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Test Catalog

Test ID: HL57V    
HLA-B*57:01 Genotype, Pharmacogenomics, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying individuals with an increased risk of hypersensitivity reactions to abacavir, based on the presence of the human leukocyte antigen HLA-B*57:01 allele

 

Identifying individuals taking pazopanib who have an increased risk of elevated alanine aminotransferase (ALT) levels based of the presence of the human leukocyte antigen HLA-B*57:01 allele

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

See Abacavir Hypersensitivity Testing and Initial Patient Management Algorithm in Special Instructions.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The human leukocyte antigen (HLA) genes help the immune system recognize and respond to foreign substances (such as viruses and bacteria). The HLA-B gene encodes a class 1 HLA molecule in the major histocompatibility complex (MHC), which acts by presenting peptides to immune cells. There are more than 1,500 different HLA-B alleles identified, one of which is the HLA-B*57:01 allele. Frequency of the HLA-B*57:01 allele varies with ethnicity, with a frequency of 6% to 7% in European populations, and up to 20% in Southwest Asian populations.

 

The HLA-B*57:01 allele has been associated with hypersensitivity to abacavir, a highly effective nucleoside analog reverse-transcriptase inhibitor used to treat HIV infection and AIDS. Per the Clinical Pharmacogenomics Implementation Consortium (CPIC) dosing guidelines for abacavir and HLA-B, individuals who are positive for the HLA-B*57:01 allele are at an increased risk for abacavir hypersensitivity and it is not recommended for use in treating these individuals.

 

Hypersensitivity reactions, which generally occur during the first 6 weeks of treatment, are often nonspecific and include skin rashes, gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, and abdominal pain), and respiratory symptoms. Fatalities have been reported with abacavir hypersensitivity. Prospective testing for the HLA-B*57:01 genotype and excluding HLA-B*57:01-positive individuals from treatment with abacavir decreases the incidence of abacavir hypersensitivity.

 

Pazopanib is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma and advanced soft tissue sarcoma who have received prior chemotherapy. In clinical trials with pazopanib, hepatotoxicity was observed, manifested as increases in serum transaminases such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks).

 

HLA-B*57:01 carriers who are taking pazopanib are at increased risk of elevated ALT levels.(1,2) According to the FDA label for pazopanib, in an analysis of data from 31 clinical studies of pazopanib administered as either monotherapy or in combination with other agents, elevation in ALT to levels greater than 3 times the upper limit of normal occurred in 32% (42/133) of HLA-B*57:01 allele carriers as compared to 19% (397/2101) of noncarriers. Furthermore, elevation in ALT to levels greater than 5 times the upper limit of normal occurred in 19% (25/133) of HLA-B*57:01 allele carriers and in 10% (213/2101) of noncarriers. All patients taking pazopanib should have hepatic function monitored, regardless of HLA-B*57:01 carrier status, and administration of pazopanib should be interrupted, reduced, or discontinued according to recommendations in the FDA label if hepatic function is impaired.

 

UGT1A1 genotype is also relevant to pazopanib-induced hyperbilirubinemia and testing may also be warranted. See U1A1V / UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Negative

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Positivity for human leukocyte antigen allele HLA-B*57:01 confers high risk for hypersensitivity to abacavir and higher risk of elevated alanine aminotransferase (ALT) levels in patient taking pazopanib.

 

See Abacavir Hypersensitivity Testing and Initial Patient Management Algorithm in Special Instructions.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic hematopoietic stem cell transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. The impact of hematopoietic stem cell transplantation on risk of abacavir hypersensitivity reactions is not defined in the literature.

 

The FDA recommends screening for the HLA-B*57:01 allele before initiating therapy with abacavir. Genotyping is also critical when there is a clinical history of, or when the physician suspects, an abacavir hypersensitivity reaction. However, FDA guidance states that, regardless of HLA-B*57:01 status, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Although the negative predictive value of the test is high, a negative HLA-B*57:01 result does not preclude the development of a hypersensitivity response to abacavir and cannot substitute for clinical vigilance whenever abacavir therapy is administered. Since symptoms of abacavir hypersensitivity are often nonspecific and can imitate other conditions commonly seen in HIV patients on antiretroviral therapy, the phenotypic diagnosis of abacavir hypersensitivity can be challenging. There is significant variability among patients identified as hypersensitive to abacavir. Not all individuals who are positive for HLA-B*57:01 will have a hypersensitivity reaction.

 

All patients taking pazopanib should have hepatic function monitored, regardless of HLA-B*57:01 carrier status, and administration of pazopanib should be interrupted, reduced, or discontinued according to recommendations in the FDA label if hepatic function is impaired.

 

Rare or novel variants may be present that could lead to false-negative or false-positive results. There may be rare or novel HLA-B alleles that could interfere with this assay. There are, as yet, no data indicating whether any other allele or subtypes are associated with abacavir hypersensitivity or pazopanib hepatotoxicity.

Supportive Data

Sensitivity of this assay for detecting the human leukocyte antigen HLA-B*57:01 allele approaches 100% with specificity near 96.(3)

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Xu CF, Johnson T, Wang X, et al: HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer. Clinical Cancer Research 2016;22(6):1371-1377

2. Pazopanib FDA label: Accessed: May 2018. Available at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeaaaf38-fb86-4d9f-a19d-0f61daac2fd7

3. Saag M, Balu R, Brachman P, et al: High sensitivity of HLA-B*5701 in whites and blacks in immunologically-confirmed cases of abacavir hypersensitivity. Fourth IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WEAB305

4. Martin M, Klein T, Dong B, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing. Clin Pharmacol Ther 2012;91(4):734-738

5. Martin M, Hoffman J, Freimuth R, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Clin Pharmacol Ther 2014;95(5):499-500

6. Faruki H, Heine U, Brown T, et al: HLA-B*5701 clinical testing: early experience in the United States. Pharmacogenet Genom 2007;17:857-860

7. Sun HY, Hung CC, Lin PH, et al: Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan. J Antimicrob Chemother 2007;60:599-604

Special Instructions Library of PDFs including pertinent information and forms related to the test