Hypersensitivity risk according to HLA alleles
A total of 4,910 patients had at least one of the eight HLA PGx alleles or were prescribed at least one of the seven PGx drugs. Of these patients, 1,597 had both one of the HLA PGx alleles and a PGx drug prescription. Table III shows the number of patients who took the PGx drugs, those who experienced SCAR or type B ADRs, and those with HLA PGx alleles, as well as their overlapping frequencies.
No case was reported with a SCAR or type B ADR among patients who took abacavir and also had the HLA-B*57:01 allele. In case of allopurinol, 2,782 patients had been prescribed the drug, and 1,321 patients had the HLA-B*58:01 allele. We identified 309 patients with the HLA-B*58:01 allele who had been prescribed allopurinol. Of these patients, 7 (2.3%) developed a SCAR and 53 (17.2%) developed type B ADRs, as shown inTable III . The OR of developing SCAR in allopurinol-prescribed patients with the HLA-B*58:01 allele was 7.13 (95% CI 2.19–22.69,P < .0001). Idiosyncratic type B ADRs, including SCAR, also showed a significant difference (P = 0.001) with an OR of 1.53 (95% CI 1.09–2.13).
For carbamazepine and oxcarbazepine administration, there was only one patient who had been diagnosed with a SCAR. This patient had the HLA-A*31 allele. Because there were no SCAR patients in the group of patients without the three risk alleles HLA-A*31:01, HLA-B*15:02, and HLA-B*15:11 who were prescribed carbamazepine, Haldane’s correction was used. After the correction, the OR of SCAR occurrence in the carbamazepine group with one of the three risk alleles was 21.72 (95% CI 1.05–1346.71, P = 0.023). The difference in type B ADR occurrence for carbamazepine was also statistically significant as 27.3% (3/11) of patients with the risk alleles and 4.8% (6/125) of patients without the risk alleles developed type B ADRs, and the OR was 7.22 (95% CI 0.99–42.64, P = 0.026). The data on oxcarbazepine (related to HLA-A*31:01 and HLA-B*15:02) administration also showed some increase in the number of patients with risk alleles. The indications for carbamazepine and oxcarbazepine were typically the same, and HLA-B*15:11 was the only difference in the reported risk alleles between the two; therefore, the data for these two drugs were combined and analyzed. The OR for SCAR was 9.0, which was not statistically significant (95% CI 0.11–714.8, P = 0.19); however, for type B ADR, the OR was 4.15 (95% CI 1.32–11.74, P = 0.007), which showed a significant difference. Among the 77 methazolamide users, there was one case of type B ADR but no one had a SCAR. Among the 12 dapsone users, 2 of 3 (66.7%) patients with the HLA-B*13:01 allele had SCARs, whereas no patients (0%) were reported with a SCAR among those without any risk alleles. Although we identified a large difference in the SCAR occurrences between the two groups (with and without risk alleles), this was not statistically significant owing to the small sample size of dapsone users. For vancomycin, a type B ADR due to vancomycin occurred in 23.1% patients with HLA-A*32:01 and 12.8% patients without HLA-A*32:01. The OR for the development of type B ADR in patients with the risk allele was 2.05 (95% CI 0.85–4.48, P = 0.086); however, it was not statistically significant. There were no cases with vancomycin-related SCARs among nine patients with the HLA-A*32:01 allele. Overall, the risk of developing SCARs due to allopurinol and carbamazepine use and type B ADRs due to allopurinol, carbamazepine, and oxcarbazepine use were significantly higher in patients with the risk alleles (Figure 3 ).
It is assumed that if patients with the risk alleles had not been prescribed the high-risk drugs, the following SCARs would have been prevented: 7/15 (46.7%) for allopurinol, 1/1 (100%) for carbamazepine, 1/2 (50%) for oxcarbazepine, and 2/2 (100%) for dapsone (Table III ).