What are the HLA genes?
The human leukocyte antigen (HLA) complex, encoded by the HLA gene family, plays a critical role in immunity. The HLA proteins are present on the surface of most cells and help the immune system to recognize foreign substances, such as viral and bacterial peptides. The HLA genes, located on chromosome 6, are highly polymorphic. HLA-A*3101 and HLA-B*1502 are two alleles that have been associated with severe cutaneous adverse drug reactions (cADRs), including Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Carbamazepine, lamotrigine, and phenytoin are some of the antiepileptic drugs most commonly associated with cADRs.
What do the data say about HLA-B*1502 and adverse events with carbamazepine and phenytoin?
The association between the HLA-B*1502 allele and carbamazepine-induced SJS/TEN has been extensively studied. A 2014 meta-analysis (n = 205 cases, n = 692 carbamazepine-tolerant controls) found a significant association between HLA-B*1502 and carbamazepine-induced SJS/TEN ( OR = 80.70, p = 1.88*10-51), with a sensitivity of 95% and a specificity of 90%.1 The robustness of these data prompted the FDA to add a black box warning to the carbamazepine package insert, stating that carbamazepine should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.2 The FDA-approved package insert for oxcarbazepine, a structural derivative of carbamazepine, also warns against the use of oxcarbazepine in patients positive for HLA-B*1502.3
The HLA-B*1502 allele has also been implicated in phenytoin-induced SJS/TEN. A meta-analysis by Li et al. (n = 46 cases, n = 246 phenytoin-tolerant controls) found a significantly increased risk of phenytoin-induced SJS/TEN in HLA-B*1502 subjects (OR = 5.65, p < 0.001).4 The FDA-approved package insert warns against the use of phenytoin in HLA-B*1502 positive patients.5
What do the data say about HLA-A*3101 and adverse events with carbamazepine and phenytoin?
A meta-analysis of seven studies (total n = 413 subjects, n = 1,020 carbamazepine-tolerant controls) found that the HLA-A*3101 allele is significantly associated with carbamazepine-induced cADRs (OR = 7.75, p = 4.28*10-27).1 The package insert discourages the use of carbamazepine in HLA-A*3101 positive patients.2 The HLA-A*3101 allele has not been well studied in other medications. A genome-wide association (GWAS) study failed to find an association between HLA-A*3101 and phenytoin-induced cADRs (OR = 0.791, p = 0.746).6
What do the data say about HLA polymorphisms and lamotrigine-induced adverse events?
Ten publications were reviewed that examined the association between the HLA-B*1502 allele and cADRs in patients receiving lamotrigine. All 10 studies (total n = 188 cases, n = 269 lamotrigine-tolerant controls) failed to find an association between HLA-B*1502 and cADRs.6-15 However, the meta-analysis by Li et al. pooled the results from five of these studies and observed an OR of 4.51 for lamotrigine-induced SJS/TEN in HLA-B*1502 positive patients (p = 0.005).4 Assurex Health updated this analysis with one additional study (unpublished data; the other four studies did not have sufficient data available to perform the statistical analysis). The addition of this study reduced the overall effect size, resulting in loss of statistical significance (OR = 2.44; p = 0.064). The lack of statistical significance means that no definitive recommendations for HLA-B*1502 and lamotrigine can be made at this time. However, the general positive trend in the data suggest that caution may be warranted in the administration of lamotrigine to HLA-B*1502 positive patients.
The HLA-A*3101 allele does not appear to be a clinically relevant predictor of lamotrigine-induced adverse events as a GWAS failed to find an association between the allele and lamotrigine-induced cADRs (OR = 0.756, p = 0.698).6
Who should be tested?
The frequency of the HLA-B*1502 allele is highest in certain Asian populations. Malaysian, Thai, Vietnamese, and Chinese populations have allele frequencies of 7-16%.16–19 Screening may be beneficial for these patients. HLA-B*1502 is much less frequent in Japanese and Caucasian populations, with allele frequencies of <1%.20,21 In contrast, up to 10-15% of Japanese, Native American, Indian, Arabic, Han Chinese, Korean, and European patients are expected to carry the HLA-A*3101 allele, but less common in African-American, Thai, and Taiwanese populations.2
While the HLA-A*3101 and HLA-B*1502 alleles are more frequent in some populations than in others, the data do not suggest that the associations with adverse drug reactions are ancestry-dependent. Therefore, caution should be exercised in any patient testing positive for the HLA-A*3101 or HLA-B*1502 alleles, regardless of ancestry.
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2. Tegretol [package Insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014.
3. Trileptal [package Insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014.
4. Li X, Yu K, Mei S, et al. HLA-B*1502 Increases the Risk of Phenytoin or Lamotrigine Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: Evidence from a Meta-analysis of Nine Case-control Studies. Drug Res (Stuttg). 2014;65:107-111. doi:10.1055/s-0034-1375684.
5. Dilantin [package Insert]. New York, NY: Parke-Davis; 2015.
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17. Hoa BK, Hang NTL, Kashiwase K, et al. HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in the Kinh population in Vietnam. Tissue Antigens. 2008;71(2):127-134. doi:10.1111/j.1399-0039.2007.00982.x.
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19. Pimtanothai N, Charoenwongse P, Mutirangura a, Hurley CK. Distribution of HLA-B alleles in nasopharyngeal carcinoma patients and normal controls in Thailand. Tissue Antigens. 2002;59(3):223-225. doi:10.1034/j.1399-0039.2002.590308.x.
20. Middleton D, Williams F, Hamill M a., Meenagh a. Frequency of HLA-B alleles in a caucasoid population determined by a two-stage PCRSSOP typing strategy. Hum Immunol. 2000;61(12):1285-1297. doi:10.1016/S0198-8859(00)00186-5.
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