Reducing severe cutaneous adverse and type B adverse drug reactions using pre‐stored human leukocyte antigen genotypes

Abstract

Background Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre‐stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre‐stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs. Methods We analyzed the incidence and the risk of ADRs for selected HLA alleles (HLA‐B*57:01, HLA‐B*58:01, HLA‐A*31:01, HLA‐B*15:02, HLA‐B*15:11, HLA‐B*13:01, HLA‐B*59:01, and HLA‐A*32:01) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre‐stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus. Results Among 11,988 HLA‐tested transplant patients, 4092 (34.1%) had high‐risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with HLA‐B*58:01 had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without HLA‐B*58:01 (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09–2.13], p = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19–22.69], p < 0.001). Higher risks of type B ADR and SCARs were observed in patients taking carbamazepine or oxcarbazepine if they had one of HLA‐A*31:01, HLA‐B*15:02, or HLA‐B*15:11 alleles. Vancomycin and dapsone use in HLA‐A*32:01 and HLA‐B*13:01 carriers, respectively, showed trends toward increased risk of type B ADRs. Conclusion Utilization of pre‐stored HLA data can prevent type B ADRs including SCARs by screening high‐risk patients.

Pharmacogenes that demonstrate high association evidence according to CPIC, DPWG, and PharmGKB

“…Thus, molecular testing should be considered. A wide range of polymorphisms in the human leukocyte antigen (HLA)-B loci, located in the major histocompatibility complex (MHC) region on chromosome 6, have been shown to be risk factors for various adverse reactions (e.g., hypersensitivity and hepatotoxicity) related to nine different medications ( 48 , 49 ). HLA-B * 57:01 is a famous example of an allele seriously associated with life-threatening reactions as a consequence of exposure to abacavir (induces severe hypersensitivity) ( 50 ) and flucloxacillin (induces liver injury) ( 51 ).…”

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

“…Recently, we reported the association between HLA-A*32:01, HLA-B*07:05, HLA-B:40:06, HLA-B*67:01 and vancomycin-induced DRESS in Taiwanese population ( Wang et al, 2022c ). However, Lee et al (2022) reported that there is no association between HLA-A*32:01 and vancomycin-induced SCARs in Korean population according to clinical data from Seoul National University Hospital. Nakkam et al (2021) elucidated the possibility of cross-reactivity between vancomycin, teicoplanin, and dalbavancin in HLA*A-32:01 patients with previous vancomycin-induced DRESS.…”

“…Satapornpong et al found that HLA-C*03:04 is associated with dapsone-induced SCARs, although dapsone-induced DRESS and SJS/TEN showed no significance owing to weak statistical power ( Satapornpong et al, 2021 ). In addition, Lee et al (2022) analyzed the clinical data warehouse from Korea and found there is no association between HLA-B*13:01 and dapsone-induced SCARs in Korean population. Zhao et al (2021) investigated that dapsone and its metabolite nitroso-dapsone are selectively interacted with HLA-B*13:01 to activate CTLs related cytotoxicity.…”

HLA‐A*24:02 increase the risk of allopurinol‐induced drug reaction with eosinophilia and systemic symptoms in HLA‐B*58:01 carriers in a Korean population; a multicenter cross‐sectional case‐control study

“…Since the information of other HLA distribution among B*58:01 carriers in Korean general population were not available, the HLA information of 11998 HLA‐tested subjects included in the data warehouse of the Seoul National University Hospital were used to define B*58:01 (+) general population control. 17 The first validation set was HLA‐tested allopurinol user cohort among 11998 HLA‐tested subjects. The history of allopurinol exposure and hypersensitivity were collected from the electronic medical records and adverse drug reaction records.…”

“…Additional comparisons in separate populations were designed to support the results. Since the information of other HLA distribution among B*58:01 carriers in Korean general population were not available, the HLA information of 11998 HLA‐tested subjects included in the data warehouse of the Seoul National University Hospital were used to define B*58:01 (+) general population control 17 . The first validation set was HLA‐tested allopurinol user cohort among 11998 HLA‐tested subjects.…”