HLA-A and HLA-B
HLA-A and HLA-B are members of the major histocompatibility complex (MHC) gene family. These genes encode proteins that present antigens to the immune cells, and thus play a critical role in the immune system.1 Substantial evidence and high medical actionability have promoted clinical pharmacogenetics implementation consortium (CPIC) to publish clinical guidelines for dosing of various drugs, including allopurinol, carbamazepine and oxcarbazepine, phenytoin, and abacavir, based on the HLA genotype.
Allopurinol is mainly used to treat gout. It is also one of the most common causes of severe cutaneous adverse reaction (SCARs), also known as allopurinol hypersensitivity syndrome. Strong evidence indicates the association of one genetic variant of HLA-B (HLA-B*58:01) with allopurinol-induced SCARs. The CPIC clinical guideline recommends that allopurinol should not be prescribed to patients who are carriers of HLA-B*58:01. However, the guideline also has noted that patients who have negative test result of HLA-B*58:01 does not eliminate the possibility of developing SCAR, especially in the European population.2
Carbamazepine and Oxcarbazepine
Carbamazepine is indicated for epilepsy, trigeminal neuralgia, and bipolar disorder. Oxcarbazepine is a keto-analog of carbamazepine. They share many therapeutic indications and adverse effects. The adverse effects include SCARs, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic syndrome (DRESS), and maculopapular exanthema (MPE). Two HLA alleles (HLA-B*15:02 and HLA-A*31:01) are associated with carbamazepine- and oxcarbazepine-induced SCARS. CPIC has published a clinical guideline based on two HLA alleles to guide treatment and dosing of these two drugs.3
Phenytoin is a widely used antiepileptic drug. Phenytoin dosing is challenging mainly due to its narrow therapeutic index and wide interpatient variability in pharmacokinetics. The CPIC guideline recommends treatment and dosing adjustment for phenytoin based on the genotypes of HLA-B and CYP2C9. HLA-B*15:02 allele is associated with higher risk of SJS/TEN. Although the evidence was mainly generated among patients of Asian ancestry, the critical CPIC recommendation is to consider using an anticonvulsant other than phenytoin and carbamazepine if the HLA-B*15:02 test result is positive, regardless of the individual’s ancestry or age, as the allele may occur in other population yet to be studied, and patients may be unaware of or fail to disclose distant Asian ancestry in their families.5 The Food and Drug Administration (FDA) also issued a warning for phenytoin: “consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patient positive for HLA-B*15:02.”6
Abacavir is used to treat HIV infection. Although the drug is generally well tolerated by most of the patients, 5-8% of patients experience abacavir-induced hypersensitive reaction (HSR). The CPIC recommends HLA-B*57:01 screening in all abacavir-naïve individuals before initiation of abacavir-containing therapy. This recommendation is consistent with the FDA, the US Department of Health and Human Services, and the European Medicine Agency.7
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- Barbarino JM, et al. PharmGKB Summary: Very Important Pharmacogene Information for Human Leukocyte Antigen B. Pharmacogenet Genom. 2015.
- Hershfield MS, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing. Clin Pharmacol Ther. 2013;93(2):153-58.
- Phillips EJ, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. (Epub ahead)
- Thorn CF, et al. PharmGKB Summary: Phenytoin Pathway. Pharmacogenet Genom. 2012
- Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing. Clin Pharmacol Ther. 2014;96(5):542-48.
- FDA approved drug label for Dilantin-125
- Martin MA, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing. Clin Pharmacol Ther. 2012;91(4):734-38.