Human Leukocyte Antigen and Adverse Drug Events: What Pharmacists Should Know

Human leukocyte antigens (HLAs) are genes that encode cell-surface proteins that are critical for distinguishing one’s own cells and proteins from foreign cells or proteins. HLAs are necessary for the proper function of our immune system; however, certain variants of HLAs (alleles) are associated with severe drug toxicities. As more research on these variants becomes available and pharmacogenomics testing becomes more widely available, it will be important for pharmacists to be familiar with clinically-significant HLA alleles and their associated drug toxicities. The FDA maintains a list of relevant pharmacogenomic biomarkers, which includes HLA alleles associated with adverse drug reactions (ADRs)¹. Below is a summary of some select clinically significant HLA alleles and drugs that are present on the FDA’s list of pharmacogenomic biomarkers.

o HLA-B*5701 (abacavir) - The allele HLA-B*5701 is generally found at a higher frequency in Han Chinese populations and is associated with abacavir hypersensitivity reactions. Abacavir is a nucleoside reverse transcriptase inhibitor used to treat HIV. These hypersensitivity reactions can include severe fever, rash, gastrointestinal upset, or respiratory issues. It is recommended that genetic testing be performed on all potential patients prior to initiation of abacavir.²

o HLA-B*1502, HLA-A*3101 (carbamazepine) - Carbamazepine is an anticonvulsant that has multiple indications, including seizure disorders and neuropathic pain. The allele HLA-B*1502 is present at a higher frequency in East Asian populations and is associated with the development of Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) when taking carbamazepine. It is recommended that patients of Asian descent be tested for the presence of this allele prior to beginning carbamazepine therapy.³ The allele HLA-A*3101 is associated with an increased risk of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) when taking carbamazepine.⁴ Many regulatory bodies recommend testing for HLA-A*3101 status in carbamazepine-naive patients.⁵

o HLA-DQA1*0201, HLA-DRB1*0701 (lapatinib) - The alleles HLA-DQA1*0201 and HLADRB1*0701 are both alleles that are associated with increased risk of hepatotoxicity in patients being treated with lapatinib, a signal transduction inhibitor used to treat certain patients with breast cancer.^6,7Currently, these biomarkers are listed in the package insert as being correlated with hepatotoxicity, but testing recommendations are not clear. It is generally recommended that liver function tests are monitored regardless of HLA status.

There are ongoing studies examining the presence of HLA alleles and drug toxicities. The list of clinically-significant HLA biomarkers will likely increase as more research becomes available. Currently, there are other HLA-ADR associations not listed on the FDA’s list of biomarkers. One example is HLA-B*5801, which has been associated with severe cutaneous reactions following allopurinol treatment⁸. HLA variants are being explored as potential biomarkers for clozapine-induced agranulocytosis.⁹ As genomic testing becomes more available, it will be important for health care professionals and patients to be aware of clinically significant HLA alleles that can impact pharmacotherapy.

References

1. FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling. 2015; http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Accessed May 11, 2016, 2016.

2. Ma JD, Lee KC, Kuo GM. HLA-B*5701 testing to predict abacavir hypersensitivity. PLoS Currents. 2010;2:RRN1203.

3. Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens—Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008;9(10):1543-1546.

4. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and Carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine. 2011;364(12):1134-1143.

5. Dean L. Carbamazepine Therapy and HLA Genotypes. 2015; http://www.ncbi.nlm.nih.gov/books/NBK321445/, 2016.

6. Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Onc. 2011;29(6):667-673.

7. Schaid DJ, Spraggs CF, McDonnell SK, et al. Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. J Clin Onc. 2014;32(22):2296-2303.

8. Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenetics and Genomics. 2009;19(9):704-709.

9. Goldstein JI, Jarskog LF, Hilliard C, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nature Comm. 2014;5.