title: Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia.
abstract: Background.  Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods.  Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results.  Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%-36%) in Black, 60% (CI, 32%-84%) in White, and 29% (CI, 8%-58%) in Hispanic participants; negative predictive values were 97% (CI, 93%-99%), 95% (CI, 90%-98%), and 97% (CI, 90%-100%), respectively. Conclusions.  Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.
authors.affiliation: Statistical Data Analysis Center , Harvard School of Public Health , Boston, Massachusetts.
authors.forename: Saran
authors.initials: S
authors.lastname: Vardhanabhuti
authors.affiliation: Statistical Data Analysis Center , Harvard School of Public Health , Boston, Massachusetts.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ribaudo
authors.affiliation: UCLA Center for Clinical AIDS Research and Education , Los Angeles, California.
authors.forename: Raphael J
authors.initials: RJ
authors.lastname: Landovitz
authors.affiliation: Emory University School of Medicine , Atlanta, Georgia.
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
authors.affiliation: Emory University School of Medicine , Atlanta, Georgia.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Lennox
authors.affiliation: UCLA Center for Clinical AIDS Research and Education , Los Angeles, California.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Currier
authors.affiliation: Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: Lana M
authors.initials: LM
authors.lastname: Olson
authors.affiliation: Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
keywords: HIV; UGT1A1; atazanavir; pharmacogenomics; pharmacokinetics