Clinical Information

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 I HLA molecule in the major histocompatibility complex (MHC), which acts by presenting peptides to immune cells. There are more than 1500 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 , 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).

Patients who are HLA-B*57:01 carriers and 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. For more information see U1A1Q / UDP-Glucuronosyltransferase 1A1 TA Repeat Genotype, UGT1A1, Varies.