Coverage Policy Manual
Policy #: 2007023
Category: Laboratory
Initiated: December 2007
Last Review: January 2024
  Genetic Test: Carbamazepine HLA-B*1502
Description:
Dangerous or even fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis), that can be caused by carbamazepine therapy, are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Genetic tests for HLA-B*1502 are already available. Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This is true for patients of any ethnicity or genotype, including patients positive for HLA-B*1502.
 
Carbamazepine is FDA-approved for treatment of epilepsy, mania/bipolar disorder, and neuropathic pain. SJS and TEN are serious blistering reactions of the skin and mucous membranes that can be permanently disabling or fatal.  This new safety information will be reflected in updated product labeling for carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics).
 
 
Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for HLA-B*1502 meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for members of Asian ancestry prior to the administration of carbamazepine therapy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for HLA-B*1502 for patients already receiving carbamazepine therapy or for those of non-Asian ancestry who are to receive carbamazepine therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, testing for HLA-B*1502 for patients already receiving carbamazepine therapy or for those of non-Asian ancestry who are to receive carbamazepine therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The risk of Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) from carbamazepine is significantly increased in patients positive for the HLA-B*1502 allele.  This allele is found almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.  Due to wide variability in rates of HLA-B*1502 even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry, screening for HLA-B*1502 should be performed for most patients of Asian ancestry.  Prevalence of HLA-B*1502 has not been studied in many regions of Asia.
 
The overall estimated risk of SJS/TEN associated with carbamazepine is based on countries with mainly Caucasian populations, and is fairly low, 1- to 6 per 10,000 new users (Tennis and Stern, 1997; Mockenhaupt et al., 2005).  Recently, post-marketing adverse events reported to the World Health Organization (WHO) and carbamazepine manufacturers pointed to a much higher rate of SJS/TEN, about 10 times higher, in some Asian countries.  Studies from Taiwan (Hung et al., 2006), Europe (Lonjou et al., 2006), and Hong Kong (Man et al., 2007), indicated that this increased risk of SJS/TEN was associated with HLA-B*1502, an inherited allelic variant of the HLA-B gene found almost exclusively in some individuals across broad areas of Asia, including South Asian Indians.
 
Hung et al. (2006) in a case control study in Taiwan found that of 59 out of 60 patients with SJS/TEN associated with carbamazepine were positive for HLA-B*1502, far higher than the 4% incidence of HLA-B*1502 in carbamazepine-tolerant controls.  These findings, combined with postmarketing data on cases per patient-year exposure, suggest an initial estimate of 5% absolute risk of SJS/TEN in HLA-B*1502 positive patients exposed to carbamazepine.
 
Lonjou et al. (2007) in a case series of European patients with SJS/TEN associated with carbamazepine found that patients with Asian ancestry were over-represented considering the small percentage of Asians in the general population.  Out of 12 patients, 4 were of Asian ancestry. All four were positive for HLA-B*1502.   
 
Man et al. (2007) in a case series in patients in Hong Kong found 4 of 4 cases of SJS/TEN associated with carbamazepine in patients positive for HLA-B*1502.   
 
HLA-B*1502 is largely absent in individuals not of Asian origin, and therefore has not been found to be a risk factor for SJS/TEN in Caucasians (Alfirevic et al., 2006).
 
The Medical Letter reviewed genetic testing for carbamazepine in 2008, and concurred with the FDA recommendation that Asian patients be tested for genetic susceptibility to carbamazepine induced Stevens-Johnson Syndrome prior to instituting carbamazepine.
 
2011 Update
A review of the literature has been conducted through December 2010.  There was no new literature identified that would prompt a change in the coverage statement.
 
Clinical Utility:
The clinical utility of a direct diagnostic test for the detection of the presence of the human leukocyte antigen (HLA) allele, HLA-B* 1502 in patients of South Asian Indian descent who are being considered for treatment with Carbamazepine has been found to have little, if any, risks associated with it, and the benefits of this test can be invaluable in this selected population of patients.
 
New York State Validation Program:
Currently there is no evidence that testing for the HLA-B* 1502 allele in patients of South Asian Indian descent who are being considered for treatment with Carbamazepine has been validated by the New York State Validation program. The web site of this organization is currently experiencing difficulties and is non functional at this juncture.
 
 Clinical Appropriateness:
HLA-B* 1502 testing is deemed appropriate for patients of Asian ancestry who are being considered for treatment with Carbamazepine. Currently this testing is a recommendation of the FDA.
 
EGAPP:
HLA-B* 1502 testing has not been evaluated by EGAPP. It has not been identified as a topic of interest, and it is not currently on the list of tests to be evaluated in the future.
 
Gene Reviews:
Gene testing for the HLA-B*1502 allele has not been evaluated by Gene Reviews, and is not mentioned on this web site.
 
American College of Medical Genetics:
Gene testing for the HLA-B* 1502 allele is not currently listed on the website of the American College of Medical Genetics.
 
Hayes Inc Assessment:
Hayes Inc. Assessment states that gene testing for the HLA-B* allele in patients of Asian ancestry who are considered to be candidates for Carbamazepine therapy should be tested for this allele as recommended by the FDA as of December 14th, 2007.
 
2012 Update
A literature search was conducted through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search was conducted through December 2013.  There was no new literature identified that would prompt a change in the coverage statement.
 
2015 Update
A literature search was conducted through December 2014. There was no new literature identified that would prompt a change in the coverage statement.
 
Aggarwar et al. (2014) published the results of a study on the evidence of association between HLA-B*1502 and anticonvulsant induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from the Indian population. Patients with a history of SJS/TEN secondary to carbamazepine or phenytoin were enrolled. The control group comprised of patients who had received carbamazepine/phenytoin for ?6months without any adverse cutaneous event. Low-resolution DNA typing for HLA-B and high resolution HLA-B*15 typing was performed. Seventeen patients with history of SJS/TEN secondary to carbamazepine (9) or phenytoin (8) and 50 tolerant controls (carbamazepine-37; phenytoin-13) were enrolled. HLA-B*1502 was observed in 2/9 (22.2%) carbamazepine-SJS/TEN patients and none of the 37 carbamazepine tolerant controls (p=0.035). HLA-B*1502 was not observed in any of the 8 phenytoin-SJS/TEN patients or the 13 phenytoin tolerant controls. The data suggested that HLA-B*1502 is a risk factor for carbamazepine induced SJS/TEN. Therefore, HLA-B*1502 testing should be performed prior to initiating carbamazepine in North Indian population.
 
Tangamornsuksan et al. published the results of a comprehensive search done to determine the relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN. The search yielded 525 articles, of which 16 met the inclusion criteria. The studies included 227 SJS or TEN cases, 602 matched control subjects, and 2949 population control subjects. The summary odd ratio (OR) for the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN was 79.84 (95% CI, 28.45-224.06). Racial/ethnic subgroup analyses yielded similar findings for Han-Chinese (115.32; 18.17-732.13), Thais (54.43; 16.28-181.96), and Malaysians (221.00; 3.85-12?694.65). Among individuals of white or Japanese race/ethnicity, no patients with SJS or TEN were carriers of the HLA-B*1502 allele. The authors concluded that a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in Han-Chinese, Thai, and Malaysian populations. HLA-B*1502 screening in patients requiring carbamazepine therapy is warranted.
 
2016 Update
A literature search was conducted through December 2015.  There was no new literature identified that would prompt a change in the coverage statement.
 
2017 Update
A literature search was conducted through December 2016.  There was no new literature identified that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage status.  
 
2019 Update
A literature search was conducted through December 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through December 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
81381HLA Class I typing, high resolution (ie, alleles or allele groups); one allele or allele group (eg, B*57:01P), each
References: Aggarwar R, Sharma M, Modi M, et al.(2014) HLA-B*1502 is associated with carbamazepine induced Stevens-Johnson syndrome in North Indian population. Hum Immunol. 2014 Oct 8;75(11):1120-1122. PMID: 25305458.

Alfirevic A, et al.(2006) HLA-B locus in caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics, 2006; 7:813-8.

Chen P, Lin J, Lu C, et al.(2011) Carbamazepine-induced toxic effects and HLAB*1502 screening in Taiwan. N Engl J Med 2011;364:1126-33.

Chung WH, Hung SI, Chen YT.(2007) Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol, 2007; 7:317-23.

Hung SI, Chung WH,et al.(2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics, 2006; 16:297-306.

Lonjou C, et al.(2006) A marker for Stevens-Johnson syndrome: ethnicity matters. Pharmacogenomics, 2006; 6:265-8.

Man CB, Kwan P, et al.(2007) Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia, 2007; 48:1015-8.

Medical Letter.(2008) Genetic test for carbamazepine induced Stevens-Johnson syndrome. Med Ltr, 2008; 50 (issue 1284):32.

Mockenhaupt M, et al.(2005) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepilepticS. Neurology, 2005; 64:1134-8.

Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, et al.(2013) Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013 Sep;149(9):1025-32. PMID: 23884208.

Tennis P, Stern RS.(1997) Risk of serious cutaneous disorders after intitiation of use of phenytoin, carbamazapine, or sodium valproate: a record linkage study. Neurology, 1997, 49:542-6.

Yang CW, Hung SI, et al.(2007) HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol, 2007; 120:870-7.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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