title: Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.
abstract: OBJECTIVE
  To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?
  
  
  METHODS
  A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus.
  
  
  RESULTS
  Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests.
  
  
  CONCLUSIONS
  This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
authors.affiliation: Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada; Department of Clinical Chemistry, University of Bern and Inselspital University Hospital, Bern, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.forename: Neil H
authors.initials: NH
authors.lastname: Shear
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Soomi
authors.initials: S
authors.lastname: Hwang
authors.forename: Vincent
authors.initials: V
authors.lastname: Fung
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Mary B
authors.initials: MB
authors.lastname: Connolly
authors.forename: Shinya
authors.initials: S
authors.lastname: Ito
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects; D002220:Carbamazepine / Q000009:adverse effects*; D004342:Drug Hypersensitivity / Q000175:diagnosis / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D015234:HLA-A Antigens / Q000235:genetics*; D059910:HLA-B15 Antigen / Q000235:genetics*; D006801:Humans; D012307:Risk Factors
chemical_list: D000927:Anticonvulsants; D005819:Genetic Markers; D015234:HLA-A Antigens; C506273:HLA-A*31:01 antigen; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen; D002220:Carbamazepine
keywords: Drug-induced hypersensitivity syndrome; Maculopapular exanthema; Pharmacogenetic testing; Rash; Stevens-Johnson syndrome; Toxic epidermal necrolysis