This article explains the relevance of Human Leucocyte Antigen (HLA) proteins/genes to psychotropic drug prescribing and explains which tests to order, when, and how. A few things made me decide to write this post:
I don’t prescribe carbamazepine frequently, but I do prescribe oxcarbazepine more often–in persons with bipolar disorder who have not done well on other mood stabilizers. Should we do HLA testing routinely in persons taking oxcarbazepine just like we are told to do before starting carbamazepine?
Recently, I read a post on Facebook by a psychiatrist telling other psychiatrists that we should do HLA testing because it can tell us about the risk of Stevens-Johnson syndrome with lamotrigine. Is that true?
Some time ago, I saw a patient of Indian origin who was on carbamazepine and had been on it for several years. Should I have ordered HLA testing in that patient?
What are HLA proteins and genes?
The human leukocyte antigen (HLA) complex are genes that code for certain proteins on the surface of cells in the body. These proteins are very important in immunity because they help the immune system to identify cells belonging to one’s own body versus cells that have entered our bodies.
These HLA genes come in many variations (called alleles) and each individual may have a different pair of HLA gene alleles.
Why are HLA proteins/genes important in mental health?
The reason the HLA proteins and corresponding genes are important to mental health clinicians is that some of HLA gene alleles have been associated with Stevens-Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN).
As you know, Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis are serious and sometimes fatal dermatologic reactions and which may occur with certain psychotropic medications, including carbamazepine, oxcarbazepine, and lamotrigine. While SJS/ TEN are rare, these reactions are important because the mortality rate for SJS is up to 5% and for TEN is about 25%.
HLA antigens and carbamazepine
The Prescribing Information for carbamazepine (Tegretol®) has a boxed warning about the association of serious dermatologic reactions and HLA-B*1502 allele. This boxed warning (reworded here) notes that:
SJS/ TEN are estimated to occur very rarely in countries with mainly Caucasian populations (1 to 6 per 10,000 new users of carbamazepine), BUT the risk in some Asian countries is estimated to be about 10 times higher.
Studies in patients of Chinese ancestry have found a STRONG association between the risk of developing SJS/TEN and the presence of HLA-B*1502 which is one of the variations (alleles) of the HLA-B gene.
This HLA-B*1502 gene is found almost exclusively in patients with Asian ancestry. Note: the risk is not the same for every Asian country; risk for some Asian countries is listed below.
Patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 before starting carbamazepine. Patients testing positive for the allele should not be treated with carbamazepine unless the benefit CLEARLY outweighs the risk.
What about the HLA-A*3101 allele?
There is also an association between HLA-A*3101 and hypersensitivity reactions (including SJS/ TEN) in patients taking carbamazepine. However, this association is not as strong as that with HLA-B*1502. Unlike HLA-B*1502, routine testing for HLA-A*3101 is not required, but should be considered.
Recommendations for carbamazepine
1. Prior to starting carbamazepine, testing for HLA-B*1502 should be performed in patients with ancestry suggesting a higher probability of carrying the HLA-B*1502 allele.
2. Carbamazepine should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.
3. Carbamazepine should be stopped at the first sign of a rash, unless the rash is CLEARLY not drug-related.
4. If signs or symptoms suggest SJS/TEN, carbamazepine should NEVER be restarted in the future.
Important clarifications about HLA*1502 testing
1.The test is considered to be “positive” if even one HLA-B*1502 allele is detected (remember, we have two of every gene on chromosomes other than sex chromosomes). The test is considered “negative” if not even one HLA-B*1502 allele is detected.
2. Routine testing is recommended only for those whose ancestry is from countries that have a higher prevalence of the HLA-B*1502 allele. It does not have to be done for everyone who is being started on carbamazepine (or oxcarbazepine).
3. However, it is the allele and not the ancestry that is relevant. What I mean by that is that once it is known whether or not a person carries the HLA-B*1502 (or HLA-A*3101) allele, it does not matter what that person’s ancestry is. The ancestry only tells us that we should do the screening in this person. So, if we have a Caucasian patient and in the course of doing pharmacogenetic testing it is found that he carries the HLA-B*1502 (or HLA-A*3101) allele, now the race and ancestry doesn’t matter. Get it?
4. It should also be kept in mind that serious cutaneous reactions can occur at times in patients who are NEGATIVE for both HLA-B*1502 and HLA-A*3101.
5. The risk of SJS/ TEN is greatest in the first few months. If a person has been on carbamazepine/ oxcarbazepine for many months, there is no need to do HLA testing. For example, I inherited a patient of Indian origin (at higher risk of having HLA-B*1502), but since he had been on carbamazepine for over ten years, I didn’t order HLA testing.
How to test for HLA-B*1502 (and HLA-A*3101)
Testing for relevant HLA alleles can be done through usual laboratories or can be an additional benefit of getting a pharmacogenetic test battery (if we are getting such a test battery for other reasons anyway).
GeneSight® Psychotropic test (provided by the company Assurex Health) is a commercially available pharmacogenetic test battery that includes testing for both the HLA alleles relevant to prescription of carbamazepine: HLA-B*1502, and HLA-A*3101. On the other hand, the Genecept Assay® (Genomind, LLC) does not include testing for HLA alleles.
As of February, 2017, the Genecept Assay® (provided by the company Genomind, LLC) does not include testing for HLA alleles.
What about oxcarbazepine (Trileptal®)?
Even though the Prescribing Information for oxcarbazepine does not contain a boxed warning about this, it too is associated with increased risk of SJS/ TEN. The association between HLA-B*1502 and increased risk of SJS/ TEN with oxcarbazepine is less certain than with carbamazepine. The Prescribing Information recommends that:
1. Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to starting treatment with oxcarbazepine. With carbamazepine, testing for HLA-B*1502 “should” be done in genetically at-risk persons, while with oxcarbazepine it simply simply says that such testing should be “considered”.
2. As with carbamazepine, the use of oxcarbazepine should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.
What about lamotrigine (Lamictal®)?
While we know that lamotrigine is associated with increased risk of SJS/ TEN, it is not clear whether the risk of SJS/TEN with lamotrigine is increased in persons who are positive for HLA-B*1502 or HLA-A*3101. Meta-analyses of very small studies have suggested that there may be an association between HLA-B*1502 and lamotrigine-induced SJS/TEN, though not as strong as that with carbamazepine (Li et al., 2015; Zeng et al., 2015). On the other hand, HLA-B*3101 has not been found to be associated with SJS/TEN in persons taking lamotrigine.
The Prescribing Information for lamotrigine does not recommend testing for HLA alleles and, in fact, does not use the term “HLA” at all.
Standard textbooks also do not recommend HLA testing for persons being started on lamotrigine (American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition; Manual of Clinical Psychopharmacology, 8th Edition).
Given the uncertain and weaker association between HLA-B*1502 and lamotrigine-induced SJS/TEN, what would we do if we ordered testing for HLA-B*1502 and the test came back positive? I follow the general principle that we should not order a test if it will not make any difference to the management. Will we avoid lamotrigine in these patients? If we do end up starting lamotrigine anyway, will a positive HLA-B*1502 test make the patient more anxious without producing any benefit? These are difficult clinical questions.
So, at this time, I am not recommending that HLA testing be done routinely in all persons of at-risk ancestries being started on lamotrigine. I will keep a close watch on the literature and will let Members know right away if the recommendations change.
Note: There is some data linking lamotrigine-induced SJS/TEN to a different HLA antigen–HLA -B*4403 (Park et al., 2015).
Prevalence of HLA-B*1502
Across Asian populations, there is variation in the prevalence of HLA-B*1502. The reason it is important to know which countries have higher prevalence of
- Hong Kong, Malaysia, and parts of the Philippines: > 15%
- Taiwan: 10%
- Thailand: 8%
- North China: 4%
- South Asia, including India: 2% to 4%, but higher in some groups
- Korea: 2%
- Japan: < 1%
- Not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans): largely absent.
Prevalence of HLA-A*3101
- Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry: > 15%
- Han Chinese, Korean, European, Latin American, and other Indian ancestry: up to 10%
- African-Americans, and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry: up to 5%
Chen CB, Hsiao YH, Wu T, Hsih MS, Tassaneeyakul W, Jorns TP, Sukasem C, Hsu CN, Su SC, Chang WC, Hui RC, Chu CY, Chen YJ, Wu CY, Hsu CK, Chiu TM, Sun PL, Lee HE, Yang CY, Kao PH, Yang CH, Ho HC, Lin JY, Chang YC, Chen MJ, Lu CW, Ng CY, Kuo KL, Lin CY, Yang CS, Chen DP, Chang PY, Wu TL, Lin YJ, Weng YC, Kuo TT, Hung SI, Chung WH; Taiwan Severe Cutaneous Adverse Reaction Consortium. Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians. Neurology. 2017 Jan 3;88(1):78-86. PubMed PMID: 27913699.
Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet Genomics. 2014 Feb;24(2):94-112. Review. Erratum in: Pharmacogenet Genomics. 2014 Apr;24(4):230. PubMed PMID: 24336023
Li X, Yu K, Mei S, Huo J, Wang J, Zhu Y, Zhao Z. 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). 2015 Feb;65(2):107-11. PubMed PMID: 24871931.
McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, Sills GJ, Marson T, Jia X, de Bakker PI, Chinthapalli K, Molokhia M, Johnson MR, O’Connor GD, Chaila E, Alhusaini S, Shianna KV, Radtke RA, Heinzen EL, Walley N, Pandolfo M, Pichler W, Park BK, Depondt C, Sisodiya SM, Goldstein DB, Deloukas P, Delanty N, Cavalleri GL, Pirmohamed M. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011 Mar 24;364(12):1134-43. PubMed PMID: 21428769; PubMed Central PMCID: PMC3113609.
Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, Ikezawa Z, Iijima M, Shiohara T, Hashimoto K, Kamatani N, Nakamura Y. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet. 2011 Mar 1;20(5):1034-41. PubMed PMID: 21149285.
Park HJ, Kim SR, Leem DW, Moon IJ, Koh BS, Park KH, Park JW, Lee JH. Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine. Eur J Clin Pharmacol. 2015 Jan;71(1):35-41. PubMed PMID: 25327504.
Pirmohamed M. Genetics and the potential for predictive tests in adverse drug reactions. Chem Immunol Allergy. 2012;97:18-31. PubMed PMID: 22613851.
Yip VL, Marson AG, Jorgensen AL, Pirmohamed M, Alfirevic A. HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review. Clin Pharmacol Ther. 2012 Dec;92(6):757-65. Review. PubMed PMID: 23132554.
Zeng T, Long YS, Min FL, Liao WP, Shi YW. Association of HLA-B*1502 allele with lamotrigine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese subjects: a meta-analysis. Int J Dermatol. 2015 Apr;54(4):488-93. PubMed PMID: 25428396.
Copyright 2016, 2017, Rajnish Mago, MD. All rights reserved. May not be reproduced in any form without express written permission.
Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other lay persons, or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.