What test is required before starting abacavir therapy?

HLA-B*5701 Genetic Testing is Required Before Starting Abacavir

HLA-B*5701 genetic testing must be performed before initiating abacavir therapy to prevent potentially life-threatening hypersensitivity reactions. This is an FDA-mandated requirement and represents one of the most successful applications of pharmacogenetic testing in clinical medicine 1, 2.

Why This Test is Critical

The HLA-B*5701 allele is directly responsible for triggering an immunologically-mediated hypersensitivity reaction to abacavir that occurs in 3-5% of unscreened patients, typically within the first 6 weeks of treatment 1. Approximately 50-61% of patients carrying this allele will develop a clinically suspected hypersensitivity reaction during abacavir treatment, compared to only 4% of patients without the allele 3, 2, 4.

The consequences of missing this test can be fatal. Hypersensitivity reactions can progress to life-threatening hypotension and death, particularly upon rechallenge with abacavir 2.

Evidence Supporting Mandatory Screening

The landmark PREDICT-1 trial (2008) definitively established the clinical utility of HLA-B*5701 screening 4. This randomized, double-blind study of 1,956 HIV-infected patients demonstrated that:

• Prospective screening eliminated immunologically confirmed hypersensitivity reactions entirely (0% vs. 2.7% in controls, P<0.001) 1, 4
• The negative predictive value was 100%, meaning a negative test virtually eliminates the risk 1, 3, 4
• The positive predictive value was 47.9%, meaning approximately half of HLA-B*5701-positive patients will develop hypersensitivity if exposed to abacavir 1, 4
• Clinically diagnosed hypersensitivity reactions decreased from 7.8% to 3.4% with screening (P<0.001) 4

Guideline Recommendations

All major HIV treatment guidelines provide the strongest possible recommendation for HLA-B*5701 testing 1, 3:

• IDSA/HIV Medicine Association (2009,2014): Strong recommendation, high quality evidence 1
• FDA: Mandates that HLA-B*5701 testing results should be available if an abacavir-containing regimen is anticipated 1, 2
• Testing should be performed upon entry into HIV care or before starting therapy with abacavir 1, 3

Clinical Implementation Algorithm

Step 1: Order HLA-B*5701 Testing

• Perform genetic testing for the HLA-B*5701 allele before prescribing any abacavir-containing regimen 1
• Testing is also recommended before reinitiation in patients of unknown HLA-B*5701 status who previously tolerated abacavir 2

Step 2: Interpret Results and Act

• If HLA-B*5701 POSITIVE: Abacavir is absolutely contraindicated under all circumstances 3, 5, 2

  • Document results prominently in the medical record to prevent future inadvertent exposure 3, 5
  • Use alternative regimens such as integrase inhibitor-based therapy (bictegravir or dolutegravir with TAF/emtricitabine) 3, 5

• If HLA-B*5701 NEGATIVE: Abacavir can be safely initiated 1

  • However, patients should still be counseled about hypersensitivity reactions, as they can rarely occur in HLA-B*5701-negative patients 1
  • The negative predictive value of 100% means immunologically confirmed reactions are eliminated, but clinical vigilance remains important 4, 6

Step 3: Monitor During First 6 Weeks

• The highest risk period for hypersensitivity reactions is the first 6 weeks of treatment 1
• Even in HLA-B*5701-negative patients, permanently discontinue abacavir if hypersensitivity cannot be ruled out on clinical grounds 2

Critical Pitfalls to Avoid

Never initiate abacavir for rapid ART start without HLA-B*5701 results available 3. If immediate antiretroviral therapy is needed before test results return, use integrase inhibitor-based regimens (bictegravir or dolutegravir with TAF/emtricitabine) instead 3, 5.

Never rechallenge with abacavir after a suspected hypersensitivity reaction, even in HLA-B5701-negative patients, as rechallenge can precipitate life-threatening reactions within hours 2. Seven of eight HLA-B5701-negative patients who were rechallenged after an initial hypersensitivity reaction re-experienced the syndrome 6.

Real-World Effectiveness

Post-guideline implementation data from the OPERA observational database (1999-2016) showed that HLA-B*5701 screening uptake increased from 43% in 2009 to 84% in 2015, with corresponding decreases in definite or probable hypersensitivity reactions from 1.3% pre-screening to 0.2% in 2015 7. However, the fact that 16% of patients in 2015 still were not screened represents missed opportunities to prevent hypersensitivity reactions 7.

Testing Methods

Multiple validated methods exist for HLA-B*5701 detection 8:

• Sequence-specific primer PCR with capillary electrophoresis (SSP PCR CE) has the highest specificity (>99%) and sensitivity (>99%) 8
• Real-time PCR (qPCR) has slightly lower specificity (97.2%) but remains highly accurate 8
• Flow cytometry can be used as a pre-screening method but has lower specificity (84.3%) and should be confirmed with genetic testing 8