UGT1A1 gene polymorphisms and their impact on plasma trough concentrations of dolutegravir in Chinese adults with human immunodeficiency virus-1 infection

BACKGROUND: Dolutegravir (DTG), a cornerstone of human immunodeficiency virus-1 (HIV-1) treatment, is primarily metabolized by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in the UGT1A1 gene have been shown to influence the pharmacokinetics of DTG across different ethnic populations. This study aims to characterize the distribution of UGT1A1 polymorphic alleles and evaluate their impact on DTG plasma trough concentrations in Han Chinese individuals living with HIV-1 infection. METHODS: This study enrolled Han Chinese adults from the Outpatient Department of Infection and Immunity, Shanghai Public Health Clinical Center, between September 2 and November 2, 2024, who were infected with HIV-1 and had been receiving DTG treatment for at least 10 days. Seven segments of the UGT1A1 gene, including exons 1-5, the promoter TATA box, and the phenobarbital-responsive enhancer module (PBREM), were amplified to identify potential polymorphisms. The association between these gene polymorphisms and DTG plasma trough concentrations was investigated. RESULTS: A total of 287 Han Chinese with HIV-1 infection were included in the study, of which 96.2% (276/287) were male, with a median age of 40 years (interquartile range [IQR]: 32-51 years). The median trough concentration of DTG was 2427 ng/mL (IQR: 1807-3107 ng/mL). The three most common alleles identified were (1) 211G>A in exon 1 (UGT1A1*6, rs4148323), (2) seven TA repeats in TATA box (UGT1A1*28, rs3064744), and (3) -3279T>G in PBREM (UGT1A1*60, rs4124874). The percentages of heterozygotes for these alleles were 31.7%, 22.0%, and 49.1%, respectively, while the frequencies of homozygotes were 4.2%, 1.4%, and 8.0%, respectively. Plasma trough concentrations of DTG were significantly higher in patients carrying one or two alleles of UGT1A1*6 compared to those with the wild-type genotype (P <0.001). However, neither UGT1A1*28 nor UGT1A1*60 alone significantly affected DTG trough concentrations. Multiple linear regression analysis revealed that low body weight, the presence of one or two UGT1A1*6 alleles, and compound heterozygote of UGT1A1*6/*60 or UGT1A1*6/*28/*60 were independent risk factors associated with high DTG plasma trough concentrations. CONCLUSIONS: The frequencies of heterozygotes for UGT1A1*6, UGT1A1*28, and UGT1A1*60 were found to be high in the studied population. In addition to low body weight, the presence of UGT1A1*6 and compound heterozygosity of UGT1A1*6/*60 or UGT1A1*6/*28/*60 were significant factors contributing to elevated DTG trough concentrations.