<i>HLA‐B*15:21</i> carrier status is a susceptibility factor of carbamazepine‐induced nonimmediate cutaneous adverse reactions in <i>HLA‐B*15:02</i> ‐negative patients: A retrospective cohort study

AIM: Pre-prescription HLA-B*15:02 screening is a standard practice to prevent carbamazepine (CBZ)-induced nonimmediate cutaneous adverse reactions (cADR) in Asian populations. However, HLA-B*15:11 and HLA-B*15:21 also increase susceptibility of CBZ-induced cADR, but its influence on the residual risk after HLA-B*15:02 screening remains limited. This study aimed to evaluate the residual risk and the nature of cADR following HLA-B*15:02 screening in a region with high HLA-B diversity. METHOD: We retrospectively reviewed HLA-B*15:02-screened cases at Songklanagarind Hospital, Thailand. HLA-B*15:02-negative cases were assessed for CBZ prescription history, follow-up history and treatment outcomes. HLA-B*15:11 and HLA-B*15:21 carrier status of HLA-B*15:02-negative cases who took CBZ was re-evaluated using a quantitative PCR, sanger sequencing and HLA typing method. Patients who received CBZ and those with confirmed CBZ-induced nonimmediate cADR were used to calculate residual risk and genetic association. RESULTS: Among 560 HLA-B*15:02-negative cases, 288 received CBZ. The carrier frequency of HLA-B*15:11 and HLA-B*15:21 were 6.9% (20/288). CBZ-induced nonimmediate cADRs were confirmed in 17 cases, translating to a residual risk of 0.059. The cADRs were observed in 20.0% (4/20) of HLA-B*15:11 or HLA-B*15:21 carriers (all four cases were HLA-B*15:21 carriers) compared to 4.85% (13/268) of non-carriers. Firth's penalized logistic regression suggested that HLA-B*15:21 increases odds of CBZ-induced nonimmediate cADR (OR 5.84, 95% CI 1.58-19.07; p = .010). CONCLUSION: This report provided the first real-world evidence of residual risk of CBZ-induced cADR after screening negative for HLA-B*15:02 that associated with other HLA-B markers. Therefore, incorporating a broader screening may further enhance drug safety in populations with a diverse HLA-B admixture.