Abacavir hypersensitivity

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir sulfate. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir sulfate (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment. Patients who carry the HLA-B*57:01 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*57:01 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*57:01 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*57:01 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir sulfate:

• All patients should be screened for the HLA-B*57:01 allele prior to initiating therapy with abacavir tablets or reinitiation of therapy with abacavir tablets, unless patients have a previously documented HLA-B*57:01 allele assessment.
• Abacavir tablet is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*57:01 -positive patients.
• Before starting abacavir tablets, review medical history for prior exposure to any abacavir-containing product. NEVER restart abacavir tablets or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*57:01 status.
• To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*57:01 status, discontinue abacavir tablets immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
• If a hypersensitivity reaction cannot be ruled out, do not restart abacavir tablets or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours.
• If a hypersensitivity reaction is ruled out, patients may restart abacavir tablets. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed.
• A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

Please review the complete therapeutic recommendations that are located here: (1).

We agree with others that HLA-B*57:01 screening should be performed in all abacavir-naive individuals before initiation of abacavir-containing therapy (see Table 2); this is consistent with the recommendations of the FDA, the US Department of Health and Human Services, and the European Medicines Agency. In abacavir-naive individuals who are HLA-B*57:01-positive, abacavir is not recommended and should be considered only under exceptional circumstances when the potential benefit, based on resistance patterns and treatment history, outweighs the risk. HLA-B*57:01 genotyping is widely available in the developed world and is considered the standard of care prior to initiating abacavir. Where HLA-B*57:01 genotyping is not clinically available (such as in resource-limited settings), some have advocated initiating abacavir, provided there is appropriate clinical monitoring and patient counseling about the signs and symptoms of HSR [hypersensitivity reaction], although this remains at the clinician’s discretion.

Please review the complete therapeutic recommendations that are located here (3, 4).

HLA-B*57:01-positive patients have a strongly increased risk of a hypersensitivity reaction to abacavir.

Recommendation:

Abacavir is contraindicated for HLA-B*57:01-positive patients.

1. Advise the prescriber to prescribe an alternative according to the current guidelines.

Background information

Mechanism:

Although the mechanism of hypersensitivity reactions to abacavir is not fully known, experimental data suggest the following mechanism.

Abacavir metabolites (aldehydes and acids) form a covalent bond with cellular proteins. Peptides derived from these modified proteins bind to HLA-B*5701 and are recognised on the cell surface as foreign by the immune cells, which triggers an immune response against cells containing abacavir. For more information about the HLA-B*57:01 genotype: see the general background information about HLA on the KNMP Knowledge Bank or on http://www.knmp.nl/ (search for HLA).

Other considerations:

If tests are performed for HLA-B57 instead of HLA-B*57:01, some patients will incorrectly be denied treatment with abacavir. This is primarily the case in patients of African descent, where HLA-B*57:03 is the most common HLA-B57 sub-type and to a lesser extent for Caucasian patients, where HLA-B*57:01 is the most common HLA-B57 sub-type. If there are enough alternatives, it is not a problem that the patient is being denied abacavir incorrectly.

Clinical consequences:

HLA-B*5701-positive patients have a strongly increased risk of a hypersensitivity reaction to abacavir (OR [odds ratio] 7 to 960 for clinically diagnosed hypersensitivity reactions and 900 to 1945 for immunologically confirmed hypersensitivity reactions).

Exclusion of HLA-B*5701-positive patients from abacavir therapy reduced the number of clinically diagnosed hypersensitivity reactions in predominantly white populations by 56-96% and the number of immunologically confirmed hypersensitivity reactions by 100%.

Hypersensitivity reactions to abacavir generally disappear spontaneously after stopping abacavir, but can be fatal in severe cases.

Please review the complete therapeutic recommendations that are located here: (5).