title: Effect of the UGT1A1*28 allele on unconjugated hyperbilirubinemia in HIV-positive patients receiving Atazanavir: a systematic review.
abstract: OBJECTIVE
  To systematically examine the literature assessing the effect of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*28 genetic polymorphisms on atazanavir-associated hyperbilirubinemia.
  
  
  METHODS
  MEDLINE (1948-November 2012), EMBASE (1980-November 2012), International Pharmaceutical Abstracts (1970-November 2012), Google, and Google Scholar were searched using combinations of the following terms: glucuronosyltransferase, glucuronosyltransferase 1A1, atazanavir, atazanavir plus ritonavir, or polymorph$. The reference lists of all identified articles were manually searched.
  
  
  METHODS
  Studies were included if at least 1 group of patients received atazanavir therapy and assessed the effect of UGT1A1*28 variants on bilirubin concentrations or atazanavir discontinuation rates. The quality of each study was ranked according to the US Preventive Services Task Force 1996 classification system. Information extracted included study design, baseline characteristics, treatment regimens, UGT1A1*28 genotype frequencies, bilirubin concentrations, incidence of hyperbilirubinemia, and atazanavir discontinuation rates.
  
  
  RESULTS
  Our search produced 12 studies, of which 9 were included (6 full manuscripts [level II-2], 2 abstracts, and 1 letter to the editor [level III]). Reported UGT1A1*28 homozygote genotype frequencies (0.8-23.8%) were in general agreement with the literature for the diverse ethnic population captured in the 9 studies. An association between the incidence of hyperbilirubinemia and UGT1A1*28 genotype (homozygotes > heterozygotes > wild-type) was demonstrated in all studies that reported such data (6 of 9 studies). However, the calculated positive predictive value for homozygosity and hyperbilirubinemia from pooled data was low (40.3%). Only 2 studies (levels II-2 and III) reported rates of atazanavir discontinuation due to hyperbilirubinemia and showed some positive correlation with presence of the UGT1A1*28 allele.
  
  
  CONCLUSIONS
  Based on the available evidence, homozygosity of the UGT1A1*28 allele does not strongly predict the incidence of severe hyperbilirubinemia. Thus, until large, prospective trials demonstrate otherwise, UGT1A1*28 testing does not appear to provide additional information to aid clinical decision-making when initiating atazanavir treatment in HIV-infected patients.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Celia L
authors.initials: CL
authors.lastname: Culley
authors.forename: Tony K L
authors.initials: TK
authors.lastname: Kiang
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Gilchrist
authors.forename: Mary H H
authors.initials: MH
authors.lastname: Ensom
mesh_terms: D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D009842:Oligopeptides / Q000009:adverse effects* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D000099148:UGT1A1 Enzyme
chemical_list: D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase; D009842:Oligopeptides; D011725:Pyridines; D000099148:UGT1A1 Enzyme