Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

14 Applying Pharmacogenomics in Therapeutics
59 of 60 patients with carbamazepine-induced SJS/TEN had tested positive for
the HLA-B*1502 allele. 89 The one patient who did not test positive for the HLA-
B*1502 allele was tested positive for the HLA-B*1558 allele. This was compared
to 6 out of 144 controls (tolerant to carbamazepine) who were carriers of the HLA-
B*1502 allele (OR = 1357, 95% CI: 193.4–8838.3, p = 1.6 × 10 –41 ). 89 In a separate
study, there was a significant difference in SJS/TEN incidences among patients
who received carbamazepine, depending on whether they were HLA-B*1502 carriers
(100%) versus noncarriers (14.5%). 93
HLA-B*1502 was also studied in 4877 Taiwanese patients who were candidates
for carbamazepine and had not received testing for the allele. 98 Of them, 7.7% of the
patients had tested positive for the allele and was given an alternative medication or
a pre-study medication. The 92.3% of the patients who tested negative for the HLA-
B*1502 allele were advised to take carbamazepine. Mild transient rash occurred in
4.3% of subjects, but SJS/TEN did not develop in any patient. This is significantly
lower than 0.23% of carbamazepine-induced SJS/TEN from historical incidence
(p < 0.001). 98
In addition to Chinese and Taiwanese patients, the HLA-B*1502 was studied
in Thai patients in two studies. A case–control study was conducted in a Thai
population in which the odds ratio for developing carbamazepine-induced SJS/
TEN was 54.76 (95% CI: 14.62–205.13, p = 2.89 × 10 –12 ) among those who were
positive for HLA-B*1502. 99 The positive predictive value and negative predictive
value of the HLA-B*1502 allele were 1.92% and 99.96%, respectively. Another
study showed a strong association between HLA-B*1502 and carbamazepine- and
phenytoin-induced SJS but not MPE. 100 Of the 81 patients with epilepsy, 31 subjects
had antiepileptic drug-induced SJS/MPE. HLA-B*1502 was associated with
carbamazepine-induced SJS and phenytoin-induced SJS (p = 0.005 and p = 0.0005,
respectively).
As discussed before, the HLA-B*1502 allele may increase the risk of toxicity
from other anticonvulsant drugs (lamotrigine, oxcarbazepine, and phenytoin) by
contributing to SJS/TEN. 89,101,102 In a case–control study, HLA-B*1502 was present
in 8/26 (30.8%) patients who received phenytoin and developed SJS/TEN (OR = 5.1,
95% CI: 1.8–15.1, p = 0.0041) and 3/3 (100%) patients who were tolerant to carbamazepine
(OR = 80.7, 95% CI: 3.8–1714.4, p = 8.4 × 10 –4 ). This may be partially due
to similarities in aromatic structure between carbamazepine, oxcarbazepine, phenytoin,
and lamotrigine. 89 Clinically, there is an estimated 20–30% cross-reactivity
probability between these drugs. 103,104
In addition to HLA-B*1502, several other HLA alleles have been recently identified
as potential markers for carbamazepine-induced HSRs. The HLA-A*3101 has
been associated with carbamazepine-induced HSRs in Japanese and Europeans. 85,86
In Japanese patients, the prevalence of HLA-B*1502 is <1% and correlates to the low
prevalence of carbamazepine-induced HSRs. Among Japanese, the HLA-B*1511 has
been shown to be a risk factor for carbamazepine-induced SJS/TEN. 81 The HLA-
B*1508, *1511, and *1521 as well as *1502 are all members of the HLA-B75 type
and have been detected in studies performed in India and Thailand. One study also
showed an association of HLA-B*1518, HLA-B*5901, and HLA-C*0704 alleles with
severe cutaneous ADRs. 81