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HLA-B*5701 screening for hypersensitivity to abacavir.

HLA-B*5701 screening for hypersensitivity to abacavir

Mallal S, Phillips E, Carosi G et al.

N Engl J Med, 2008, 358, 568-579

The complications of antiretroviral therapy are by no means limited to the long term, and the abacavir hypersensitivity syndrome is a potentially fatal complication that occurs in approximately 5% of individuals within a few weeks of starting this nucleoside reverse transcriptase inhibitor (NRTI). This has led to a dilemma for clinicians, since the pharmacokinetics and long-term side-effect profile of abacavir are generally favourable, with once-daily dosing possible and fewer metabolic effects than many other NRTIs. The hypersensitivity reaction is mediated by CD8+ T cells, and although skin-patch testing is useful in identifying individuals with a prior reaction, it cannot be used as a predictive screening tool.

Since almost all individuals confirmed to have had an abacavir hypersensitivity reaction carry the B*5701 class I HLA allele, Mallal and colleagues randomly allocated almost 2000 HIV-infected (predominantly white, male) individuals to either pre-treatment screening for this allele, with no abacavir administration to those found to be B*5701-positive, or to the standard clinical practice of abacavir administration and clinical monitoring. 'True' abacavir hypersensitivity (immunologically mediated, positive on skin-patch test) was eradicated from the pre-screened group, and was seen in just under 3% of participants receiving standard care. Clinically diagnosed hypersensitivity was reduced but not eradicated (from 7.8% to 3.4%), implying that a substantial proportion of such patients do not have true, immunologically mediated abacavir hypersensitivity. Such reactions were felt to be largely due to rash/hypersensitivity to nevirapine or efavirenz, or to gastrointestinal intolerance to protease inhibitors. Just under half of the B*5701-positive individuals in the 'standard care' arm tolerated abacavir, demonstrating that the presence of this allele is necessary but not sufficient for the development of hypersensitivity.

As the authors point out, this is the first time that a pharmacogenetic test has been used to prevent a specific toxic effect of a drug. While it may seem counterintuitive to go to the trouble of building the infrastructure necessary for abacavir pre-screening when there are several alternative NRTIs, the convenient dosing and lack of long-term toxicity of this agent mean that in most populations it will be worth doing so. Indeed, this is already routine practice at many institutions. Of course, the need for such pre-screening may be tempered in different populations based on local access to molecular testing, physician prescribing patterns and population distribution of the B*5701 allele.

Review by Rupert Kaul

Clinical Sciences Division, University of Toronto, Canada
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Article Details
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Title Annotation:human leukocyte antigen
Author:Kaul, Rupert
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:1CANA
Date:Mar 1, 2008
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