Stable ordering of tests nism. Although the drug-bound peptide involved in abacavir hypersensitivity has not been isolated or identified, it appears to interact somewhat specifically with the product of HLA-B*57:01, an HLA-B polymorphism found more commonly in European populations (Table 5–1). Other HLA-B polymorphisms are not associated with abacavir-induced hypersensitivity reactions. However, it is noteworthy that HLA-B*57:01, though necessary for SJS or TEN associated with abacavir, is not sufficient. That is, many individuals with the polymorphism do not get the hypersensitivity reaction. This lack of specificity is not understood and clearly warrants further study.
Abacavir hypersensitivity reactions are known to vary in frequency among ethnic groups, consistent with the population frequencies of the HLA-B*57:01 allele. As a prodrug, abacavir is activated to carbovir triphosphate, a reactive molecule that may be involved in the immunogenicity of abacavir. Abacavir-induced hypersensitivity reactions are probably mediated by the activation of cytotoxic CD8 T cells. In fact, there is an increased abundance of CD8 T cells in the skin of patients with abacavir hypersensitivity reactions. Experiments demonstrating that CD8-positive T cells can be stimulated by lymphoblastoid cell lines expressing HLAB*57:01, but not HLA-B*57:02 or HLA-B*58:01, suggest that the HLA-B*57:01 protein may recognize and bind an abacavir-associated peptide, which is not recognized by the other polymorphisms. Alternatively, the HLA-B*57:01 gene product complex may present the ligand-bound peptide on the cell surface in a structurally different configuration, which is recognized by cytotoxic T cells.
Because of the importance of abacavir in therapeutics, genetic testing of the HLA-B*57:01 biomarker associated with abacavir hypersensitivity has been rapidly incorporated into clinical practice, much faster than typical genetic tests (Figure 5–1). CPIC
FIGURE 5–1 Increasing use of testing for genetic variants of drug metabolism over time. Adoption of testing in clinical medicine typically undergoes three phases. Testing for HLA-B*5701 was rapidly adopted. (Adapted, with permission, from Lai-Goldman M, Faruki H: Abacavir hypersensitivity: A model system for pharmacogenetic test adoption. Genet Med 2008;10:874. Copyright 2008 Macmillan Publishers Ltd.) recommendations based on genotyping results are shown in Table 5–2.
Example 2: Flucloxacillin hypersensitivity reactions may lead to drug-induced liver toxicity. In particular, in 51 cases of flucloxacillin hepatotoxicity, a highly significant association was identified with a polymorphism linked to HLA-B*57:01 (Figure 5–2). HLA polymorphisms also contribute to liver injury from other drugs (Table 5–4). For example, reaction to the anticoagulant