Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population

Abstract

for the GENCAT Study Group IMPORTANCE Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated.OBJECTIVE To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs.DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016.EXPOSURES Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. MAIN OUTCOMES AND MEASURES Incidence of carbamazepine-induced cADRs.RESULTS Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001).CONCLUSIONS AND RELEVANCE Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

Shared Genetic Risk Factors Across Carbamazepine‐Induced Hypersensitivity Reactions

“…Indeed, our meta‐analysis shows that HLA‐A*31:01 carriers have eightfold higher risk of developing CBZ‐SCAR than noncarriers. Interestingly, a recent prospective study in Japan was able to show that pre‐prescription genotyping for HLA‐A*31:01 reduces the incidence of CBZ hypersensitivity reactions . Taken together, the overwhelming evidence of the role of HLA‐A*31:01 in predisposing to CBZ‐SCAR shows that there is a need to implement its use in clinical settings, as outlined in the recent Clinical Pharmacogenetics Implementation Consortium guideline .…”

“…Interestingly, a recent prospective study in Japan was able to show that pre-prescription genotyping for HLA-A*31:01 reduces the incidence of CBZ hypersensitivity reactions. 19 Taken together, the overwhelming evidence of the role of HLA-A*31:01 in predisposing to CBZ-SCAR shows that there is a need to implement its use in clinical settings, as outlined in the recent Clinical Pharmacogenetics Implementation Consortium guideline. 20 Independent of the HLA-A*31:01 association, we identified a residual effect in the MHC region mapping to MUC22 gene (lead SNP rs116071718).…”

Utility evaluation of HLA-B*13:01 screening in preventing trichloroethylene-induced hypersensitivity syndrome in a prospective cohort study

“…Clinical practice records demonstrated that identification of population at high risk and the subsequent elimination of offending drugs were effective to prevent drug-induced hypersensitivity syndrome. To date, prospective screening of genetic risk factors (especially HLA alleles) for incidence reduction of drug-induced hypersensitivity syndrome has been adopted into routine clinical practice, such as HLA-B*15:02 and HLA-B*31:01 for carbamazepine induced Stevens-Johnson syndrome, toxic epidermal necrolysis or cutaneous adverse reactions,19 20 HLA-B*57:01 testing to prevent abacavir induced adverse drug reaction with eosinophilia and systemic symptoms21 and HLA-B*58:01 for allopurinol induced severe cutaneous adverse reactions 22. In the present study, HLA-B*13:01 was used as a predictor exhibiting excellent performance to discriminate the TCE-exposed workers at high risk for TIHS with the sensitivity of 75% and specificity of 91.1%.…”

HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

“…85 The predicted cost effective benefits of HLA-A*31:01 screening suggest a need to test between 47-67 individuals of either Caucasian or Japanese descent to avoid a single cADR case, 88 and testing has resulted in a 40% decreased incidence of carbamazepine-induced cADRs in the latter population. 89 Given the rising incidence of reported HLA-A*31:01-related AED-induced cADRs there is accumulating evidence to support pre-treatment genetic screening in at risk populations.…”