Characterisation of susceptibility to abacavir hypersensitivity carried on the HLA-B-5701, -DRB*07 and -DQ3 haplotype

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Drug hypersensitivity reactions (HSR) are a significant iatrogenic cause of morbidity, and even of mortality. Unfortunately the underlying mechanisms are poorly understood, making it difficult to predict which individuals may be at risk of these reactions. Research indicates that the interaction between specific drugs and the host immune system in HSR is similar to that observed in transplantation and that the major histocompatibility complex (MHC) region of the human genome assumes importance in this setting, as it does in determining if a transplanted organ is 'rejected' or 'accepted'. We have identified a striking association between MHC genetic markers (HLA-B*5701, -DRB1*0701, and -DQ3) and HSR to the HIV drug abacavir. Carriage of these markers was found in 72% (13-18) of individuals with this reaction, and 0% (0-185) of those who tolerated abacavir (odds ratio 822), thus predicting HSR in 100% of cases, and abacavir tolerance in 97%. This represents one of the most powerful MHC gene associations with a clinical syndrome yet described. As abacavir HSR affects ~5% of abacavir users, knowledge of these genetic factors would be predicted to significantly reduce the risk of susceptible individuals developing HSR, without inappropriately denying access to abacavir. This association between the MHC and abacavir HSR in the clinical setting provides a unique opportunity to characterise mechanisms that underlie this HSR, which may give insights into drug HSR generally. Continued support of this research in the public domain, rather than in the commercial sector, will ensure that commercial considerations do not restrict the dissemination of these findings. Given the high predictive value of this readily performed genetic test in identifying at-risk individuals, there is also a clinical imperative to rapidly identify the gene(s) involved, to provide the most targeted risk assessment possible.