HLA-B*5701 Screening for Hypersensitivity to Abacavir
ABSTRACT Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir.
This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir.
The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001).
HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
- SourceAvailable from: Steve Schrodi
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- "The importance of these genetic variants in avoiding adverse drug reactions is underscored by FDA black-box warnings (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm), as well as by recommendations of other groups (https://www.pharmgkb.org/). For example, individuals carrying the HLA-B*5701 allele are warned against taking abacavir (Mallal et al., 2008), dapsone-treated patients with certain G6PD variants are at higher risk for hemolysis as are patients receiving primaquine, many sulfonamides, nitrofurantoin, acetanilide, niridazole, and naphthalene (Cappellini and Fiorelli, 2008), and the beta blocker propranolol can cause adverse reactions in those with variants conferring compromised CYP2D6 function (Cascorbi, 2003; Samer et al., 2013). In all, the FDA currently lists 155 pharmacogenetic warnings across numerous therapeutic areas. "
ABSTRACT: Translation of results from genetic findings to inform medical practice is a highly anticipated goal of human genetics. The aim of this paper is to review and discuss the role of genetics in medically-relevant prediction. Germline genetics presages disease onset and therefore can contribute prognostic signals that augment laboratory tests and clinical features. As such, the impact of genetic-based predictive models on clinical decisions and therapy choice could be profound. However, given that (i) medical traits result from a complex interplay between genetic and environmental factors, (ii) the underlying genetic architectures for susceptibility to common diseases are not well-understood, and (iii) replicable susceptibility alleles, in combination, account for only a moderate amount of disease heritability, there are substantial challenges to constructing and implementing genetic risk prediction models with high utility. In spite of these challenges, concerted progress has continued in this area with an ongoing accumulation of studies that identify disease predisposing genotypes. Several statistical approaches with the aim of predicting disease have been published. Here we summarize the current state of disease susceptibility mapping and pharmacogenetics efforts for risk prediction, describe methods used to construct and evaluate genetic-based predictive models, and discuss applications.Frontiers in Genetics 06/2014; 5:162. DOI:10.3389/fgene.2014.00162
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- "Abacavir-induced hypersensitivity is present at a high frequency only in Caucasians and at a very low frequency in Asian and Black populations [49, 50]. Because of a considerable rate of false-positive result of HLA-B∗57:01 test, abacavir patch testing was used as a specific test to identify true abacavir hypersensitivity [51–54]. "
ABSTRACT: T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.Research Journal of Immunology 05/2014; 2014(6982):565320. DOI:10.1155/2014/565320
Therapeutic Advances in Drug Safety 03/2014; 5(2):62-66. DOI:10.1177/2042098613520030
- "One example of an RCT where participants were randomised to use of a pharmacogenomic marker was with the antiretroviral abacavir. Abacavir was plagued by hypersensitivity reactions in up to 6% of treated patients, and in this study screening for the HLA-B*5701 allele eliminated these hypersensitivity reactions [Mallal et al. 2008]. Prior to this trial the association between HLA-B*5701 and abacavir hypersensitivity had been identified by two independent groups and observed in several noncontrolled environments, but retrospective methodologies, lack of control populations and racial diversification, small sample sizes and issues of overdiagnosis had led to uncertainty about its clinical utility. "