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Screening for Abacavir Hypersensitivity
Abstract & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Source: Chui CK, et al. Simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase. Clin Infect Dis 2007; 44:1503-1508.
Synopsis: A major drawback to the routine use of abacavir in the treatment of HIV-1 infection is the occurrence of a hypersensitivity reaction in as many of 8% of recipients of this nucleoside analog reverse transcriptase inhibitor. Individuals carrying the HLA class I allele B*5701 have a >100-fold increased risk of such hypersensitivity reactions. T Direct screening for the presence of HLA-B*5701 is an alternative but expensive. The authors describe an alternative, relatively inexpensive screening method.
The immune response to HIV exerts a selective pressure, just as do antiretroviral drugs. Cytotoxic T lymphocytes (CTL) that recognize HLA class I-restricted viral epitopes expressed on the surface of infected cells exert a pressure on these epitopes. Mutation in these viral epitopes may allow escape of HIV-1 from the CTL immune response. Just as viral mutations allowing escape from the action of antiretroviral drugs often follow a predictable path, similar predictable sequences of HLA-restricted epitope mutations may also occur so that this aspect of viral evolution may potentially be predictable on the basis of the HLA profile of the infected host.
As a consequence of the above, Chui and colleagues have examined the hypothesis that identification of a signature CTL-driven immune escape that resides within the viral reverse transcriptase (RT) may represent a simple means, available by routine HIV-1 genotypic assays used to screen for antiretroviral associated resistance mutations, capable of abacavir hypersensitivity risk screening. They set out to demonstrate that detection of a HLA-B*5701 amino acid change at HIV-1 RT codon 245, which is known to lie within the epitopes restricted to this HLA allele, predicts the presence of HLA-B*5701 and, therefore, an increased risk of hypersensitivity to abacavir.
The relationship between codon 245 variation, the presence of HLA-B*5701, and premature abacavir discontinuation was investigated in 392 HIV infected adults receiving their initial antiretroviral therapy. The sensitivity of codon 245 mutations in predicting the presence of HLA-B*5701 was 96% and its specificity was 75%, while the positive and negative predictive values were 20% and 99.6%, respectively. This association remained strong even after the patients had received antiretroviral therapy. The presence of codon 245 substitutions was significantly associated with premature discontinuation of abacavir therapy.
Thus, the inclusion of RT codon 245 in genotypic assays meant to assess antiretroviral resistance could provide an effective means, without significant added cost, of screening for risk of hypersensitivity to abacavir in North America and Europe where clade B virus are prevalent and HLA-B*5701 is present in up to 10% of whites.