| Title | A simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase. | | Author(s) | Chui CK, Brumme ZL, Brumme CJ, Yip B, Phillips EJ, Montaner JS, Harrigan PR | | Institution | British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia, Vancouver, Canada. | | Source | Clin Infect Dis 2007 Jun 1; 44(11):1503-8. | | Abstract | BACKGROUND: Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)-B*5701 allele; however, the cost of routine high-resolution HLA typing before initiation of therapy remains prohibitive. We propose a simple approach to reduce B*5701-associated abacavir hypersensitivity based on the screening of human immunodeficiency virus (HIV) reverse transcriptase (RT) for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245.
METHODS: The correlation between HLA-B*5701 and RT codon 245 variation was investigated in 392 HIV-infected, antiretroviral-naive adults who were initiating highly active antiretroviral therapy. The relationship between codon 245 variation and premature abacavir discontinuation was investigated in a larger cohort of treated individuals (n=982). Associations between HLA-B*5701 and codon 245 variants were determined using Fisher's exact test or the chi (2) test.
RESULTS: A very strong association between HLA-B*5701 and RT codon 245 variation was observed. Only 1 (4.2%) of 24 subjects with B*5701 harbored virus with the clade B "wild-type" amino acid 245V, compared with 278 (75.5%) of 368 who did not have B*5701 (P<.001). The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75%, respectively, and the positive and negative predictive values were 20% and 99.6%, respectively. This association remained robust even after antiretroviral treatment was administered (negative predictive value, 100%; n=269). In abacavir-treated individuals (n=982), codon 245 substitutions were predictive of premature abacavir discontinuation (P=.02).
CONCLUSIONS: As HIV RT sequence is incidentally obtained as a part of routine drug-resistance testing, the examination of sequence variation at RT codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir and/or who could benefit from HLA characterization. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 17479950 |
|
