Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin‐related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).

[1]  L. Olson,et al.  Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia , 2015, Open forum infectious diseases.

[2]  L. Mofenson,et al.  Long-term Safety and Efficacy of Atazanavir-based Therapy in HIV-infected Infants, Children and Adolescents: The Pediatric AIDS Clinical Trials Group Protocol 1020A , 2015, The Pediatric infectious disease journal.

[3]  Zhiwei Chen,et al.  UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: a quantitative analysis. , 2014, Gene.

[4]  David W. Haas,et al.  Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. , 2014, Annals of internal medicine.

[5]  M. Ritchie,et al.  Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202 , 2014, Pharmacogenetics and genomics.

[6]  Julia M. Barbarino,et al.  PharmGKB summary: very important pharmacogene information for UGT1A1 , 2014, Pharmacogenetics and genomics.

[7]  R. Bertz,et al.  Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. , 2013, AIDS research and human retroviruses.

[8]  F. Antunes,et al.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. , 2013, The Journal of infectious diseases.

[9]  F. Hu,et al.  A Genome‐Wide Association Study for Serum Bilirubin Levels and Gene‐Environment Interaction in a Chinese Population , 2013, Genetic epidemiology.

[10]  P. Sax,et al.  Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS Clinical Trials Group Study A5202. , 2013, The Journal of infectious diseases.

[11]  A. Santos-Silva,et al.  Bilirubin Dependence on UGT1A1 Polymorphisms, Hemoglobin, Fasting Time and Body Mass Index , 2012, The American journal of the medical sciences.

[12]  Xinxin Ding,et al.  Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues , 2012, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  C. Rotimi,et al.  UGT1A1 is a major locus influencing bilirubin levels in African Americans , 2011, European Journal of Human Genetics.

[14]  V. Soriano,et al.  Short communication: use of serum bilirubin levels as surrogate marker of early virological response to atazanavir-based antiretroviral therapy. , 2011, AIDS research and human retroviruses.

[15]  P. Flandre.  Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1 , 2011, Annals of Internal Medicine.

[16]  A. Sönnerborg,et al.  Bilirubin—A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy , 2011, The AAPS Journal.

[17]  G. Gourley,et al.  Assessment of UGT polymorphisms and neonatal jaundice. , 2011, Seminars in perinatology.

[18]  D. Katzenstein,et al.  Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1 , 2011, Annals of Internal Medicine.

[19]  Mark George Thomas,et al.  Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations , 2011, Annals of human genetics.

[20]  Matthias Cavassini,et al.  Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. , 2011, The Journal of infectious diseases.

[21]  Tae-Wook Kang,et al.  Genome-wide association of serum bilirubin levels in Korean population. , 2010, Human molecular genetics.

[22]  P. G. Choe,et al.  Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[23]  Ming-Huei Chen,et al.  Genome-wide association meta-analysis for total serum bilirubin levels. , 2009, Human molecular genetics.

[24]  G. Abecasis,et al.  Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. , 2009, Human Molecular Genetics.

[25]  K. Makar,et al.  Cruciferous Vegetable Feeding Alters UGT1A1 Activity: Diet- and Genotype-Dependent Changes in Serum Bilirubin in a Controlled Feeding Trial , 2009, Cancer Prevention Research.

[26]  R. Maserati,et al.  Hyperbilirubinemia during Atazanavir Treatment in 2,404 Patients in the Italian Atazanavir Expanded Access Program and MASTER Cohorts , 2009, Infection.

[27]  J. Molina,et al.  Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study , 2008, The Lancet.

[28]  C. Strassburg.  Pharmacogenetics of Gilbert's syndrome. , 2008, Pharmacogenomics.

[29]  J. Hammond,et al.  Efficacy and Safety of Atazanavir, With or Without Ritonavir, as Part of Once-Daily Highly Active Antiretroviral Therapy Regimens in Antiretroviral-Naive Patients , 2008, Journal of acquired immune deficiency syndromes.

[30]  Shih-Ming Huang,et al.  Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter , 2007, Pharmacogenetics and genomics.

[31]  J. Singer,et al.  UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia , 2007, Leukemia.

[32]  Donglu Zhang,et al.  IN VITRO INHIBITION OF UDP GLUCURONOSYLTRANSFERASES BY ATAZANAVIR AND OTHER HIV PROTEASE INHIBITORS AND THE RELATIONSHIP OF THIS PROPERTY TO IN VIVO BILIRUBIN GLUCURONIDATION , 2005, Drug Metabolism and Disposition.

[33]  K. Petersen,et al.  Use of bilirubin as a marker of adherence to atazanavir-based antiretroviral therapy , 2005, AIDS.

[34]  C. Guillemette,et al.  UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver , 2005, Hepatology.

[35]  M. Mori,et al.  Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. , 2002, Biochemical and biophysical research communications.

[36]  M. Manns,et al.  Developmental aspects of human hepatic drug glucuronidation in young children and adults , 2002, Gut.

[37]  S. Ghosh,et al.  Genetic lesions of bilirubin uridine‐diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler‐Najjar and Gilbert syndromes: Correlation of genotype to phenotype , 2000, Human mutation.

[38]  J. J. Henning,et al.  Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, January 28, 2000 , 1998, HIV clinical trials.

[39]  A. Di Rienzo,et al.  Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. , 1999, Pharmacogenetics.

[40]  D Lindhout,et al.  The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. , 1995, The New England journal of medicine.

[41]  P. Bosma,et al.  Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. , 1994, The Journal of biological chemistry.

[42]  J. R.,et al.  Quantitative analysis , 1892, Nature.