Abacavir HLA-B*57:01 tolerance and genetic variation within the MHC.

Abacavir HLA-B*57:01 tolerance and genetic variation within the MHC.

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The discovery of HLA-B*5701 has been successfully translated into primary HIV clinical practice as a genetic marker that can predict and prevent abacavir hypersensitivity reaction. This unprecedented clinical success in personalised medicine was predicated by the inherent biological properties and pathogenic mechanisms underlying abacavir hypersensitivity. Although it is known that HLA-B*57:01 is necessary for development of abacavir hypersensitivity, it is not sufficient and approximately 45% of subjects carrying HLA-B*57:01 will tolerate abacavir. We have previously studied factors leading to the abrogation of abacavir hypersensitivity using a candidate gene approach with indication that these factors lie outside of the MHC and may involve genes important in innate immune response. Abacavir, in fact may differ from other drugs in its ability to activate innate immune responses and hence provide the danger signals necessary to trigger a hypersensitivity reaction. Abrogation of Hsp70 redistribution in the presence of 4-MP which block ADH-mediated abacavir metabolism provides some clues that a reactive aldehyde metabolite may be important in this process. Processes leading to abrogation of drug hypersensitivity, SCAR and other serious immunologically mediated drug reactions have not been defined, however are clearly important. For most drugs associated with drug hypersensitivity, SCAR and drug-induced liver disease for instance such as allopurinol, carbamazepine (and other aromatic amine anticonvulsants) and flucloxacillin only a very small percentage of those carrying a given class I MHC genetic marker will go on to develop the adverse drug reaction in question (Table 1). This greatly impacts on both the ability of these HLA alleles to be used as predictive markers in clinical practice but also highlights our lack of understanding of the complete picture of innate and adaptive immunologic factors and non-immunologic factors that are critical contributors to the clinical manifestation of these adverse drug reactions. In this context abacavir is an ideal candidate to study and model this effect in that 1) a specific marker (patch testing) exists that defines the presence of true immunologically mediated abacavir hypersensitivity 2) carriage of HLA-B*5701 is common in Caucasian populations (6-8%) and 3) the positive predictive value for the development of hypersensitivity is high (55%) relative to that of other drugs which allows the extreme phenotypes of abacavir hypersensitivity and tolerance to be studied which would not be feasible for other drugs. 4) The phenotypes of HLA-B*5701 positive abacavir hypersensitivity and tolerance are static over time 5) There are no other identified epidemiological or environmental factors other than race, which is a marker of HLA-B*57:01 carriage, that predict development of abacavir hypersensitivity.

[{ "PostingID": 1375, "Title": "VIIV-CNA106030", "Description": "A phase IV, randomised, multicentre, double-blind, study to evaluate the clinical utility of prospective genetic screening (HLA-B*5701) for susceptibility to abacavir hypersensitivity

Medicine: abacavir, Condition: Infection, Human Immunodeficiency Virus, Phase: 4, Clinical Study ID: CNA106030, Sponsor: ViiV" }]

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