Why is HLA (Human Leukocyte Antigen) B 5701 testing necessary before starting abacavir (Ziagen) in a patient newly diagnosed with HIV (Human Immunodeficiency Virus)?

Why HLA-B*5701 Testing is Performed First Before Starting Abacavir

HLA-B*5701 testing must be performed before initiating abacavir because patients who carry this allele have approximately a 50% risk of developing a potentially life-threatening hypersensitivity reaction, and screening has been proven to eliminate immunologically confirmed hypersensitivity reactions with 100% negative predictive value. 1, 2, 3

The Critical Link Between HLA-B*5701 and Abacavir Hypersensitivity

Mechanism and Risk

• Abacavir causes an immunologically-mediated hypersensitivity reaction driven by activation of HLA-B*5701, occurring in 3-5% of unscreened patients during the first 6 weeks of treatment 1
• The hypersensitivity reaction is a multi-organ clinical syndrome characterized by signs or symptoms in 2 or more organ systems: fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (malaise, fatigue, achiness), and respiratory symptoms (dyspnea, cough, pharyngitis) 3
• Life-threatening complications include anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death 3
• Rechallenge with abacavir after a hypersensitivity reaction is absolutely contraindicated due to risk of precipitating fatal reactions 3, 4

Evidence for Screening Effectiveness

• The landmark PREDICT-1 trial demonstrated that prospective HLA-B*5701 screening eliminated immunologically confirmed hypersensitivity reactions entirely (0% vs 2.7% in controls, P<0.001) with a negative predictive value of 100% 1, 5
• In predominantly white populations, 94% of patients do not carry the HLA-B*5701 allele and are at low risk when screened 5
• Real-world data from the OPERA database showed that increased screening uptake (from 43% in 2009 to 84% in 2015) was accompanied by decreased hypersensitivity reactions (from 1.3% pre-screening to 0.2% in 2015) 6

Guideline Recommendations Across All Major Organizations

Strength of Recommendations

• All major HIV treatment guidelines—DHHS, IDSA, IAS-USA, and WHO—recommend HLA-B*5701 testing with the highest evidence rating (strong recommendation, high quality evidence) before initiating abacavir 1
• The FDA mandates that HLA-B*5701 testing results should be available if an abacavir-containing regimen is anticipated 1, 3
• For HLA-B*5701-positive patients, abacavir-containing regimens are absolutely contraindicated under all circumstances 2, 3

Clinical Implementation

• Testing should be performed upon entry into HIV care or before starting therapy with abacavir 1
• Results must be documented prominently in the medical record to prevent future inadvertent abacavir exposure 2
• If screening is not available or a patient declines testing, abacavir can be initiated only with extensive counseling and close monitoring for hypersensitivity symptoms, though this is not recommended practice 1

Why This Test is Prioritized Over Other Genetic Tests

Unique Characteristics of HLA-B*5701 Screening

• This represents one of the most successful applications of pharmacogenetic testing in clinical medicine, with clear actionable results that directly prevent mortality 1, 4
• Unlike other genetic tests that may modify dosing or provide risk stratification, HLA-B*5701 testing provides a binary decision: use abacavir (if negative) or absolutely avoid it (if positive) 2, 3
• The test has exceptional predictive value: 100% negative predictive value and 47.9% positive predictive value 1, 5

Comparison to Other HIV-Related Testing

• While HIV resistance testing, CD4 counts, and viral load are also performed at baseline, HLA-B*5701 is the only test that must be completed before prescribing a specific antiretroviral agent to prevent immediate life-threatening toxicity 1
• Other baseline tests (resistance genotyping, hepatitis screening, renal function) guide regimen selection but do not carry the same immediate mortality risk if omitted 1

Common Clinical Pitfalls and How to Avoid Them

Critical Errors to Prevent

• Never initiate abacavir-containing regimens for rapid ART start without HLA-B*5701 results available—use integrase inhibitor-based regimens (bictegravir or dolutegravir) with TAF/emtricitabine instead for immediate initiation 1, 2, 7
• Do not assume that absence of symptoms during initial abacavir exposure means a patient is HLA-B*5701 negative—hypersensitivity can occur at any time during therapy, though 89% occur within the first 6 weeks 3
• Even HLA-B*5701-negative patients can develop hypersensitivity reactions (occurring in 4.8% of allele-negative patients in real-world cohorts), so clinical vigilance remains essential 8

Practical Management Points

• If a patient develops suspected hypersensitivity to abacavir, permanently discontinue the drug immediately even if other diagnoses are possible (e.g., viral illness, other drug reactions) 3
• Seven out of eight HLA-B*5701-negative patients who were rechallenged after a confirmed hypersensitivity reaction experienced recurrent reactions, confirming that rechallenge is dangerous regardless of genetic status 8
• The prevalence of HLA-B*5701 is approximately 5-6% in predominantly white populations, with variation by ethnicity 5, 6