The CPIC dosing guideline recommends considering advising individuals who carry two decreased function UGT1A1 alleles about a substantial likelihood of developing jaundice, which may cause non-adherence. The dosing guideline recommends that alternative agents be considered if the risk of non-adherence due to jaundice is high. The risk of discontinuation is low and very low for individuals carrying one, or no decreased function UGT1A1 alleles, respectively.
This annotation is based on the CPIC® guideline for atazanavir and UGT1A1.
Advance online publication September 2015
Guidelines regarding the use of pharmacogenomic tests in determining whether atazanavir treatment should be undertaken have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
These guidelines are applicable to:
- At the time of this writing there are no pediatric data regarding associations between UGT1A1 genotypes and likelihood of bilirubin-related discontinuation of atazanavir. However, UGT1A1 genotypes are expected to affect atazanavir-related hyperbilirubinemia similarly in adults and children. Therefore, recommendations for adults may be directly adapted to pediatric patients.
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Table 1: Recommended therapeutic use of atazanavir based on UGT1A1 genotype
Adapted from Tables 1 and 2 of the 2015 guideline manuscript.
|Likely phenotype||Genotypes||Examples of diplotypes||Implications for phenotypic measures||Recommendations for atazanavir therapy||Classification of recommendation for atazanavir therapy|
|Extensive Metabolizer||An individual carrying 2 reference b function and/or increased function alleles; or individuals of genotype CC at rs887829||*1/*1; *1/*36; *36/*36; rs887829 CC||Reference c UGT1A1 activity; very low likelihood of bilirubin-related discontinuation of atazanavir.||There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result.||Strong|
|Intermediate Metabolizer||An individual carrying one reference b function (*1) c or increased function allele (*36) plus one decreased function allele (*6, *28, *37). Alternatively identified by heterozygosity for rs887829 C/T.||*1/*28; *1/*37; *36/*28; *36/*37; rs887829 C/T, *1/*6||Somewhat decreased UGT1A1 activity; low likelihood of bilirubin-related discontinuation of atazanavir.||There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely||Strong|
|Poor Metabolizer||An individual carrying two decreased function alleles (*6, *28, *37). Alternatively identified by homozygosity for rs887829 T/T (*80/*80)||*28/*28; *28/*37; *37/*37; rs887829 T/T (*80/*80), *6/*6 a||Markedly decreased UGT1A1 activity; high likelihood of bilirubin-related discontinuation of atazanavir.||Consider an alternative agent particularly where jaundice would be of concern to the patient.||Strong|
a Homozygosity for UGT1A1*6, which occurs almost exclusively in individuals of Asian descent, is associated with Gilbert syndrome. However, at this time, it is unclear if patients with this diplotype are at increased risk of severe atazanavir-associated hyperbilirubinemia.
b “reference” function refers to the UGT1A1 alleles to which other alleles are compared.
c The reference function *1 allele is a fully functional refers to the rs8175347 TA6 allele.