Which patients should undergo pharmacogenetic testing for the HLA-B*5801 allele before starting allopurinol?

Pharmacogenetic Testing for HLA-B*5801 Before Starting Allopurinol

Pharmacogenetic testing for HLA-B*5801 should be performed prior to initiating allopurinol in patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients, but is not recommended for patients of other ethnic backgrounds. 1

Patient Populations Requiring HLA-B*5801 Testing

The 2020 American College of Rheumatology (ACR) guidelines provide clear recommendations on which patients should undergo HLA-B*5801 testing before starting allopurinol:

• Recommended for testing:

  • Southeast Asian descent (Han Chinese, Korean, Thai)
  • African American patients

• Not recommended for testing:

  • Patients of other ethnic or racial backgrounds (including Caucasians and Hispanics)

Rationale for Selective Testing

The recommendation for selective testing is based on:

1. Prevalence of HLA-B*5801 allele:

   • Southeast Asian populations: 7.4% 1
   • African Americans: 3.8% 1
   • Caucasians and Hispanics: 0.7% each 1

2. Risk of allopurinol hypersensitivity syndrome (AHS):

   • Asian and African American patients have a 3-fold increased risk of AHS compared to white patients 1
   • HLA-B*5801 is associated with markedly elevated risk for AHS with odds ratios estimated between 80 to 580:1 1

3. Cost-effectiveness:

   • Testing is cost-effective in Asian and African American populations (incremental cost-effectiveness ratios <$109,000 per quality-adjusted life years) 1

Clinical Significance

Allopurinol hypersensitivity syndrome (AHS) is a severe adverse reaction with:

• 25% mortality rate 1
• Manifestations including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug reaction with eosinophilia and systemic symptoms), and severe cutaneous adverse reactions (SCAR) 1

Evolution of Recommendations

The 2012 ACR guidelines were more specific about certain subpopulations:

• Korean descent with CKD stage 3 or worse (HLA-B*5801 allele frequency ~12%)
• Han Chinese or Thai extraction regardless of renal function (HLA-B*5801 allele frequency ~6-8%) 1

The 2020 guidelines broadened these recommendations to include all Southeast Asian descent patients and African Americans.

Testing Method

• PCR-based approach is recommended 1
• Only about 10% of tests require more cumbersome follow-up HLA-B*5801 sequencing for inconclusive results 1
• Rapid, robust, and inexpensive screening methods are available with high sensitivity and specificity 2

Management Based on Test Results

• If HLA-B*5801 positive: Alternative urate-lowering therapy should be prescribed instead of allopurinol 1
• If HLA-B*5801 negative: Allopurinol can be initiated with appropriate dosing (starting at ≤100 mg daily, and lower doses in patients with CKD) 1

Additional Risk Factors for AHS

Beyond HLA-B*5801 status, other risk factors for allopurinol hypersensitivity include:

• Recent initiation of therapy
• Impaired renal function (which elevates levels of allopurinol and its metabolite oxypurinol)
• Concurrent thiazide use 1

Clinical Impact of Testing

Studies have shown that cases of severe cutaneous adverse reactions continue to occur in high-risk populations when testing is underutilized 3. Implementation of HLA-B*5801 testing before allopurinol initiation has the potential to prevent these serious and potentially fatal adverse reactions.

The strong association between HLA-B*5801 and allopurinol-induced severe cutaneous adverse reactions has been confirmed in multiple populations, including Han Chinese 4, 5 and European populations 6.

By following these testing recommendations, clinicians can significantly reduce the risk of potentially fatal hypersensitivity reactions while appropriately managing gout in all patient populations.