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• W1987351366 endingPage "e37" @default.
• W1987351366 startingPage "e36" @default.
• W1987351366 abstract "To the Editors: In 2012, there were approximately 4.7 million people living with HIV in Asia and approximately 1.25 million in the region accessing combination antiretroviral treatment (cART).1 With longer duration of cART treatment, increasing numbers of patients will be switched from first- to second-line cART. Recommended second-line regimens are ritonavir-boosted atazanavir (ATV/r) or lopinavir (LPV/r) together with 2 nucleoside reverse transcriptase inhibitors, one of which should be zidovudine or tenofovir.2 Advantages of ATV/rover LPV/r include convenient once-daily dosing and minimal effect on lipid profiles, but higher plasma concentrations correlate with hyperbilirubinemia as a consequence of inhibition of the uridine-glucuronosyltransferase (UGT) 1A1 enzyme responsible for bilirubin conjugation.3 Polymorphisms in the UGT1A1 gene influence the risk of hyperbilirubinemia. Six thymine adenine repeats (TA6) are found in the promoter region of the wild-type allele. A less common variant containing 7 repeats (TA7) results in lower promoter activity. The presence of at least 1 TA7 allele has been significantly associated with grade 3–4 hyperbilirubinemia in whites.4 We previously reported that Thai subjects taking ATV/r 200/100 mg QD showed equivalent plasma concentrations to white subjects taking standard dose (300/100 mg). The prevalence of grade 3 and 4 hyperbilirubinemia fell significantly from 36% to 14% after subjects were switched to the reduced dose,5 and reduced dose ATV/r demonstrated virological efficacy in a small study conducted in Thai patients over a median of 68 weeks.6 The P-glycoprotein (P-gp) membrane transporter, encoded by the multidrug resistance 1 (MDR1) gene, influences intracellular and plasma ATV concentrations. MDR1 gene polymorphisms have been shown to influence ATV plasma concentrations. At least 1 polymorphic nucleotide change at position 3435 (3435C>T) resulted in significantly lower ATV trough concentrations (Ctrough), but no difference in viral load reduction after 12 weeks of treatment in subjects initiating treatment with ATV/r-based cART.7 The extent to which polymorphisms in the MDR1 and UGT1A1 genes influence the plasma concentrations and prevalence of hyperbilirubinemia in Asian patients has not been described. In this study, we describe the prevalence of nucleotide polymorphisms in these genes in Thai patients taking ATV/r, and their relationship to ATV Ctrough and serum bilirubin concentrations. All subjects taking ATV 200 mg or 300 mg and 2 nonnucleoside reverse transcriptase inhibitors had genotypes assessed, and ATV concentrations assessed using HPLC as previously described.5 Ctrough concentrations were obtained 24 hours after the previous dose was taken. Eighty-eight patients (47% female) with median (interquartile range) age 41 (36–47) years were studied: 24 (27%) taking ATV/r 200/100 mg QD, 35(40%) taking ATV/r 300/100 mg QD, and 29 (33%) taking ATV/r initially at 300/100 mg QD who thereafter had their dose reduced to 200/100 mg QD had MDR1 and UG1A1 genotypes assessed. Patients who were taking ATV/r reduced dose switched from the higher to the lower dose for at least 4 weeks before measurement of the Ctrough. After written informed consent was obtained, 3 mL of peripheral blood was drawn and genomic DNA extracted from peripheral blood mononuclear cells using Qiagen DNA extraction kits (Qiagen, Valencia, CA). To determine the numbers of the TA repeats in the UGT1A1 promoter, a pair of primers, 5-FAM (carboxyfluorescein)-labeled forward primer (5′-CACGTGACACAGTCAAAC-3′) and unlabeled reverse primer (5′-CAACAGTATCTTCCCAGC-3′), was used to polymerase chain reaction (PCR) amplify its promoter region.8 Then, PCR products were electrophoresed and their sizes determined by GeneMapper version 4.0 software (Applied Biosystems, Carlsbad, CA). The genotype of MDR1 nucleotide position 3435 was assessed by PCR-restriction fragment length polymorphism using primers and restriction enzyme, DpnII, as previously described.9 UGT1A1 genotype was not available in 1 subject. The distribution of UGT1A1 genotypes was 65 (75%) common homozygotes (TA6/TA6), 22 (25%) heterozygotes (TA6/TA7), and there were no rare homozygotes (TA7/TA7). The distribution of MDR1 3435C>Tgenotypes was 28 (31%) common homozygotes (CC), 45 (51%) heterozygotes (CT), and 15 (17%) rare homozygotes (TT). Statistical comparisons between groups were made using a Wilcoxon test for continuous data, and Fisher exact test for categorical data. Median (interquartile range) ATV Ctrough and total bilirubin concentrations at both ATV doses, by MDR1 genotypes with 1 T allele and UGT1A1 genotype are shown in Table 1. Although ATV Ctrough concentrations were lower in those with at least 1 T allele in position 3435 of the MDR1 gene taking ATV/r 300/100 mg versus common homozygotes, no significant differences in ATV Ctrough concentrations were noted in patients with at least 1 T allele in either dose group. Likewise, no significant differences in bilirubin concentrations were noted between UGT1A1 homozygotes and heterozygotes in either dose group. However, patients taking ATV/r 200/100 mg with a TA6/TA7 genotype had a significantly higher prevalence of grade 3–4 hyperbilirubinemia compared with common homozygotes [4/15 (27%) versus 2/37 (5%), respectively, P = 0.05]. No difference in the prevalence of grade 3–4 hyperbilirubinemia was noted in heterozygotes versus common homozygotes was noted in subjects taking standard dose ATV/r [4/16 (25%) versus 8/48 (17%), respectively, P = 0.48].TABLE 1: Median (IQR) ATV Trough Concentrations, and Total Serum Bilirubin Concentrations in Patients by Genotype and ATV/r Dose RegimenAlthough the frequencies of the UGT1A1 TA7 allele in Thai (15.6%)10 and Asians (11.6%–14.5%) are approximately half of those in whites (26.0%–33.2%),11 hyperbilirubinemia is a common problem in Thai patients taking ATV/r. Although not life threatening, it is extremely disturbing to patients and heightens stigma. UGT1A1 genotype testing is a useful tool to determine which patients might have an elevated risk of hyperbilirubinemia, even after being treated with a reduced dose of ATV/r." @default.
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• W1987351366 date "2015-05-01" @default.
• W1987351366 modified "2023-09-27" @default.
• W1987351366 title "Pharmacogenetic Testing Can Identify Patients Taking Atazanavir at Risk for Hyperbilirubinemia" @default.
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• W1987351366 doi "https://doi.org/10.1097/qai.0000000000000540" @default.
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