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

The once-daily human immunodeficiency virus (HIV)-1 protease inhibitor atazanavir with low-dose ritonavir as a pharmacokinetic enhancer (atazanavir/r) is generally safe and effective as a first-line regimen for HIV-1 infection [1–4]. Atazanavir increases plasma indirect bilirubin concentrations by inhibiting uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated bilirubin glucuronidation [5]. This provides a reliable biomarker of very recent medication adherence [6–8]. Atazanavir-associated indirect hyperbilirubinemia does not indicate hepatic injury [2, 9–11], but some patients discontinue atazanavir due to cosmetic jaundice [3, 12, 13], and many are not prescribed atazanavir to avoid this possibility. Better pretreatment prediction of atazanavir intolerance due to hyperbilirubinemia could reduce jaundice-related atazanavir discontinuations. Polymorphisms in UGT1A1 are associated with interindividual differences in plasma indirect bilirubin concentrations in the general population (ie, Gilbert's syndrome). A promoter tandem TA repeat, UGT1A1*28 (TA)7, is associated with reduced UGT1A1 transcription compared with UGT1A1*1 (TA)6 [14, 15]. Among atazanavir recipients, UGT1A1*28 has been strongly associated with unconjugated hyperbilirubinemia [16, 17], as has a C→T single-nucleotide polymorphism (rs887829) in almost complete linkage disequilibrium with UGT1A1*28 [18]. In a genome-wide study involving individuals who had been randomized to atazanavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocol A5202, rs887829 genotype, baseline indirect bilirubin, and baseline hemoglobin were each independently associated with peak on-treatment total bilirubin concentration [18]. However, reported associations between UGT1A1 genotype and atazanavir discontinuation have been inconsistent [17, 19]. In ACTG protocol A5257, participants were randomized to receive atazanavir/r, darunavir/ritonavir (darunavir/r), or raltegravir, all with concomitant tenofovir disoproxil fumarate (TDF)/emtricitabine. The present study examined whether UGT1A1 genotype, baseline indirect bilirubin, and/or baseline hemoglobin were associated with bilirubin-related discontinuation of atazanavir/r in A5257, and whether associations differed by race or ethnic group. We also assessed whether tolerability of regimens containing atazanavir/r compared with darunavir/r or raltegravir differed by UGT1A1 genotype.