Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.

TitleGenomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
Publication TypeJournal Article
Year of Publication2014
AuthorsJohnson DH, Venuto C, Ritchie MD, Morse GD, Daar ES, McLaren PJ, Haas DW
JournalPharmacogenet Genomics
Volume24
Issue4
Pagination195-203
Date Published2014 Apr
ISSN1744-6880
KeywordsAcquired Immunodeficiency Syndrome, Adult, Antiretroviral Therapy, Highly Active, Atazanavir Sulfate, Bilirubin, Female, Genome-Wide Association Study, Glucuronosyltransferase, HIV Protease Inhibitors, Humans, Hyperbilirubinemia, Male, Middle Aged, Multivariate Analysis, Oligopeptides, Polymorphism, Single Nucleotide, Prospective Studies, Pyridines, Ritonavir
Abstract

BACKGROUND: Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.

METHODS: Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.

RESULTS: Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.

CONCLUSION: Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

DOI10.1097/FPC.0000000000000034
Alternate JournalPharmacogenet. Genomics
PubMed ID24557078
PubMed Central IDPMC4059003
Grant ListAI-025859 / AI / NIAID NIH HHS / United States
AI-027658 / AI / NIAID NIH HHS / United States
AI-027661 / AI / NIAID NIH HHS / United States
AI-027666 / AI / NIAID NIH HHS / United States
AI-027675 / AI / NIAID NIH HHS / United States
AI-032782 / AI / NIAID NIH HHS / United States
AI-034853 / AI / NIAID NIH HHS / United States
AI-038855 / AI / NIAID NIH HHS / United States
AI-038858 / AI / NIAID NIH HHS / United States
AI-045008 / AI / NIAID NIH HHS / United States
AI-046370 / AI / NIAID NIH HHS / United States
AI-046376 / AI / NIAID NIH HHS / United States
AI-050409 / AI / NIAID NIH HHS / United States
AI-050410 / AI / NIAID NIH HHS / United States
AI-054907 / AI / NIAID NIH HHS / United States
AI-054999 / AI / NIAID NIH HHS / United States
AI-058740 / AI / NIAID NIH HHS / United States
AI-068634 / AI / NIAID NIH HHS / United States
AI-068636 / AI / NIAID NIH HHS / United States
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AI-069450 / AI / NIAID NIH HHS / United States
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AI-069471 / AI / NIAID NIH HHS / United States
AI-069472 / AI / NIAID NIH HHS / United States
AI-069474 / AI / NIAID NIH HHS / United States
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UL1 RR024156 / RR / NCRR NIH HHS / United States
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UL1 RR024996 / RR / NCRR NIH HHS / United States
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UM1 AI069439 / AI / NIAID NIH HHS / United States
UM1 AI069450 / AI / NIAID NIH HHS / United States
UM1 AI069452 / AI / NIAID NIH HHS / United States
UM1 AI069465 / AI / NIAID NIH HHS / United States
UM1 AI069467 / AI / NIAID NIH HHS / United States
UM1 AI069470 / AI / NIAID NIH HHS / United States
UM1 AI069471 / AI / NIAID NIH HHS / United States
UM1 AI069472 / AI / NIAID NIH HHS / United States
UM1 AI069474 / AI / NIAID NIH HHS / United States
UM1 AI069477 / AI / NIAID NIH HHS / United States
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