The presence of HLA-B*5701, -DRB1*0701, and -DQ3 Is highly predictive of hypersensitivity to the HIV reverse transcriptase inhibitor abacavir
Mallal, S., Nolan, D., Witt, C., Masel, G., Martin, A., Moore, C., Sayer, D., Castley, A., Mamotte, C., Maxwell, D., James, I. and Christiansen, F. (2002) The presence of HLA-B*5701, -DRB1*0701, and -DQ3 Is highly predictive of hypersensitivity to the HIV reverse transcriptase inhibitor abacavir. In: 9th Conference on Retroviruses and Opportunistic Infections, 24 - 28 February 2002, Seattle, U.S.A
Background: The use of abacavir, a potent HIV nucleoside analogue reverse transcriptase inhibitor, is complicated by a potentially life-threatening hypersensitivity syndrome in approximately 5% of cases. Genetic factors influencing the immune response to abacavir may confer susceptibility.
Methods: Major histocompatibility complex region typing was performed in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases and was excluded in 167 individuals with >6 weeks exposure (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity.
Results: HLA-B*5701 was present in 78% of patients with abacavir hypersensitivity, and 2.3% of abacavir-tolerant patients (OR = 117, p<0.0001), whilst the HLA-DRB1*0701 and -DQ3 combination was found in 72% of hypersensitive and 3.0% of tolerant patients (OR = 72, p< 0.0001). HLA-B*5701 and HLA-DRB1*0701+DQ3 were present in combination in 72% hypersensitive and 0% tolerant patients (OR = 822, p<0.0001). Other MHC markers also present on the 57.1 ancestral haplotype (D6S1014*137, C4A6, D6S273*135, TNF -238A, MICA*194, MIB*344) confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701 and DRB1*0701+DQ3 had a positive predictive value for hypersensitivity of 100% and a negative predictive value of 97.3%.
Conclusions: Genetic susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, -DRB1*0701, and -DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient. These findings need to be confirmed in other populations before such a practice could be generalised. Furthermore, testing for the haplotype is not 100% sensitive and therefore, cannot be considered a screening test, and current clinical practices should continue to underpin the management of abacavir hypersensitivity.
|Publication Type:||Conference Paper|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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