Updated experience of abacavir hypersensitivity genetic testing within the major histocompatibility complex (MHC): addressing diagnostic precision and predictive value
Martin, A., Nolan, D., Gaudieri, S., Almeida, C., Carvalho, F., Witt, C., Sayer, D., Nolan, R., Herrmann, S., Christiansen, F. and Mallal, S. (2003) Updated experience of abacavir hypersensitivity genetic testing within the major histocompatibility complex (MHC): addressing diagnostic precision and predictive value. In: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 8 - 11 July, Paris, France.
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OBJECTIVES: To assess the predictive value (PV) of genetic testing for abacavir hypersensitivity syndrome (HSR) in the Western Australian HIV Cohort Study, and to extend genetic mapping of genetic susceptibility locus/loci. Abacavir-specific immunological responses were assessed to improve precision of the HSR diagnostic classification, and to provide insights into possible underlying mechanisms.
METHODS: The abacavir-exposed cohort comprised prospectively tested patients (n=48) and retrospectively analysed abacavir-exposed individuals (n=200). Diagnostic precision was assessed using epicutaneous patch testing, and immunological response to ex vivo abacavir exposure measured by peripheral blood mononuclear cell tumour necrosis factor alpha (TNF-α) expression (three-colour flow cytometry) or whole blood extracellular TNF-α (chemiluminescence). Depletion of CD4 and CD8 cells was undertaken to determine the characteristics of the major histocompatibility complex (MHC)-restricted immune response. MHC typing utilized standard molecular techniques, and genetic mapping within the MHC Class III region analysed single nucleotide polymorphisms (SNP) to identify recombinant MHC haplotypes.
RESULTS: Application of revised diagnostic criteria (including a positive ex vivo test) identified abacavir HSR 18 cases out of 248 abacavir-exposed patients (2/48 prospectively tested). HLA-B*5701 was present in 94% of cases and 1.7% of controls (OR 587, PV+ 81%, PV– 99.6%). Based on these data, prospective testing for HLA-B*5701 carriage would be predicted to reduce abacavir HSR incidence from 7.3% to 0.4%, while inappropriately denying 1.6% of the population access to abacavir. Presence of HLA-B*5701 and a central MHC polymorphism (hspA1L rs2227956C) was found in 94% of cases and 0.43% of controls (OR 3910, PV+ 94%, PV– 99.5%). Depletion of CD8 cells resulted in marked attenuation of abacavir-stimulated TNF-α expression ex vivo, consistent with a Class I-restricted immune response. Recombinant mapping in patients carrying markers of the 57.1 ancestral/extended haplotype suggest a susceptibility locus within the highly conserved heat shock protein 70 (hsp70) gene cluster, although these data suggest that the HLA-B*5701 may provide specificity to the abacavir-induced immune response.
CONCLUSION: Presence of HLA-B*5701 is highly predictive of abacavir HSR in the Western Australian HIV Cohort, with evidence that an abacavir-specific Class I-restricted immune response may involve the concurrence of HLA-B*5701 and a second locus within the central MHC that is carried on the 57.1 extended haplotype.
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|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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