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 ).