Carbamazepine Therapy and HLA Genotype

Introduction

Carbamazepine (brand names include Carbatrol, Epitol, Equetro, and Tegretol) is an effective antiseizure drug that is often used as a first-line agent in the treatment of epilepsy. Carbamazepine is also used to treat bipolar disorder and to relieve pain in trigeminal neuralgia.

Hypersensitivity reactions associated with carbamazepine can occur in up to 10% of patients, and typically affect the skin. Some of these reactions are mild, as in the case of maculopapular exanthema (MPE); however, conditions such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening.

The risk of hypersensitivity is increased by the presence of specific human leukocyte antigen (HLA) alleles. The HLA-B*15:02 allele is strongly associated with carbamazepine-induced SJS/TEN in populations where this allele is most common, such as in Southeast Asia.

According to the FDA-approved drug label for carbamazepine, testing for HLA-B*15:02 should be done for all patients with ancestry in populations with increased frequency of HLA-B*15:02, prior to initiating carbamazepine therapy (Table 1). The label states that greater than 15% of the population is reported HLA-B*15:02 positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. The label states that South Asians, including Indians, appear to have intermediate prevalence of HLA-B*15:02, averaging 2 to 4%, but higher in some groups. In Japan and Korea, the HLA- B*15:02 is present in less than 1% of the population. In individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans), the HLA-B*15:02 allele is largely absent. These prevalence rates of HLA-B*15:02 may be used to guide which patients should be screened. However, the FDA cautions to keep in mind the limitations of prevalence rate data when deciding which patients to screen. This is because of the wide variability in HLA-B*15:02 rates (even within ethnic groups), the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry (1).

The FDA label also states that carbamazepine should not be used in patients who are positive for HLA-B*15:02 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN.

The HLA-A*31:01 allele may also be a risk factor for SJS/TEN but is more strongly associated with other carbamazepine-induced reactions, such as DRESS and MPE. HLA-A*31:01 is found in most populations, worldwide. HLA-B*15:11 is another allele that has been linked with SJS/TEN. The FDA states that the risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*31:01, but does not discuss HLA-B*15:11 (1).

Carbamazepine dosing guidelines based on HLA genotype have been published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) (2-5).

DPWG recommendations include avoiding the use of carbamazepine and selecting an alternative, if possible, for individuals positive for HLA-B*15:02, HLA-A*31:01 and HLA-B*15:11 (Table 2). CPIC recommendations include not using carbamazepine in carbamazepine-naïve patients who are positive for HLA-B*15:02 and any HLA-A*31:01 genotype (or HLA-A*31:01 genotype unknown) (Table 3). CPNDS recommends genetic testing for all carbamazepine-naïve patients before they start treatment, with a moderate level of evidence for HLA-A*31:01 testing, and strong to optional evidence for HLA-B*15:02 testing (based on the frequency of HLA-B*15:02 in the population the patient originates from, and if this is known or not) (Table 4).

Drug: Carbamazepine

Carbamazepine is an antiseizure drug used in the treatment of epilepsy. Carbamazepine is also used as an analgesic in trigeminal neuralgia and may be used in the treatment of bipolar disorder (5, 7, 8).

Epilepsy is characterized by spontaneous recurrent epileptic seizures, which may be classified as focal or generalized. Carbamazepine is one of the first-line treatments for focal seizures in adults, adolescents, and children, and it may also be considered for general tonic-clonic seizures.

The symptoms of focal seizures depend upon where the focus of the seizure originates in the brain e.g., jerking of a limb indicates a focus in the contralateral motor cortex. In contrast, generalized seizures appear to originate in all regions of the cortex simultaneously and include absence seizures (sudden impaired consciousness and staring) and general tonic-clonic seizures (loss of consciousness, stiffening of limbs in the tonic phase, and twitching or jerking muscles in the clonic phase).

Carbamazepine is a tricyclic compound that belongs to the class of antiseizure drugs that act by blocking voltage-dependent sodium channels present on neuronal cell membranes. Carbamazepine stabilizes the sodium channel in the inactivated state, leaving fewer of the channels available to open. This prolonged inactivated phase of the channel inhibits the rapid and repetitive generation of action potentials in the epileptic focus (3, 9).

Carbamazepine is metabolized in the liver by the cytochrome P-450 (CYP) system. The major metabolite is carbamazepine-epoxide, which has an anticonvulsant activity of uncertain significance. CYP3A4 is the main enzyme involved in the metabolism of carbamazepine; a lesser role is played by CYP2C8 and possibly CYP3A5. Minor metabolic pathways include multiple CYP enzymes, such as CYP2B6.

Carbamazepine stimulates transcriptional upregulation of CYP3A4 and other genes involved in its own metabolism. In addition, there are many drug-drug interactions with carbamazepine, because numerous drugs have been shown to induce or inhibit CYP3A4, or are metabolized by CYP3A4. Therefore, when carbamazepine is given with drugs that can decrease or increase carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required (10, 11).

HLA gene family

The human leukocyte antigen (HLA) genes code for more than 200 different major histocompatibility complex (MHC) proteins. The MHC family has been subdivided into three subgroups based on the structure and function of the encoded proteins: Class I, Class II, and Class III.

The class I region contains the proteins encoded by the HLA genes HLA-A, HLA-B, and HLA-C. These MHC molecules are expressed on the surfaces of almost all cells and play an important role in processing and presenting antigens. The MHC class I gene region also contains a variety of other genes, many of which are not known to be involved in immune function.

An important role of MHC class I molecules is to present peptide fragments to immune cells (CD8+ T cells). Most of these peptides originate from the breakdown of normal cellular proteins (“self”). However, if foreign peptide fragments are presented, e.g., from a pathogen, CD8+T cells will recognize the peptides as “non-self” and will be activated to release inflammatory cytokines and launch an immune response to dispose of the pathogen (or foreign body).

Because MHC molecules need to present such a wide variety of “self” and “non-self” peptides, the HLA genes are both numerous and highly polymorphic. More than 1,500 HLA-B alleles have been identified (7). HLA allele nomenclature includes the HLA prefix, followed by the gene, an asterisk and a two digit number that corresponds to antigen specificity, and the assigned allele number (21). For example, the HLA-B*15:02 allele is composed of:

• HLA: the HLA prefix (the HLA region on chromosome 6)
• B: the B gene (a particular HLA gene in this region)
• 15: the allele group (historically determined by serotyping, i.e., a group of alleles that share the same serotype)
• 02: the specific HLA allele (a specific protein sequence; determined by genetic analysis).

Additional digits have recently been added to the nomenclature to discriminate alleles that do not differ in the protein amino acid sequence but differ in their genetic sequence (i.e., because of synonymous and noncoding genetic variants).

Variation in HLA genes plays an important role in the susceptibility to autoimmune disease and infections. They are also critical in the context of transplant surgery where better outcomes are observed if the donor and recipient are HLA-compatible.

More recently, HLA variants have been associated with an increasing number of drug hypersensitivity responses (Type B adverse drug reactions). The strongest HLA-associated drug responses are HLA-B*15:02 and carbamazepine-induced SJS/TEN in Asian populations, HLA-B*57:01 and abacavir hypersensitivity syndrome in the Caucasian population, and HLA-B*58:01 in allopurinol hypersensitivity syndrome and SJS/TEN (22).

Gene: HLA-B, Allele HLA-B*15:02

HLA-B*15:02 is strongly associated with carbamazepine-induced SJS/TEN in populations where the HLA-B*15:02 is common (China, Thailand, India, Malaysia, Taiwan). In patients of Asian origin, pharmacogenetic testing for HLA-B*15:02 is recommended before initiation of carbamazepine therapy (23). The clinical benefits of screening for HLA-B*15:02 have been confirmed in a Taiwanese study, where genetic testing reduced the incidence of carbamazepine-induced SJS/TEN from ten expected cases to zero (24).

The association between HLA-B*15:02 and SJS/TEN was first reported in the Han Chinese. In the initial study, every patient who had carbamazepine-induced SJS/TEN was found to have the HLA-B*15:02 allele (44/44, 100%), whereas the allele was much less common in carbamazepine-tolerant patients (3/101, 3%) (25). The HLA*15:02 allele has since been associated with carbamazepine-induced SJS/TEN in Taiwanese, Chinese, Indians, Malay, and Chinese-Americans, but not in Caucasians or Japanese individuals (25-32).

The prevalence of carbamazepine-induced SJS/TEN is higher in populations where the HLA-B*15:02 allele is most common. HLA-B*15:02 is highly prevalent in Southeast Asia, with an allele frequency of over 15% in Hong Kong, Thailand, Malaysia, Vietnam, and parts of the Philippines. It is slightly less prevalent (10–13%) in Taiwan and Singapore, and in North China (4%). South Asians, including Indians, have intermediate prevalence of HLA-B*15:02 (2–4%), with higher frequencies in some sub-populations (3, 5, 33-37).

The HLA-B*15:02 allele is rare (frequency of less than 1%) in East Asia (Japan and Korea) and in individuals who are not of Asian descent. For example, the variant is rare in Europeans, Hispanics, Africans, African Americans, and Native Americans (5, 34). The absence of this variant in these population explains the lack of association of HLA-B*15:02 with carbamazepine-induced SJS/TEN in Caucasians and Japanese individuals.

Current data suggest that HLA-B*15:02 is a risk factor only for SJS/TEN because it does not appear to increase the risk of other carbamazepine-induced cutaneous reactions such as MPE and DRESS (5).

Gene: HLA-A, Allele HLA-A*31:01

The HLA-A*31:01 allele is important for all types of carbamazepine hypersensitivity reactions. Also, in contrast to HLA-B*15:02 which is predominantly found in Southeast Asia, the HLA-A*31:01 is found in many populations worldwide (Table 5) (38-40).

Table 5.

Comparison of HLA-B*15:02 and HLA-A*31:01 and Carbamazepine Therapy

The association between HLA-A*31:01 and DRESS and MPE has been found in Europeans, Han Chinese, Japanese, and North Americans of mixed ancestries (14, 26, 41-43). HLA-A*31:01 is also associated with SJS/TEN, but not in Southeast Asians, where the more common HLA-B*15:02 allele has an extremely strong association with SJS/TEN (5, 38).

The HLA-A*31:01 variant is common globally with frequencies of at least 3% in many populations (2–5% in Northern Europeans, 2% in Han Chinese, 7–12% in Japanese populations) (5, 14, 38, 42). The highest frequencies have been reported in South American countries, such as Argentina (25%–38.6%) (38).

Gene: HLA-B, HLA-B*15:11 and other alleles

The HLA-B*15:11 variant has been found to be a risk factor for SJS/TEN in Japan (44, 45) and Korea (46). In Central China, HLA-B*15:11 may be a risk factor for some patients with CBZ-induced SJS negative for HLA-B*15:02 (47), and one study found that HLA-A*11:01 for CBZ-induced SJS/TEN was a risk factor in the Spanish Caucasian population (39).

The HLA-B*15:11 variant is found in frequencies above 1% in specific Asian populations only:Han Chinese, Koreans, Thai (34, 48).

Other alleles considered to be high risk, particularly in high-frequency areas such as Indonesia, Malaysia, and Thailand, include HLA-B*15:08 and HLA-B*15:21 (49, 50).

Genetic Testing

The NIH Genetic Testing Registry provides examples of the genetic tests that are currently available for the carbamazepine response, and the HLA-B and HLA-A genes.

The FDA recommends testing for HLA-B*15:02 prior to initiating carbamazepine therapy in patients with ancestry in populations with increased frequency of HLA-B*15:02. In deciding which patients to screen, the FDA states that the prevalence rates of HLA-B*15:02 (Table 1) may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry (1).

The genotype results for an HLA allele such as HLA-B*15:02 can either be “positive” or “negative” (Table 6). There are no intermediate phenotypes because the HLA genes are expressed in a codominant manner. A positive result is either “heterozygous” or “homozygous”, depending upon whether the patient has one or two copies of the *15:02 allele, respectively.

For patients who are positive for HLA-B*15:02, the FDA states that carbamazepine should not be used unless the benefits clearly outweigh the risks. For patients who are known to be positive for HLA-A*31:01, the FDA states that the risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine.

A negative result indicates that the patient does not have the HLA-B*15:02 allele. However, a negative result does not rule out the possibility of a patient developing carbamazepine hypersensitivity. Therefore, clinicians should carefully monitor all patients according to standard practices.

Table 6.

CPIC (2017). Assignment of likely HLA-B and HLA-A genotype

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2014 Recommendations from the Canadian Pharmacogenomics Network for Drug Safety (CPNDS)

Recommendation 1.1: Genetic testing for HLA- B*15:02 is recommended for all carbamazepine (CBZ)-naive patients before initiation of carbamazepine therapy (Level A – strong in patients originating from populations where HLA- B*15:02 is common, its frequency unknown or whose origin is unknown; Level C – optional in patients originating from populations where HLA-B*15:02 is rare). Genetic testing for HLA-A*31:01 is recommended for all carbamazepine-naive patients before initiation of carbamazepine therapy (Level B – moderate in all patients; Table 6).

Recommendation 1.2: In patients who have previously taken carbamazepine for > 3 months without any adverse effects, and in whom reinitiation of carbamazepine is considered, genetic testing is NOT recommended (B). In patients who have previously taken carbamazepine for a shorter period, genetic testing should be considered (B).

Recommendation 1.3: In patients who have previously experienced a hypersensitivity reaction (HSR) potentially related to carbamazepine, genetic testing is recommended as part of the differential diagnosis and for the direction of future therapy (B).

Recommendation 1.4: In patients for whom no alternative treatment options are available, genetic testing is recommended to ensure increased alertness to hypersensitivity symptoms in positive patients (B).

Recommendation 2.1: Genetic testing for HLA- B*15:02 is most beneficial in patients originating from a population where HLA-B*15:02 is common (e.g., Chinese, Thai, Indian, Malay, Filipino, Indonesian; A). Nevertheless, genotyping for HLA-B*15:02 should be considered in ALL patients, irrespective of their ancestry, as the safest option (C).

Recommendation 2.2: HLA-A*31:01 is common in most populations studied so far. Therefore, genetic testing for this variant is recommended in patients of all ancestries (B).

Recommendation 3.1: In patients who are positive for HLA-B*15:02 or HLA-A*31:01, alternative medications should be used as first-line therapy (A). Consideration in the choice of alternative medications should be given to the possibility of cross-reactivity with structurally similar antiepileptic drugs (AED) (oxcarbazepine, lamotrigine, phenytoin, phenobarbital, primidone).

Recommendation 3.2: In patients who are negative for HLA-B*15:02 and HLA-A*31:01, carbamazepine can be used as first-line therapy (A). However, the occurrence of a hypersensitivity reaction cannot be excluded based on a negative genetic test result.

Table 7.

Grading scheme used for clinical practice recommendations

Please review the complete therapeutic recommendations that are located here: (5).

Nomenclature

Table

Nomenclature for selected HLA alleles

Acknowledgments

The author would like to thank Saeed Alzghari, MS, MBA, PharmD, BCPS Director of Clinical Pharmacy, Gulfstream Genomics; Inge Holsappel, Pharmacist at the Royal Dutch Pharmacists Association (KNMP), the Netherlands, for reviewing the information regarding the guidelines of the Dutch Pharmacogenetics Working Group (DPWG); Hyun Kim, PharmD, Fellow, Clinical Pharmacogenomics Service, Boston Children’s Hospital, Boston, MA; Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of pharmaceutical Services, Children's Cancer Hospital, Egypt; and Chonlaphat Sukasem, PhD, PharmB, Associate Professor and Head, Division of Pharmacogenomics and Personalized Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; for reviewing this summary.

2015 Edition:

The author would like to thank Michael A. Rogawski, Professor of Neurology, University of California, Davis; and Ursula Amstutz, Research Group Leader at the Institute of Clinical Chemistry, Inselspital University Hospital, University of Bern; and an investigator of the Canadian Institutes of Health Research Drug Safety and Effectiveness Network and the Canadian Pharmacogenomics Network for Drug Safety, for reviewing this summary.

Version History

To view the 2015 version of this summary (created: October 14, 2015) please click here.

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