HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity

The presence of the HLA-B*58:01 allele shows strong association with allopurinol-induced SCAR, including SJS and TEN.

Prevalence and/or Incidence

HLA-B*58:01 allele frequency varies by ethnicity. The highest frequencies are found in Asian populations: up to 20% in Taiwan, Singapore, and among Han Chinese; 15.4% in India; 14.2% in Hong Kong; 12% in China and Korea; and 11% in Indonesia.

Symptoms

• Allopurinol is a major cause of SCAR, with an estimated risk of 0.1-0.4%.
• SCAR is manifested by SJS, TEN, or a drug reaction with eosinophilia, and systemic symptoms.
• Symptoms include rash combined with eosinophilia, leukocytosis, fever, hepatitis, and progressive kidney failure.
• Allopurinol-induced SCAR typically develops within weeks or a few months after initiation of treatment, and can be serious, with up to 25% mortality.

Diagnostic Issues

• In addition to SCAR, a mild skin rash not associated with systemic symptoms or organ damage may develop in patients taking allopurinol.
  • These less severe rashes may occur in 2-3% of patients, and cannot be predicted by HLA-B*58:01 allele status.
• FDA guidelines recommend discontinuing allopurinol if a rash develops, regardless of allele status.

Screening/Detection

• Allopurinol is the most commonly used drug to treat hyperuricemia and gout. It inhibits xanthine oxidase, a key enzyme involved in uric acid formation.
• Due to the severity of allopurinol-induced SCAR, guidelines from the Clinical Pharmacogenomics Implementation Consortium (CPIC) recommend testing for the HLA-B*58:01 allele prior to initiation of therapy.

Gene 

HLA-B*58:01 allele

Inheritance

Codominant

Structure/Function

• The HLA-B*58:01 allele is located in the Class I HLA region, on human chromosome 6 (6p21.1-6p21.3).
• HLA-B58 encoded by the HLA-B*58:01 allele is expressed on the surface of all nucleated cells and has important immunological role in antigen presentation to T lymphocytes.

Sensitivity/Specificity

• Overall 50-60% sensitivity and ~90% specificity in pooled populations.
  • Higher in populations with increased HLA-B*58:01 allele frequency
    • 90-100% sensitivity in Korean, Thai, Sardinia Italian, and Han Chinese populations.
• Low positive-predictive value (~1.5%), and high negative-predictive value for the HLA-B*58:01 allele, especially in patients of Asian descent (>99%).
• Analytical sensitivity/specificity is >99%.

Results

Positive

• HLA-B*58:01, heterozygous or homozygous, is detected.
• The presence of this allele increases risk for allopurinol-induced SCAR, including SJS or TEN.
  • Allopurinol treatment is contraindicated.
  • Alternative medication should be used as first-line therapy.
• Therapy should be discontinued immediately if symptoms of SJS or TEN develop.

Negative

• HLA-B*58:01 is not detected.
• The patient is not at risk for allopurinol-induced SCAR, including SJS or TEN.
  • Allopurinol can be used per standard dosing guidelines.
• Testing negative for HLA-B*58:01 does not totally eliminate the possibility of developing SCAR, especially in the White population with low-risk allele frequency.
• Allopurinol therapy should be discontinued in all patients if symptoms of SJS or TEN develop, regardless of HLA-B*58:01 status.

Limitations

• Copy number of HLA-B*58:01 will not be reported.
• Negative result for HLA-B*58:01 does not replace the need for therapeutic drug monitoring or other clinical testing.
• Other genetic and nongenetic factors that influence allopurinol-related adverse reactions are not evaluated.
• Diagnostic errors can occur due to rare sequence variations, or the presence of rare and undocumented alleles.