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EFFECT OF DOLUTEGRAVIR PLASMA CONCENTRATION ON CENTRAL NERVOUS SYSTEM SIDE EFFECTS
Hiroki Yagura1, Dai Watanabe1, Takao Nakauchi1, Kosuke Tomishima1, Daisuke Kasai1, Yasuharu Nishida1, Munehiro Yoshino2, Tomoko Uehira1, Kunio Yamazaki1, Takuma Shirasaka1
1Natl Hosp, Osaka, Japan,2Natl Hosp Org Osaka Minami Med Cntr, Osaka, Japan
Dolutegravir (DTG), a second-generation HIV integrase inhibitor that can easily be administered once daily, was shown to have apparent non-inferior efficacy in comparison with other medications in phase III trials. At present, it is being prescribed increasingly, especially in developed countries, including Japan, and has been previously reported to induce side effects in the central nervous system (CNS), such as insomnia and headache. However, its mechanism including association between DTG plasma concentration and CNS side effects remains unknown.
We recruited 162 HIV-infected patients who had undergone anti-retroviral treatment, including DTG treatment, from Osaka National Hospital, Japan, from April 2014 to March 2016. DTG plasma trough concentration was measured, and the association between DTG concentration and CNS side effects was statistically analyzed within 6 months of DTG introduction.
Of the 162, 154 (95%) were male and 8 (5%) were female. Their age at enrollment was median 43 years old (inter quartile range 38-52). 36 (22%) patients introduced DTG in the first antiretroviral treatment.In the rest of 126 (78%), DTG was switched from other antiretroviral agents. At least one of the CNS side effects was observed in 41 (25%) patients, which include dizziness [14/41 (34%)], headache [11 (27%)], insomnia [11 (27%)], restlessness [4 (10%)], and anxiety [3 (7%)]. According to the analyses: 1) patients with CNS side effects scored higher trough DTG plasma concentration compared with the subjects without symptoms (median 1.34 vs 1.03 ug/ml, p=0.003 by univariate Mann-Whitney U-test, and p=0.005 by multivariate binary regression test); 2) positive correlation was observed between DTG concentration and frequency of CNS side effects (p=0.002;Figure) ; and 3) no significant difference in DTG concentration was observed among CNS symptoms (p=0.56).
In this study, a positive correlation between trough plasma DTG concentration and CNS side effects was identified among Japanese population. This implied the importance of DTG concentration measurement for the evaluation of CNS side effects.