Human leukocyte antigen (HLA) encoded by the HLA gene is an important modulator for immune responses and drug hypersensitivity reactions as well. Genetic polymorphisms of HLA vary widely at population level and are responsible for developing severe cutaneous adverse drug reactions (SCARs) such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), maculopapular exanthema (MPE). The associations of different HLA alleles with the risk of drug induced SJS/TEN, DRESS and MPE are strongly supportive for clinical considerations. Prescribing guidelines generated by different national and international working groups for translation of HLA pharmacogenetics into clinical practice are underway and functional in many countries, including Thailand. Cutting edge genomic technologies may accelerate wider adoption of HLA screening in routine clinical settings. There are great opportunities and several challenges as well for effective implementation of HLA genotyping globally in routine clinical practice for the prevention of drug induced SCARs substantially, enforcing precision medicine initiatives.

Objective: This study aimed to investigate the clinical impact of HLA-B*15:02 pharmacogenomics (PGx) testing before carbamazepine (CBZ)/oxcarbazepine (OXC) prescriptions and to determine whether this PGx testing was associated with the reduction of CBZ/OXC-induced cutaneous adverse drug reactions (CADRs) in Thailand.Methods: This retrospective observational cohort study was conducted by obtaining relevant HLA-B*15:02 PGx-testing and clinical data from electronic medical records during 2011–2020. 384 patient data were included in this study to investigate the clinical decision on CBZ/OXC usage before and after the HLA-B*15:02 PGx testing, and 1,539 patient data were included in this study to demonstrate the incidence of CBZ/OXC-induced SCARs and SJS between HLA-B*15:02 tested and non-tested patients. To analyze and summarize the results, descriptive statistics were employed, and Fisher exact test was used to compare the clinical difference between the HLA-B*15:02 positive and negative groups and to compare the differences of SCARs incidence.Results: 384 patients were included in this study as per the inclusion criteria. Of these, 70 patients carried HLA-B*15:02, of which 63 and 65 patients were not prescribed with CBZ/OXC before and after the availability of genotyping results, respectively. In the remaining HLA-B*15:02 non-carriers, 48, and 189 patients were prescribed CBZ/OXC before and after genotyping results were available, respectively. The findings of this study showed that the incidence of SCARs of CBZ/OXC was significantly lower (p < 0.001) in the HLA-B*15:02 screening arm than in the non-screening arm.Conclusion:HLA-B pharmacogenetics testing influenced the selection of appropriate AEDs. The presence of mild rash in the HLA-B*15:02 negative group indicates that other genetic biomarker (HLA-A*31:01) and/or non-genetic variables are involved in CBZ/OXC-induced CADRs, emphasizing that CBZ/OXC prescriptions necessitate CADR monitoring. The hospital policy and clinical decision support (CDS) alert system is essential to overcome the barriers associated with the utilization of PGx guidelines into clinical practice.

The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9–24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06–15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25–13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA94C > A, ITPA123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy.