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Review
. 2013 Jul;33(7):765-75.
doi: 10.1002/phar.1278. Epub 2013 May 3.

Abacavir pharmacogenetics--from initial reports to standard of care

Michael A Martin  1 , Deanna L Kroetz
Affiliations
Review

Abacavir pharmacogenetics--from initial reports to standard of care

Michael A Martin et al. Pharmacotherapy. 2013 Jul.

Abstract

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice.

Keywords: AIDS; HIV; HLA; abacavir; drug hypersensitivity; genetic testing; pharmacogenetics.

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Figures

Figure 1
Figure 1. Metabolism and activation of abacavir
Abacavir is rapidly absorbed following oral dosing and is quickly taken up into cells via passive diffusion, where it is then phosphorylated by adenosine phosphotransferase to produce abacavir. A cytosolic deaminase converts abacavir monophosphate to carbovir monophosphate, which is then subject to processing by other intracellular kinases to produce the active metabolite, carbovir triphosphate.
Figure 2
Figure 2. Binding of abacavir to HLA-B*57:01
Abacavir (shown in red) binds within the F pocket of HLA-B*57:01 where the C-terminal residues of bound peptides would normally bind, altering its binding repertoire. Presentation of alternative peptides (shown in blue) to the immune system is hypothesized to trigger abacavir HSR. This image was rendered from PDB file 3UPR.
See this image and copyright information in PMC

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