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Objective: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value., Methods: We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity., Results: In the primary analysis, nine variants reached genome-wide significance (p < 5e-08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA-B*15:02-negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA-B*15:02 status or zygosity. HLA-B*15:02-positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p < .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p < 5e-6) identified through the primary and subanalyses (stratified by HLA-B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology-related genes. The genes implicated were specific either to the primary analysis (CD9), HLA-B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA-E), or phenytoin exposure (CD24)., Significance: We identified variants that could explain why some carriers of HLA-B*15:02 tolerate treatment, and why some noncarriers develop ASM-induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA-B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM-induced SJS/TEN is complex, likely involving multiple risk variants., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Carbamazepine, widely used in the treatment of partial and generalized tonic-clonic seizures, has been associated with life-threatening Stevens-Johnson syndrome/toxic epidermal necrolysis among some Asians. The HLA-B*1502 genotype that occurs with varying frequency among Asians is recommended for screening prior to starting carbamazepine. Our goal is to explore the cost-effectiveness of screening for the presence of this genetic allele., Methods: We constructed a Markov model in a hypothetical cohort of adult Asian patients with epilepsy in the United States being considered for carbamazepine to investigate the cost-effectiveness of two alternative strategies: (1) no HLA-B*1502 gene allele screening and using carbamazepine and (2) HLA-B*1502 gene allele screening and starting levetiracetam in the case of a positive screen., Results: For the lifetime horizon, HLA-B*1502 gene screening was the cost-effective choice compared to no gene screening, with an incremental cost-effectiveness ratio of $27 058 per quality-adjusted life-year (QALY), below the $50 000/QALY threshold in 99.69% of probabilistic sensitivity analyses. Although gene screening strategy was more expensive than a no screening strategy, it was more effective, yielding more QALYs, across all Asian ethnic groups., Significance: Our analysis confirms the 2007 US Food and Drug Administration recommendation to screen for HLA-B*1502 allele before starting treatment with carbamazepine in patients of Asian ancestry in the United States., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: After discovering the association between the HLA-B*15:02 allele and carbamazepine-related severe cutaneous adverse reactions (SCARs), particularly in Southeastern Asian populations, clinical strategies to prevent carbamazepine-related SCARs have changed. We aimed to investigate 10-year trends in carbamazepine use and carbamazepine-related SCARs and to examine the patterns and determinants of HLA-B*15:02 screening in Taiwan., Methods: A nationwide study was performed using Taiwan's National Health Insurance Research Database. In the first part of the study, new users of carbamazepine were included, and those who experienced SCAR-related admissions were further identified. In the second part of the study, recipients of HLA-B*15:02 screening (reimbursed by Taiwan's National Health Insurance since June 2010) were included and multivariate logistic regression was used to explore factors associated with the use of screening., Results: The numbers of new users of carbamazepine and SCAR cases decreased remarkably during the 10-year period (-82.6% and -87.1%, respectively), and the incidence rates of SCARs showed a downward trend after 2011. The screening rate of the HLA-B*15:02 allele increased to 24.9% in 2014. Neurologists (odds ratio 12.33, 95% confidence interval 9.30-16.35), psychiatrists (9.97, 7.31-13.61), and neurosurgeons (3.23, 2.42-4.32) were more likely to perform screening tests than other specialties were. Physicians practicing in medical centers (6.00, 5.51-6.54) were more likely to perform screening tests than those practicing in other hospitals, whereas the screening rates in clinics remained at 0.0% throughout the study period., Significance: In recent years, the number of carbamazepine-related SCAR cases has decreased substantially in Taiwan. However, only one-fourth of new users of carbamazepine received HLA-B*15:02 screening, and there were considerable disparities in the screening rates across different physician groups. Policymakers should consider solutions to barriers to implementing screening tests in clinical practice and should not neglect the value of other safety communications and regulations to complement the limitations of pharmacogenomic testing., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

This study aimed to investigate the prevalence and association of HLA-B*15:02 with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA-B alleles in five Indian case patients with CBZ-SJS/TEN and 52 CBZ-tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA-B*15:02 with CBZ-SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA-B*15:02 and CBZ-SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25-162.21, p = 1.05 × 10(-3)). Subsequent meta-analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA-B*15:02 and CBZ-SJS/TEN (OR 38.54; 95% CI 6.83-217.34, p < 1.0 × 10(-4)). Our study is the first on Indians predominantly from Southern India that demonstrated HLA-B*15:02 as a strong risk factor for CBZ-SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA-B*15:02, irrespective of the ancestral background, including populations with low allele frequency., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

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., Significance: 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., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)