9.9%#
• 43/624 males HLA B*5701 positive = 6.9%#
# p-value 0.35, Yates’ Correction
Results
Ethnicity
White
Total
number
523
HLA B*5701+;
number (%)
40 (7.6%)
Black
134
12 (9.0%)
Other
61
2 (3.3%)
Unknown
17
0
TOTAL
741
54 (7.3%)
Results
Subjects testing
HLA B*5701 positive (n=54)
Naïve
(n=25)
Experienced
(n=29)
- 14 did not commence therapy
- 9 commenced non-ABC cART
- 2 commenced ABC; both HSR
- None commenced ABC
- 7 history of ABC exposure
- 4/7 symptoms of HSR
- 2/6 tolerated ABC (for 6 W & 5 Y)
- 1/6 switched at 9/7 with result
Results
Subjects testing
HLA B*5701 negative (n=681)
Naïve
(n=285)
- 163 remain off therapy
- 122 commenced cART
- 47 commenced ABC with no
discontinuations
Experienced
(n=396)
- 151 switched to ABC
- 8 discontinued ABC (5.3%)
- 4/8 suspected HSR (2.6%)
B*5701- Suspected HSR
Clinical Features
1
SPP
Increasing fever, myalgia, rash, nausea POSITIVE +
& SOB 8 weeks into ABC therapy
systemic
symptoms
2
Nausea, fever, myalgia 3 weeks into
ABC; resolve with cessation
NEGATIVE
3
Fatigue & GI symptoms 10 days into
ABC; resolve with cessation
REFUSED
4
Fever, dizziness & GI symptoms 2
weeks into ABC; resolve with cessation
PENDING
SPP = Skin Patch Testing
Suspected HSR Pre & Post
Prospective B*5701 Testing
Number individuals
201
200
180
160
140
120
100
80
60
40
20
0
Starting ABC
p = 0.10
Suspected HSR
134
7.5%
10
Pre-B*5701
testing
3.0%
6
Pre-B*5701
testing
Suspected HSR Pre & Post
Prospective B*5701 Testing
Number individuals
199
200
180
160
140
120
100
80
60
40
20
0
Starting ABC
p = 0.03
Suspected HSR
134
7.5%
10
Pre-B*5701
testing
2.0%
4
Pre-B*5701
testing
ABC HSR Rates in TreatmentNaïve & Experienced Subjects
151
160
Starting ABC
p = 0.57*
140
Suspected HSR
120
100
80
60
2.6%
47
40
20
0
4
0
Naïve individuals
*by Fisher’s exact test
Experienced individuals
Conclusions
• The introduction of prospective HLA B*5701
screening reduced the incidence of ABC
HSR in our cohort
• Despite testing HLA B*5701 negative, 4
individuals (2.0%) discontinued ABC for
suspected HSR
Conclusions
• 1 HLA B*5701 negative subject developed
HSR with a positive SPP and systemic
symptoms
• Our data highlight the importance of
maintaining clinical vigilance when
prescribing ABC regardless of the HLA
B*5701 result
Acknowledgements
• Sundhiya Mandalia
• Marta Boffito
• St Stephen’s Centre staff & patients