Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations

Abstract

Abacavir is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with abacavir develop a hypersensitivity reaction that requires discontinuation of the drug. In an initial pharmacogenetic study conducted in a predominantly White male population, multiple markers in the human leukocyte antigen (HLA)-B chromosomal region were associated with hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x 10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78, p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients at risk for hypersensitivity to abacavir across diverse patient populations. Efforts are ongoing to identify markers with sufficient sensitivity and specificity to be clinically useful. Even after a marker set is identified, appropriate clinical identification and management of hypersensitivity to abacavir must remain the cornerstone of clinical practice.

Pharmacogenetics of cutaneous adverse drug reactions

“…36,37 However, abacavir-induced hypersensitivity is present at a high frequency only in Caucasians and at a very low frequency in Asian and black populations. 38,39 In fact, the allele frequency of HLA-B*5701 is approximately 8% in Caucasians, but lower in Asian and African populations. 36,37 To examine the universality of the sensitivity and specificity of HLA-B*5701 association with abacavir hypersensitivity across ethnicities, the Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation (SHAPE) was performed.…”

Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

“…Hetherington et al 10 reported a strong association between ABC HSR and the HLA-B*5701 allele, which has been extensively reproduced. 17,18 We retrospectively assessed the likelihood that this region would have been identified had the genome-wide screen been conducted with a limited number of cases and population controls.…”

“…17 Following an initial clinical diagnosis of HSR, the case report forms of the HSR were subjected to a thorough review by a GSK physician. Subjects were categorized as follows: (1) a definitive/probable case, (2) a possible case or (3) not a case.…”

Studies on abacavir-induced hypersensitivity reaction: a successful example of translation of pharmacogenetics to personalized medicine

“…The advantage of the patch test will be further discussed below. In a more comprehensive study, Hughes et al [17] performed genetic association studies among Caucasians, African Descendants and Hispanics, and results showed that HLA-B*57:01 was strongly associated with abacavirinduced HSR in Caucasians with a sensitivity of 40%52% (p=4.7×10 18 in males), depending on the study and analysis population. The association was moderate in Hispanics with a reduced sensitivity of 20%22% (p=2.1×10 4 ).…”