Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia

Saran Vardhanabhuti, Heather J Ribaudo, Raphael J Landovitz, Ighovwerha Ofotokun, Jeffrey L Lennox, Judith S Currier, Lana M Olson, David W Haas, Saran Vardhanabhuti, Heather J Ribaudo, Raphael J Landovitz, Ighovwerha Ofotokun, Jeffrey L Lennox, Judith S Currier, Lana M Olson, David W Haas

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.

Keywords: HIV; UGT1A1; atazanavir; pharmacogenomics; pharmacokinetics.

Figures

Figure 1.
Figure 1.
Derivation of the study population. Of 605 participants randomized to the atazanavir/r arm in A5257, a total of 481 were included in genetic association analyses for treatment discontinuation and 438 in analyses with baseline covariates. Of participants randomized to the darunavir/r and raltegravir arms, 491 and 478, respectively, were included in analyses for treatment discontinuation. Abbreviations: ART, antiretroviral therapy; SNP, single-nucleotide polymorphism.
Figure 2.
Figure 2.
Cumulative incidence of time to bilirubin-associated discontinuation of atazanavir/r stratified by UGT1A1 genotype. Lines estimate the cumulative incidence of time to bilirubin-associated discontinuation of atazanavir, stratified by UGT1A1 rs887829 genotype and self-reported race or ethnicity. (A) All participants; (B) Black participants; (C) White participants; (D) Hispanic participants. P values are given by Gray's test for testing equality of cumulative incidence functions. Solid lines represent rs887829 T/T, dashed lines represent rs887829 C/T, and dotted lines represent rs887829 C/C. Number of participants in the risk set over time for each genotype are shown in each plot.
Figure 3.
Figure 3.
Pairwise treatment differences in cumulative probability of all-cause tolerability failure by 96 weeks. (Top) Comparison between atazanavir/r and darunavir/r arms. (Bottom) Comparison between atazanavir/r and raltegravir arms. Within each treatment comparison, the following are shown: Overall, primary result from ACTG A5257; Overall (analysis), result restricted to participants with UGT1A1 genotype data; rs887829, results stratified by UGT1A1 genotype. Estimates of pairwise treatment differences are shown with 97.5% confidence interval. The equivalence boundary for treatment comparison is ±10% and is represented by the shaded area. Abbreviations: ATV, atazanavir; DRV, darunavir; RAL, raltegravir.

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