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.

Keywords: adverse drug reaction; human leukocyte antigen; hypersensitivity; pharmacogenomics; preemptive genotyping.

FIGURE 1

Inclusion pipeline of the ADR‐related HLA variants and drugs. ADR, adverse drug reactions; HLA, human leukocyte antigen

FIGURE 2

Frequency of pharmacogenomics HLA allele, drug, and adverse drug reactions in patients with pre‐stored HLA data. The left side process represents patients with HLA alleles associated with ADRs (seven alleles); the middle process represents patients who were prescribed medications (seven drugs) with known HLA‐associated ADRs; and the right side process represents HLA‐related ADRs from the Drug Safety Center reports and review of the diagnoses. HLA, human leukocyte antigen; PGx, pharmacogenomics; ADRs, adverse drug reactions; SNUH, Seoul National University Hospital; SJS, Steven–Johnson syndrome; DE, drug reaction with eosinophilia and systemic symptoms

FIGURE 3

Comparison of the frequency of type B ADR and SCAR incidence for allopurinol, carbamazepine, oxcarbazepine, and vancomycin. ADR, adverse drug reactions; HLA, human leukocyte antigen; SCAR, severe cutaneous adverse reaction