HLA-B*57:01 for Abacavir Sensitivity

  • Standard of care before abacavir therapy per FDA
  • Predicts risk of abacavir hypersensitivity syndrome
  • Screening before reinitiation of treatment in individuals who have previously tolerated abacavir but whose HLA-B*57:01 status is unknown
  • Relevant to most populations

Abacavir sulfate is a nucleoside reverse transcriptase inhibitor (NRTI) used in combination with other antivirals in treatment of HIV infection. Serious and sometimes fatal abacavir hypersensitivity reaction (ABC HSR) occurs within the first 6 weeks of treatment in 5-8% of Caucasians and 2-3% of African Americans.  Administration of abacavir following ABC HSR is contraindicated because continued treatment can cause a more severe reaction. 

Disease Overview

Allele Frequency

The frequency of the HLA-B*57:01 allele varies by population; specific frequencies have been reported as :

  • Southwest Asian: 11%
  • Other Asian: 0-6.7%
  • European: 6.8%
  • South American: 2.6%
  • Middle Eastern: 2.5%
  • Mexican: 2.2%
  • African: 1%

Symptoms

Symptoms typically appear suddenly, worsen with each subsequent dose of abacavir, and improve within 48-72 hours of abacavir discontinuation. ABC HSR is often associated with two or more of the following symptoms :

  • Fever
  • Rash
  • Malaise/fatigue
  • Headache
  • Respiratory symptoms
  • Gastrointestinal symptoms (nausea, vomiting, abdominal pain)

Treatment Issues

Hypersensitivity to abacavir has been strongly associated with the major histocompatibility complex class I human leukocyte antigen (HLA), specifically the HLA-B*57:01 allele. DNA-based testing to assess the presence of HLA-B*57:01 offers higher specificity than serologic testing because monoclonal antibodies may show cross-reactivity with other HLA subtypes. The U.S. Food and Drug Administration (FDA) recommends pretherapeutic screening for the HLA-B*57:01 allele. Patients testing positive should not be treated with a regimen containing abacavir.  Routine screening has been shown to reduce the incidence of ABC HSR from 8% to <0.5% in abacavir-naïve patients. Because ~2% of individuals who are HLA-B*57:01 positive are tolerant to abacavir, HLA-B*57:01 status is necessary, but not sufficient by itself, for development  of ABC HSR. 

Genetics

Gene

HLA-B

Inheritance

Autosomal dominant

Allele

HLA-B*57:01 is strongly associated with ABC HSR.

Test Interpretation

Sensitivity/Specificity

Clinical sensitivity/specificity: 100% for immunologically confirmed hypersensitivity reaction

Analytical sensitivity/specificity: >99%

Results

Result Allele Detected Clinical Significance

Positive

HLA-B*57:01 heterozygous or homozygous

Predicts significantly increased risk for abacavir hypersensitivity

Avoidance or discontinuation of abacavir is advised

Negative

HLA-B*57:01 not detected

Predicts no increased risk for abacavir hypersensitivity

Limitations

  • Alleles other than HLA-B*57:01 will not be evaluated
  • Does not distinguish between heterozygote and homozygote carriers
  • Diagnostic errors can occur due to rare sequence variations
  • Risk of therapeutic failure or adverse reactions with abacavir may be affected by genetic and nongenetic factors not detected by this test
  • This test does not replace the need for therapeutic drug or clinical monitoring

References