Effect of the UGT1A1*28 Allele on Unconjugated Hyperbilirubinemia in HIV-Positive Patients Receiving Atazanavir: A Systematic Review

OBJECTIVE: To systematically examine the literature assessing the effect of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*28 genetic polymorphisms on atazanavir-associated hyperbilirubinemia. DATA SOURCES: 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. STUDY SELECTION AND DATA EXTRACTION: 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. DATA SYNTHESIS: 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.