Initiating With Confidence: Avoiding Abacavir Hypersensitivity Through Pharmacogenetics Jean Michel Molina, France    - Biography English - 2007-10-25

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The management of HIV typically involves lifelong administration of multiple drugs, with the potential for host–drug interactions only exacerbated by the need for repeated modification of the patient’s drug regimen. While tailoring therapy to the needs of the individual is a long-standing goal across all branches of medicine, it comes as no surprise therefore that personalised medicine is of particular interest to many HIV-treating physicians.

Pharmacogenetics is the study of how therapeutic outcomes vary according to individual genetics, and how genetic data can be used to select or modify treatment. Despite the complexity of human variability, a number of genetic markers have been established that demonstrate a link between particular alleles and antiretroviral treatment outcomes. The best studied of these associations, and one of the most intensely studied in pharmacogenetics as a whole, is the link between HLA-B*5701 and hypersensitivity to abacavir.

Since the first two reports in 2002 identifying a high incidence of the Class I MHC allele HLA-B*5701 among patients diagnosed with abacavir hypersensitivity reactions (HSR), evidence has continued to accumulate, positing a strong association between carriage of this allele and predisposition to abacavir HSR. Despite this ever-increasing body of evidence, significant questions remained that limited the uptake of prospective HLA-B*5701 screening into routine practice. In particular, there has been a lack of definitive and generalisable prospective data on the level of association and clinical implications. This is driven partly by variable case ascertainment for HSR between studies, partly by the variability of HLA-B*5701 allelic carriage by race and geographical location, and partly by a degree of uncertainty as to whether the robust association between HLA-B*5701 and HSR observed in Caucasians also applies for other races.

With this in mind, GlaxoSmithKline commissioned two large studies to establish both the clinical utility of prospective HLA-B*5701 screening and the strength of the association between HLA-B*5701 and HSR in non-Caucasians. Both these studies – the European/Australian PREDICT-1 study that is the first randomised, blinded, prospective study of the impact of screening on HSR incidence against a contemporary control population, and the retrospective case-control SHAPE study assessing HLA-B*5701 carriage and HSR in White and Black US patients – have used epicutaneous abacavir patch testing to refine HSR case ascertainment.

Results now emerging from these two studies will address many of the remaining issues and move us further towards the confident integration of prospective HLA-B*5701 testing into routine HIV patient management. By fostering improved drug prescribing, the use of pharmacogenetics has the potential to benefit individuals and communities affected by HIV, not least by removing some of the uncertainty associated with the short term safety and tolerability of HAART regimens.