Gilbert Syndrome and the Development of Antiretroviral Therapy–Associated Hyperbilirubinemia

Abstract

Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

“…It is well known that ATV causes a concentrationdependent increase in s-bilirubin due to the inhibition of the enzyme UGT1A1, which is responsible for the conjugation of bilirubin, an effect that is influenced by genetic polymorphisms of UGT1A1 [29][30][31]. Still, an inverse relation between ATV-associated hyperbilirubinemia and the risk of virological failure has been reported, prompting the suggestion that this widely available and inexpensive test may be potentially useful as a biomarker of ATV exposure and predictor of the risk of treatment failure.…”

Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype

“…25 This situation can be expected to affect individuals who already suffer from reduced UGT activity such as homozygous carriers of UGT1A1*28 with only approximately 30% of UGT1A1 activity. 31 However, this also affects genetically determined low-activity alleles of other UGT proteins inhibited by ATV, the effects of which will not necessarily be evident as a hyperbilirubinemic phenotype linked to the specific bilirubin activity of UGT1A1. This view is further strengthened by the clinical observation that the degree of hyperbilirubinemia in Gilbert's patients and in ATV-treated patients is variable even in those patients who exhibit the UGT1A1*28 genotype, suggesting that the pharmacogenetic risk profile may involve additional factors.…”

“…31 In many instances drug reactions occur when a single enzyme/pathway is the primary route of elimination of a drug. Recently, this has been prominently recognized with cerivastatin and gemfibrozil.…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…Alelle *28 contains seven repeats of the dinucleotide TA (TA 7 ) at the promoter of the gene instead of six (TA 6 ) typically of the common allele (UGT1A1*1). In this setting, plasma bilirubin levels are further increased in ATV recipients when the UGT1A1*28 allele is present [48,61,62] (Figure 3). Another polymorphism in the UGT1A1 promoter (rs887829) associated with ATV hyperbilirubinemia has been proposed as the strongest genetic predictor of peak bilirubin in a GWAS conducted very recently.…”