Clinical data

A number of studies have been performed to investigate whether HLA-B*5701 screening is an effective and feasible procedure to reduce the incidence of abacavir HSR.

  • The PREDICT-1 study (CNA106030) was a pivotal, double blinded, randomised clinical trial to establish the effectiveness of the HLA-B*5701 allele as a predictive marker for abacavir (ABC) hypersensitivity reaction (HSR).

    1,956 ABC naive subjects randomised 1:1 in a double blinded fashion to:

    • Arm A) Retrospective HLA-B*5701 testing after starting ABC therapy (Controls)
    • Arm B) Prospective HLA-B*5701 screening; positive patients excluded pre- ABC therapy

    Retrospective epicutaneous patch testing (EPT) was carried out in all cases of clinically suspected ABC HSR.

    Study design

    Demographics

      Prospective screen
    ITT (EV1)
    (n=803)
    Control
    ITT (EV1)
    (n=847)
    Male, n (%)
    595 (74) 602 (71)
    Female, n (%) 208 (26) 245 (29)
    Mean age, y (range) 42 (18-77) 42 (18-76)
    Self-reported race, n (%)b    
      White: White / Caucasian / European heritage 665 (83) 702 (83)
      African American / African heritage 96 (12) 96 (11)
      White: Arabic / North African heritage 12 (2) 13 (2)
      American Indian or Alaskan native 8 (1) 10 (1)
      Mixed race 7 (1) 11 (1)
      Otherc 14 (2) 15 (2)
    Antiretroviral naive, n (%) 147 (18) 149 (18)
    Antiretroviral experienced, n (%) 656 (82) 698 (82)

    ITT (EV1), intention-to-treat evaluable population.
    a HLA-B*5701–negative.
    b One subject in the prospective pharmacogenetics screening arm failed to provide information on race. 
    c Other includes all race categories for which there were <1% of subjects in either study arm (ie, South East Asian heritage, East Asian heritage, Central/South Asian heritage, native Hawaiian or other Pacific islander, and white mixed race.

    HLA-B*5701 Status by Race

    • Incidence of an HLA-B*5701–positive screen in the white population was 106 / 1650 (6%), whereas incidence in the African American/African heritage group was 1 / 232 (<1%)
    • No other race category was reported by more than 1% of subjects in either the HLA-B*5701–positive or –negative groups, so no conclusions can be drawn

    Incidence of Immunologically Suspected Abacavir Hypersensitivity

    a Intention-to-treat evaluable population.
    b Prospective screen versus control adjusted for actual strata of race, ART status, introduction of NNRTI, and concurrent PI use.

    Incidence of Immunologically Confirmed Abacavir Hypersensitivity

    a Intention-to-treat evaluable population. b Prospective screen versus control adjusted for actual strata of race, ART status, introduction of NNRTI, and concurrent PI use.

    a Intention-to-treat evaluable population.
    b Prospective screen versus control adjusted for actual strata of race, ART status, introduction of NNRTI, and concurrent PI use.

    Conclusions

    It was estimated that 48% - 61% of patients with HLA-B*5701 will develop HSR on ABC containing therapy vs. 0% to 4% of patients who do not have the allele.

  • SHAPE (ABC107442) is a retrospective case-control study to estimate the sensitivity and specificity of the HLA-B*5701 allele in self-reported White and Black subjects with and without suspected ABC HSR, using EPT to supplement clinical diagnosis of abacavir hypersensitivity.

    Study Design

    Inclusion criteria

    Subjects had retrospectively identified, clinically suspected abacavir hypersensitivity:

    • Documented abacavir use and hypersensitivity event:
      • Within 6 weeks of treatment initiation;
      • Symptoms in ≥2 categories (rash, fever, gastrointestinal, constitutional); and
      • Improvement or resolution upon discontinuation of abacavir.
    • HLA-B*5701 determination and abacavir skin patch testing

    Controls:

    • Retrospectively identified with no evidence of abacavir hypersensitivity after ≥12 weeks of abacavir use
    • Pharmacogenetic blood sample and consent collected as part of a previous study
    • Did not undergo skin patch testing

    Demographics

      Skin patch
    test–positive
    hypersensitivity
    reaction
    Clinically
    suspected
    hypersensitivity
    reaction
    Controls
      White
    (n=42)
    Black
    (n=5)
    White
    (n=130)
    Black
    (n=69)
    White
    (n=202)
    Black
    (n=206)
    Mean age, y 44 47 45 45 41 41
    Mean age, (range) (23-57) (32-57) (22-73)
    (22-76) (19-72) (19-73)
    Sex, n (%)
    Male 38 (90) 5 (100) 106 (82) 41 (59) 187 (93) 146 (71)
    Female 4 (10) 0 24 (18) 28 (41) 15 (7) 60 (29)

    Results

    White subjects

      SPT-positive
    HSR (n=42)
    SPT-negative
    HSR (n=85)a
    All HSR
    (n=130)a
    Controls
    (n=202)
    HLA-B*5701 positive, n 42 15 57 8
    HLA-B*5701 negative, n 0 69 72 194
    Sensitivity (95% CI) 1.0 (0.92, 1.00) - 0.44 (0.35, 0.53) -
    Specificity (95% CI) - - - 0.96 (0.92, 0.98)

    Black subjects

      SPT-positive
    HSR (n=5)
    SPT-negative
    HSR (n=63)a
    All HSR
    (n=69)a
    Controls
    (n=206)
    HLA-B*5701 positive, n 5 5 10 2
    HLA-B*5701 negative, n 0 58 59 204
    Sensitivity (95% CI) 1.0 (0.48, 1.00) - 0.14 (0.07, 0.25) -
    Specificity (95% CI) - - - 0.99 (0.97, 1.00)
    • Immunologically confirmed HSR cases (SPT+) odds ratio = 1945 [110, 334352; white]; 900 [38, 21045; black]
    • All clinically suspected HSR cases odds ratio = 19 [8, 48; white]; 17 [3, 164; black]

    HSR, hypersensitivity reaction; SPT, skin patch test.
    a One subject did not have HLA-B*5701 result; 3 subjects did not have results for skin patch tests.
    b One subject had unknown skin patch test.

    Conclusions

    • 100% sensitivity of HLA-B*5701 in white and black subjects with EPT confirmed ABC HSR
    • Lower sensitivity of HLA-B*5701 screening observed when ABC HSR was defined by clinical diagnosis alone
    • Not all HLA-B*5701 positive subjects had a positive EPT test result
    • Prospective HLA-B*5701 screening may reduce ABC HSR rates in white and black subjects
    • The presence of the HLA-B*5701 allele is associated with increased risk of ABC HSR, regardless of race
  • A limitation of the PREDICT-1 study was that investigators were blinded to subjects HLA-B*5701 status during the study, which would not be the case in clinical practice.

    Recent marketing authorisation holder (MAH) trials, which prospectively screened for the HLA-B*5701 allele and excluded subjects testing positive, more accurately reflect experience and reporting rates in clinical practice.

    MAH Sponsored Clinical Trials with prospective HLA-B*5701 screening ABC containing treatment group HSR Reporting Rate
    % (n/N)
    ASSERT (CNA109586)3 ABC/3TC + EFV 3.1 (6/192)
    ARIES (EPZ108859)4 ABC/3TC + ATV+ RTV 1 (4/491)
    ASSURE (EPZ113734)5 ABC/3TC + ATV <1 (1/199)
    SINGLE (ING114467)6 ABC/3TC + DTG <1 (1/414)
    Total   1 (12/1320)

    ABC/3TC = KIVEXA; ATV = atazanvir; DTG = dolutegravir; EFV = efavirenz; RTV = ritonavir.