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Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Carbamazepine Dosing

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Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Carbamazepine Dosing CPIC Guidelines nature publishing group CPIC GUIDELINES Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Carbamazepine Dosing SG Leckband1,2, JR Kelsoe1,2, HM Dunnenberger3, AL George Jr4, E Tran1, R Berger1, DJ Müller5,6, M Whirl-Carrillo7, KE Caudle3 and M Pirmohamed8 Human leukocyte antigen B (HLA-B) is a gene that encodes protein involved in presenting intracellular antigens to the a cell surface protein involved in presenting antigens to the immune system. These intracellular antigens are usually the immune system. The variant allele HLA-B*15:02 is associated normal breakdown products of intracellular proteins and are with an increased risk of Stevens–Johnson syndrome recognized as “self.” However, if the antigen presented derives (SJS) and toxic epidermal necrolysis (TEN) in response to from a pathogen or, in some cases, a transplanted tissue, it may carbamazepine treatment. We summarize evidence from be recognized as “nonself” and trigger an immune response. the published literature supporting this association and HLA-B is part of a large cluster of genes known as the human provide recommendations for the use of carbamazepine major histocompatibility complex. The cluster contains three based on HLA-B genotype (also available on PharmGKB: subgroups: classes I, II, and III. The HLA-B gene is a part of the http://www.pharmgkb.org). The purpose of this article is to class I complex, along with HLA-A and HLA-C. provide information to allow the interpretation of clinical Because HLA proteins present a wide variety of peptides for HLA-B*15:02 genotype tests so that the results can be used immune recognition, the HLA genes, and specifically HLA-B, are to guide the use of carbamazepine. The guideline provides among the most highly polymorphic genes in the human genome. recommendations for the use of carbamazepine when HLA- HLA polymorphisms were previously ascertained serologically, B*15:02 genotype results are available. Detailed guidelines but newer approaches that exploit genotyping and DNA sequenc- regarding the selection of alternative therapies, the use of ing methods have revealed much greater complexity of genetic phenotypic tests, when to conduct genotype testing, and cost- variation within this locus. For example, according to the World effectiveness analyses are beyond the scope of this document. Health Organization Nomenclature Committee for Factors of the Clinical Pharmacogenetics Implementation Consortium HLA System (http://hla.alleles.org), there are >2,000 identified (CPIC) guidelines are published and updated periodically on HLA-B alleles, many of which differ from one another by more the PharmGKB website at (http://www.pharmgkb.org). than one nucleotide. Each allele is designated by the gene name followed by an asterisk and a four- or six-digit identifier giving FOCUSED LITERATURE REVIEW information about the allele type (designated by the first two dig- A systematic literature review focused on HLA-B*15:02 geno- its) and specific protein subtypes (second set of digits). The allele 12February2013 type and carbamazepine use (see Supplementary Material type may correspond to the antigen detected by serological meth- online) was conducted. Reviews were included to summarize ods. Subtypes differ at one or more nucleotide positions that alter 9May2013 much of the earlier literature. the protein-coding sequence. The details of HLA nomenclature have been described in a previous CPIC guideline.1 The guidelines GENE: HLA-B 10.1038/clpt.2013.103 we present here specifically discuss only the HLA-B*15:02 allele as Background it relates to carbamazepine-induced Stevens–Johnson syndrome Human leukocyte antigen B (HLA-B) is a gene located on the (SJS) and toxic epidermal necrolysis (TEN), serious blistering Clinical Pharmacology & Therapeutics short arm of chromosome 6 (6p21.3) that encodes a cell surface cutaneous adverse drug reactions. 00 1Veterans Affairs San Diego Healthcare System, San Diego, California, USA; 2Department of Psychiatry, University of California, San Diego, San Diego, California, USA; 3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; 4Division of Genetic Medicine, Vanderbilt 00 University, Nashville, Tennessee, USA; 5Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 6Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 7Department of Genetics, Stanford University, Palo Alto, California, USA; 8Department of Pharmacology, University of Liverpool, Liverpool, UK. Correspondence: KE Caudle ([email protected]) 19 June2013 Received 12 February 2013; accepted 9 May 2013; advance online publication 19 June 2013. doi:10.1038/clpt.2013.103 CLINICAL PHARMACOLOGY & THERAPEUTICS 1 CPIC GUIDELINES Genetic test interpretation quite rare in African populations (not observed) and Europeans Clinical genotyping tests exist for identifying HLA-B alleles, (0–0.02%). including HLA-B*15:02. The HLA-B*15:02 allele predisposes to Carbamazepine can cause a wide variety of cutaneous adverse the development of carbamazepine-induced SJS/TEN but is not drug reactions, including mild maculopapular eruptions known to affect either carbamazepine pharmacokinetics or the (MPEs), drug hypersensitivity syndrome, in which a cutane- development of other types of cutaneous adverse reactions (see ous eruption is associated with systemic manifestations, and below). Genotyping results are presented as “positive” if one or SJS/TEN,12 the most severe manifestation. It is important to two copies of HLA-B*15:02 are present or as “negative” if no cop- note that HLA-B*15:02 is specific for SJS and TEN; there is ies of HLA-B*15:02 are present. There is no intermediate geno- no evidence that it predisposes to MPEs or hypersensitivity type or phenotype. Phenotype assignments for HLA-B*15:02 syndrome.13 By contrast, another HLA allele, HLA-A*31:01, genotypes are summarized in Table 1. is associated with a wider range of carbamazepine hypersen- sitivity reactions, including MPEs, hypersensitivity syndrome, Available genetic test options and SJS/TEN in both Caucasian and Japanese populations13 Several methods of HLA-B genotyping are commercially avail- (see Supplementary Material online for further discussion). able. TheSupplementary Material online and http://www. These associations underscore the potential importance pharmgkb.org contain more information on available clinical of other alleles in other populations with different clinical testing options. manifestations.14,15 Incidental findings DRUG: CARBAMAZEPINE No other diseases have been linked to HLA-B*15:02. However, Background there have been reports linking the HLA-B*15:02 allele to SJS/ Carbamazepine, an aromatic anticonvulsant related to the tri- TEN from oxcarbazepine and phenytoin use, particularly in cyclic antidepressants, is approved by the US Food and Drug Asian populations.2–8 Other HLA-B alleles are also associated Administration for the treatment of epilepsy and other sei- with adverse reactions to drugs, such as the association between zure disorders, trigeminal neuralgia, and bipolar disorder. HLA-B*57:01 and abacavir-induced hypersensitivity reaction,9 Carbamazepine reduces the propagation of abnormal impulses and the association between HLA-B*58:01 and increased risk in the brain by producing a frequency- and voltage-depend- of allopurinol-induced severe cutaneous adverse reactions ent blockade of sodium channels, thereby inhibiting the gen- (including but not limited to SJS/TEN).10 CPIC guidelines are eration of repetitive action potentials in the epileptic focus.16 available for the latter two HLA-B–associated adverse drug Carbamazepine is commercially available as a regular-release or reactions.1,11 extended-release oral formulation, and therapy may be targeted by testing serum concentrations, with the traditionally accepted Other considerations therapeutic range for treatment of epilepsy being 4–12 μg/ml.17 HLA-B*15:02 has a very distinct ethnic and regional distri- Above this therapeutic range, adverse effects include diplopia, bution that is important to consider when evaluating popu- drowsiness, nausea, and sedation. Carbamazepine adverse lation risk. Specifically, HLA-B*15:02 is most prevalent in effects that are not clearly dose or concentration dependent Oceanian, East Asian, and South/Central Asian populations include aplastic anemia, hyponatremia, leucopenia, osteopo- (see Supplementary Tables S1 and S2 online), ranging from 1 rosis, and hypersensitivity reactions such as MPEs, hypersen- to >10% in some cases. The frequency of HLA-B*15:02 is high- sitivity syndrome, SJS/TEN, or drug-induced liver injury. For est in Han Chinese, for which some estimates from the Yunnan additional information regarding the pharmacokinetics and province have been as high as 36%. In general, rates in China pharmacogenomics of carbamazepine, refer to the PharmGKB range from 1 to 12%. Rates in Singapore and Hong Kong have website (http://www.pharmgkb.org/pathway/PA165817070).18 also been estimated at 10–12%. Rates in Malaysia and Thailand Approximately 10% of patients develop mild cutaneous are estimated at 6–8%, whereas in different regions of India, the adverse drug reactions, e.g. MPEs,13 within the first 3 months rates range from 2 to 6%. Korea and Japan have low frequen- of therapy.19,20 HLA-B*15:02 is specific for the carbamaze- cies of the allele at 0.5 and 0.1%, respectively. The allele is also pine-induced SJS and TEN. SJS is characterized by epidermal
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