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HLA Testing A Single Centre Experience

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					              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 cohorts. 7,8

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
                                      0.20      Before               After               Possible ABC-related
                                                genetic             genetic              symptoms
                                               screening           screening
   discontinuing ABC within 6 weeks
   Proportion of ABC-naïve patients




                                                                                         Definite ABC HSR
                                      0.15                                               # 2 patients results not
                                                                                         reviewed prior to therapy
                                                                                         $ 1 patient with informed
                                                                                         choice/incomplete haplotype
                                      0.10



                                      0.05

                                                                                             *p<0.05
                                                                    #$          #
                                       0.0
                                         1998/1999   2000/2001   2002/2003 2004–7/2005
                                           n=68        n=131       n=102      n=49

Rauch A et al 2006.
                      Clinician assessed HSR pre
                      and post-B*5701
                      350

                      300                          p = 0.001
 Number of subjects




                      250

                      200

                      150                                                            total
                                         6.2% (4.1-9.4%)
                                                                                    HSR
                      100
                                                                             0.5% (0.1-3.0%)
                      50

                       0
                            Pre B*5701                         Post B*5701

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
                Total   HLA B*5701+;
   Ethnicity
               number    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)
               - 14 did not commence therapy
Naïve          - 9 commenced non-ABC cART
(n=25)         - 2 commenced ABC; both HSR

               -   None commenced ABC
Experienced    -   7 history of ABC exposure
(n=29)         -   4/7 symptoms of HSR
               -   2/7 tolerated ABC (for 6 W & 5 Y)
               -   1/7 switched at 21 days with result
Results
                Subjects testing
          HLA B*5701 negative (n=681)
             - 163 remain off therapy
Naïve
             - 122 commenced cART
(n=285)
             - 47 commenced ABC; no discontinuations

            - 151 switched to ABC
Experienced
            - 8 discontinued ABC (5.3%)
(n=396)
            - 4/8 suspected HSR (2.6%)
 B*5701- Suspected HSR
                    Clinical Features                SPT

                                                   POSITIVE +
       Increasing fever, myalgia, rash, nausea &
 1          SOB 8 weeks into ABC therapy
                                                     systemic
                                                    symptoms
      Nausea, fever, myalgia 3 weeks into ABC;
 2            resolved with cessation
                                                   NEGATIVE

      Fatigue & GI symptoms 10 days into ABC;
 3             resolved with cessation
                                                   REFUSED

       Fever, dizziness & GI symptoms 2 weeks
 4        into ABC; resolved with cessation
                                                   PENDING

SPP = Skin Patch Testing
Suspected HSR Pre & Post
Prospective B*5701 Testing
                                               201
                     200            p = 0.10
                     180                                    Starting ABC
                     160                                    Suspected HSR
                           134
Number individuals




                     140
                     120
                     100          7.5%               3.0%
                      80
                      60
                      40
                                  10
                      20                              6
                       0
                           Pre-B*5701          Pre-B*5701
                             testing             testing
Suspected HSR Pre & Post
Prospective B*5701 Testing
                                               199
                     200            p = 0.03
                     180                                    Starting ABC
                     160                                    Suspected HSR
                           134
Number individuals




                     140
                     120
                     100          7.5%               2.0%
                      80
                      60
                      40
                                  10
                      20                              4
                       0
                           Pre-B*5701          Pre-B*5701
                             testing             testing
ABC HSR Rates in Treatment-
Naïve & Experienced Subjects

160                              p = 0.57*        151
                                                                 Starting ABC
140
120                                                              Suspected HSR
100
 80
                                                            2.6%
 60                    47
 40
 20                                                          4
                                0
  0
                    Naïve individuals        Experienced individuals

      *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 SPT 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

				
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