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Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1.
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.
Affiliation
  • Yagura H; Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Watanabe D; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan. dai@onh.go.jp.
  • Kushida H; Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Tomishima K; Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Togami H; Department of Pharmacy, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya City, Aichi, 460-0001, Japan.
  • Hirano A; Department of Pharmacy, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya City, Aichi, 460-0001, Japan.
  • Takahashi M; Department of Pharmacy, National Hospital Organization Suzuka Hospital, 3-2-1 Kasado, Suzuka, Mie, 513-8501, Japan.
  • Hirota K; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Ikuma M; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Kasai D; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Nishida Y; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Yoshino M; Department of Pharmacy, National Hospital Organization Utano Hospital, Narutaki, Ondoyama-cho 8, Ukyo-ku, Kyoto, Japan.
  • Yamazaki K; Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Uehira T; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
  • Shirasaka T; AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan.
BMC Infect Dis ; 17(1): 622, 2017 09 16.
Article in En | MEDLINE | ID: mdl-28915895
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.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polymorphism, Genetic / HIV Infections / Glucuronosyltransferase / Heterocyclic Compounds, 3-Ring Type of study: Risk_factors_studies Limits: Adult / Female / Humans / Male / Middle aged Language: En Journal: BMC Infect Dis Journal subject: DOENCAS TRANSMISSIVEIS Year: 2017 Document type: Article Affiliation country: Japan Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polymorphism, Genetic / HIV Infections / Glucuronosyltransferase / Heterocyclic Compounds, 3-Ring Type of study: Risk_factors_studies Limits: Adult / Female / Humans / Male / Middle aged Language: En Journal: BMC Infect Dis Journal subject: DOENCAS TRANSMISSIVEIS Year: 2017 Document type: Article Affiliation country: Japan Country of publication: United kingdom