Drug hypersensitivity: Pharmacogenetics and clinical syndromes

Abstract

Severe cutaneous adverse reactions (SCARs) include syndromes such as drug reaction, eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes including abacavir hypersensitivity reaction, allopurinol DRESS/DIHS and SJS/TEN and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of SCARs. The roll-out of HLA-B*5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs such as carbamazepine where the positive predictive value of HLA-B*1502 is low and the negative predictive value of HLA-B*1502 for SJS/TEN may not be 100% in all ethnic groups. International collaborative consortia have been formed with the goal of developing phenotype standardization and undertaking HLA and genome-wide analyses in diverse populations with these syndromes.

Mechanisms involved in the Abacavir-mediated hypersensitivity syndrome

“…This antiepileptic drug causes severe adverse effects in individuals expressing HLA B*15:02. Although the odds ratio is above 1 000 in some Asian populations, its positive and negative predictive values are lower [13] and the data are not as impressive as those for ABC. Particularly, CBZ seems to cause fewer changes in the peptide cargo of HLA B*15:02 molecules (15% compared to 25% for ABC) and induce less dramatic changes in preferred primary and secondary anchor residues.…”

Reply

“…HLA-B*1502 is common in Asians and is specific for carbamazepine-induced SJS/TEN, but not other reactions, whereas HLA-DRB1*0101 is implicated only in nevirapine-induced skin and liver injury when CD4 counts are 25%. (5) To better delineate the role and extent of injury from drug, genetic, and environmental factors, close collaboration between drug-induced liver and skin injury experts are needed.…”

Genomics in medicine: From promise to practice

“…The finding that the HLA-B*5701 allele has good predictive value for abacavir hypersensitivity, and that this allele has a 5% prevalence in Caucasians, led to widespread implementation of genetic testing prior to initiation of therapy. [17] July 2015, Vol. 105, No.…”