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

UGT1A1 star alleles that lower UDP-glucuronosyltransferase 1A1 activity reduce dolutegravir glucuronidation and raise its plasma trough concentration.

This cross-sectional study enrolled 287 Han Chinese adults living with HIV-1 at a Shanghai centre who had been receiving dolutegravir for at least ten days, and amplified seven segments of UGT1A1 (exons 1-5, the promoter TATA box and the PBREM enhancer module). The cohort was 96.2% male (276/287) with a median age of 40 years, and the median dolutegravir plasma trough concentration was 2427 ng/mL (IQR 1807-3107). The three most common star alleles were allele 6 (211G>A, rs4148323), allele 28 (seven TA repeats in the TATA box, rs3064744) and allele 60 (-3279T>G, rs4124874), with heterozygote frequencies of 31.7%, 22.0% and 49.1% and homozygote frequencies of 4.2%, 1.4% and 8.0% respectively. Trough concentrations were significantly higher in carriers of one or two copies of allele 6 (P < 0.001), whereas alleles 28 and 60 alone had no significant effect. In multiple linear regression, low body weight, one or two copies of allele 6, and compound heterozygosity of allele 6 with allele 60 or with alleles 28 and 60 were independent factors for high trough concentrations.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The study documents UGT1A1-related pharmacokinetic variability in a population where it was poorly described, but it stops at plasma concentration: no link with virological efficacy or tolerability is established and no exposure threshold is proposed. Single-centre, almost exclusively male recruitment further limits generalization. As it stands, nothing justifies UGT1A1 genotyping before starting dolutegravir; showing that these high concentrations translate into clinical events would be the next step.

Analysis by Dr Thibaut Benquey