HLA Testing: A Single Centre Experience

Laura Waters, Andrea Gritz, Desmond Maitland, Brian Gazzard & Mark Nelson.

Research Fellow PKR/SSRSt. 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.

0.0

0.05

0.10

0.15

0.20

1998/1999 2000/2001 2002/20032004–7/2005

Possible ABC-related symptomsDefinite ABC HSR# 2 patients results not

reviewed prior to therapy $ 1 patient with informed choice/incomplete haplotype

Pro

port

ion

of

AB

C-n

aïv

e

pati

en

ts d

iscon

tin

uin

g A

BC

w

ith

in 6

weeks

n=68 n=131 n=102 n=49

#

Beforegenetic screening

Aftergenetic screening

#$

*p<0.05

Rauch A et al 2006.

Fall in early ABC discontinuation with genetic screening

Clinician assessed HSR pre and post-B*5701

0.5% (0.1-3.0%)

6.2% (4.1-9.4%)

p = 0.001

total

HSRNu

mb

er o

f su

bje

cts

Pre B*5701 Post B*5701

0

50

100

150

200

250

300

350

Reeves I et al. ADRL 2006

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 Total

number

HLA B*5701+;

number (%)

White 523 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)

- 14 did not commence therapy

- 9 commenced non-ABC cART

- 2 commenced ABC; both HSR

Experienced (n=29)

- 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 SPP

1 Increasing fever, myalgia, rash, nausea & SOB 8 weeks into ABC therapy

POSITIVE + 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

0

20

40

60

80

100

120

140

160

180

200

Num

ber

indi

vidu

als 134

106

201

Pre-B*5701testing

Pre-B*5701testing

Starting ABC

Suspected HSR

7.5% 3.0%

p = 0.10

Suspected HSR Pre & Post Prospective B*5701 Testing

0

20

40

60

80

100

120

140

160

180

200

Num

ber

indi

vidu

als 134

104

199

Pre-B*5701testing

Pre-B*5701testing

Starting ABC

Suspected HSR

7.5% 2.0%

p = 0.03

Suspected HSR Pre & Post Prospective B*5701 Testing

0

20

40

60

80

100

120

140

160

Naïve individuals Experienced individuals

47

0

151

4

p = 0.57*

2.6%

ABC HSR Rates in Treatment-Naïve & Experienced Subjects

Starting ABC

Suspected HSR

*by Fisher’s exact test

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