Clinical significance of the UGT1A1*28 allele detection in HIV‐infected patients

Abstract

Introduction The UGT1A1*28 (rs8175347) polymorphism is associated with hyperbilirubinemia. The presence of 6 TA-repeats in the UGT1A1 gene promoter region corresponds to normal UGT1TA1 activity. A detection of 7 TA-repeats in hetero- or homozygous individuals [(TA)6/(TA)7 and (TA)7/(TA)7] is associated with lower UGT1TA1 activity, which may eventually result in the development of Gilbert syndrome and/or modified individual response to drugs metabolized by this enzyme. ATV contributes to the decreased levels of UGT1A1, which may lead to elevations of indirect bilirubin, jaundice and even to therapy discontinuation. We evaluated the prevalence of the UGT1A1*28 among HIV-infected patients and the dependence of the frequency and severity of AE during ATV treatment on individual genetic characteristics.Materials and Methods 47 HIV-infected patients was screen for UGT1A1 genotype and the presence of UGT1A1*28. All patients received ATV in the HAART regimen for 48 weeks. Changes in the total, direct and indirect bilirubin, ALT, AST, GGT and jaundice were evaluated. Statistical analysis was performed using Microsoft Office Excel for Windows XP Professional 2007 and Biostat.Results All patients were followed up in the AIDS Center (males 72.3%, median age 33 years, median CD4+ count-282 cells/µl (19.5%)). HBV/HCV was in 36.2% patients. Ten patients had risk factors that could affect bilirubin turnover (chronic cholecystitis, biliary dyskinesia, etc.). Genotype (TA)6/(TA)6 was found in 42.6% patients, (TA)6/(TA)7-42.6% and (TA)7/(TA)7-14.9%. Overall prevalence of UGT1A1*28 was 57.4%, and homozygous allele frequency was 14.9%. G3/4 of indirect bilirubin were detected in 36.2% patients [(TA)6/(TA)6 in 10–20%, (TA)6/(TA)7-25-40%, (TA)7/(TA)7-72-86%], and significant jaundice in 10.6% [80% with (TA)7/(TA)7]. The OR for hyperbilirubinemia>40 µmol/L in patients with heterozygous UGT1A1*28 was increased 3 times over patients without this allele (OR 3.07, 95% CI 1.54–4.6) and 34 times as compared with homozygotes (OR 33.9, 95% CI 31.45–36.35). The presence of additional risk factors increased the probability of G3/4 hyperbilirubinemia. No significant changes in the ALT, AST, and GGT levels were observed.ConclusionsThe risk of severe hyperbilirubinemia during ATV treatment is minimal for patients without UGT1A1*28 and no more than one additional risk factor and for patients with UGT1A1*28 and no additional risk factors; patients with homozygous genotype UGT1A1*28 are at the highest risk.

Gilbert's Syndrome, Bilirubin Level and UGT1A1∗28 Genotype in Men of North-West Region of Russia

“…21 Pharmacogenetic assays link mutant UGT1A1 genotype to toxicity of antiretroviral therapy containing protease inhibitors atazanavir and indinavir. 5,40,44 These drugs induce hyperbilirubinemia in HIV-infected patients with GS by suppressing the activity of uridineglucuronosyltransferase 1A1 in the liver by competitive inhibition. More than half of the population is UGT1A1 gene pathological homozygous and heterozygous carriers.…”

Pharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolism

“…In Caucasians, UGT1A1*28 is a prevalent risk allele, and it even was investigated as a diagnostic test in Russia and included as a supporting test for hyperbilirubinemia correction in patients taking ART. Consideration of UGT1A1*28 (rs8175347) homozygosity was unveiled to lower ATV discontinuation rate in patients down to 4,7%, and it was recommended for patients with high bilirubin levels detected prior to, or in the duration of treatment [10]. ATV-associated hyperbilirubinemia is also linked with UGT1A1*80 rs887829 allele (which is in very strong linkage disequilibrium (LD) with UGT1A1*28), baseline bilirubin levels, and baseline haemoglobin level, while is best predicted using all these factors combined [11,12].…”

Hyperbilirubinemia in atazanavir treated HIV-infected patients: the impact of the UGT1A1*28 allele

“… 8 Individuals homozygous to (TA 7 /TA 7 ) are at higher risk than heterozygous patients (TA 6 /TA 7 ). 9 …”