UGT1A1*6 associated with higher dolutegravir concentrations in Chinese adults with HIV-1 infection

Dolutegravir (DTG) is a cornerstone of antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV-1), valued for its high resistance barrier and favorable safety. In recent years, DTG-based regimens have been widely adopted as first-line treatment in China. However, substantial interindividual variability in DTG plasma concentrations persists, raising questions about underlying mechanisms and clinical implications. DTG is primarily metabolized by UDP-glucuronosyltransferase 1A1 (UGT1A1), a highly polymorphic enzyme. Although prior studies in other populations have linked certain UGT1A1 variants to altered DTG clearance, large-scale pharmacogenetic data in Chinese adults have remained scarce. 

To address this gap, Professor Yinzhong Shen’s team at Shanghai Public Health Clinical Center, Fudan University, China, conducted a real-world study in 287 Han Chinese adults with HIV-1 who had received DTG-based ART for at least 10 days. The cohort was predominantly male (96.2%), with a median age of 40 years and median treatment duration of 16 months. Researchers sequenced seven key regions of the UGT1A1 gene, covering exons 1–5, the TATA box, and the Phenobarbital-Responsive Enhancer Module (PBREM) enhancer. DTG plasma trough concentrations, a robust measure of steady-state exposure, were quantified using ultra-performance liquid chromatography-tandem mass spectrometry. 

Three prevalent variants were identified: UGT1A1*6 (211G>A in exon 1, rs4148323), UGT1A1*28 (7‑TA repeat in TATA box, rs3064744), and UGT1A1*60 (-3279T>G in PBREM, rs4124874). Genotype frequencies were notable: heterozygotes for UGT1A1*6, UGT1A1*28, and UGT1A1*60 accounted for 31.7%, 22.0%, and 49.1%, respectively, while homozygotes comprised 4.2%, 1.4%, and 8.0%. The median DTG trough concentration across all participants was 2,427 ng/mL—more than double the median reported in a Japanese cohort and nearly 38‑fold higher than the protein‑adjusted 90% inhibitory concentration (IC₉₀) for the wild‑type virus (64 ng/mL). 

Critically, only UGT1A1*6 was significantly associated with elevated DTG trough concentrations. Carriers of one or two copies had markedly higher levels than the wild‑type individuals (P < 0.001), with the strongest effect in homozygotes. In contrast, neither UGT1A1*28 nor UGT1A1*60 alone significantly affected DTG concentrations, suggesting that UGT1A1*6 is the primary genetic determinant in this population. The researchers then explored combinatorial effects across six genotype patterns. Compared with the wild‑type group (median 2,050 ng/mL), patients carrying UGT1A1*6 alone (2,814 ng/mL), UGT1A1*6/*60 (2,805 ng/mL), or UGT1A1*6/*28/*60 (3,149 ng/mL), all exhibited significantly higher concentrations. Genotypes containing UGT1A1*60 or UGT1A1*28/*60 without UGT1A1*6 did not differ from the wild‑type, indicating that the other variants only potentiate the effect of UGT1A1*6. 

Multivariable regression, adjusting for age, sex, body weight, and renal function confirmed that UGT1A1*6 (B = 630.42), UGT1A1*6/*60 (B = 793.23), and UGT1A1*6/*28/*60 (B = 985.87) were independent predictors of higher DTG trough concentrations (all P < 0.001). Additionally, lower body weight was significantly associated with higher DTG levels: each 1‑kg decrease corresponded to a 25.53 ng/mL increase in trough concentration (P < 0.001). Female sex showed a borderline association (P = 0.08). 

Despite these clear pharmacokinetic differences, no significant correlation was found between DTG trough concentrations and virologic outcomes. Among 248 patients treated for more than 3 months, 96% achieved HIV-1 RNA < 50 copies/mL, and DTG levels did not differ between those with viral suppression and those with low‑level viremia. Similarly, no associations were observed between DTG trough concentrations and adverse effects, including weight gain, psychiatric symptoms, digestive issues, or rash. These findings suggest the relationship between DTG exposure and clinical endpoints is complex and likely influenced by additional factors such as immune status and individual susceptibility. 

This study provides the first large‑scale evidence in Han Chinese adults that UGT1A1*6 is a key genetic determinant of elevated DTG trough concentrations, with compound genotypes and low body weight further increasing exposure. While these results do not immediately support routine dose adjustment, they highlight the potential value of therapeutic drug monitoring and pharmacogenetic testing in selected high‑risk patients. Future prospective studies with larger, more diverse Chinese cohorts are needed to translate these findings into clinical practice. 

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Reference 
DOI: 10.1097/CM9.0000000000004204 

About Professor Yinzhong Shen from Fudan University, China 
Dr. Yinzhong Shen is a Professor, Chief Physician, and Doctoral Supervisor at Fudan University. He serves as Chair‑elect of the Tropical Disease and Parasitology Branch, Chinese Medical Association, and Chair of the HIV‑associated Tumor Committee, Chinese STD/AIDS Association. His research focuses on HIV opportunistic infections and emerging infectious diseases. He leads major national projects, has received multiple science and technology awards, and has published > 30 SCI papers as first/corresponding author in the past 5 years, editing three monographs and co‑editing seven. 

About Dr. Xiaoqin Le from Fudan University, China 
Dr. Xiaoqin Le earned her Ph.D. in Internal Medicine from Fudan University (2026) and currently works as an infectious disease physician at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. She has published eight SCI‑indexed and five Chinese core journal articles as the first/co‑first author. Her research focuses on individualized antimicrobial therapy and precision dosing strategies.  

Funding information 
This study was funded by the Science and Technology Commission of Shanghai Municipality (No.21Y31900400) and Shanghai Shenkang Hospital Development Center (No. SHDC22024317).