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BMC Infect Dis. 2017 Sep 16;17(1):622. doi: 10.1186/s12879-017-2717-x.

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

Author information

1
Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
2
AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan. dai@onh.go.jp.
3
Department of Pharmacy, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya City, Aichi, 460-0001, Japan.
4
Department of Pharmacy, National Hospital Organization Suzuka Hospital, 3-2-1 Kasado, Suzuka, Mie, 513-8501, Japan.
5
AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
6
Department of Pharmacy, National Hospital Organization Utano Hospital, Narutaki, Ondoyama-cho 8, Ukyo-ku, Kyoto, Japan.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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 < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 μg/mL) than in those without NP-AEs (1.01 μg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454).

CONCLUSION:

In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.

KEYWORDS:

Dolutegravir; Neuropsychiatric adverse events; Plasma trough concentration; UGT1A1 gene polymorphism

PMID:
28915895
PMCID:
PMC5603066
DOI:
10.1186/s12879-017-2717-x
[Indexed for MEDLINE]
Free PMC Article

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