Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1

• Published in: BMC infectious diseases 2017-09, Vol.17 (1), p.622-8, Article 622
• Main Authors: Yagura, Hiroki, Watanabe, Dai, Kushida, Hiroyuki, Tomishima, Kosuke, Togami, Hiroaki, Hirano, Atsushi, Takahashi, Masaaki, Hirota, Kazuyuki, Ikuma, Motoko, Kasai, Daisuke, Nishida, Yasuharu, Yoshino, Munehiro, Yamazaki, Kunio, Uehira, Tomoko, Shirasaka, Takuma
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Alleles; Analysis; Antiretroviral drugs; Anxiety; Anxiety - chemically induced; Anxiety - genetics; Asian Continental Ancestry Group - genetics; Clinical trials; Complications and side effects; Cytochrome; Cytochrome P450; Dizziness - chemically induced; Dizziness - genetics; Dolutegravir; Dosage and administration; Drug therapy; Female; Gene Frequency; Gene polymorphism; Genetic aspects; Genetic polymorphisms; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Headache; Health aspects; Heterocyclic Compounds, 3-Ring - adverse effects; Heterocyclic Compounds, 3-Ring - blood; Heterozygotes; HIV; HIV Infections - drug therapy; HIV Infections - genetics; HIV Integrase Inhibitors - adverse effects; HIV Integrase Inhibitors - blood; HIV-1 - pathogenicity; Homozygotes; Human immunodeficiency virus; Humans; Infection; Insomnia; Male; Middle Aged; Multivariate analysis; Neuropsychiatric adverse events; Patients; Plasma trough concentration; Polymorphism; Polymorphism, Genetic; Risk factors; Sleep disorders; Sleep Initiation and Maintenance Disorders - chemically induced; Sleep Initiation and Maintenance Disorders - genetics; Statistical analysis; UGT1A1 gene polymorphism; Uridine; Viruses
• ISSN: 1471-2334; 1471-2334
• DOI: 10.1186/s12879-017-2717-x

Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 μg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of