Background: Analysis of phIII clinical trials for DTG concluded that selected neuropsychiatric symptoms (NPs) occurred at similar frequencies compared with controls. Some observational cohort data suggest that NPs result in higher rates of discontinuation among DTG users. Potential factors associated with discontinuations due to NPs reported in some cohorts include ABC co-administration, older age and female gender. We performed a meta-analysis to assess variables associated with NPs, and explored whether insomnia was associated with subsequent NPs.
Methods: Studies included: SPRING-2, SINGLE, FLAMINGO, ARIA, SAILING. NPs included: Insomnia, anxiety, depression, suicidality, nightmares/abnormal dreams, headache. Exposure adjusted incidence of NPs was calculated from frequencies of reported adverse events (AEs); 95%CIs are based on exact binomial 2-sided CIs. Poisson mixed effects meta-regression models were used to conduct two analyses of pre-specified variables in a backward selection on the incidence rate of AEs in patients treated with A) DTG (N=1,672) versus nonDTG (n =1,681) and B) DTG+ABC (n=943) vs DTG+nonABC (n=729). Significance level was 10%. Insomnia as a precursor to other NPs was analyzed descriptively.
Results: Identified variables associated with NPs are shown in the figure. Overall, adjusted estimates [SE] for NPs rates per 1,000 person years were 5.26 [0.068] with DTG versus 5.21 [0.07] with nonDTG (aRR 1.05 [95%CI 0.9, 1.21, p=0.55]), and 5.4 [0.079] with DTG+ABC versus 5.3 [0.085] with DTG+nonABC (aRR 1.1 [95%CI 0.89, 1.37, p=0.37]). Descriptive analyses of first insomnia events and subsequent non-insomnia events are in the table. First insomnia events with subsequent non-insomnia NPs occurred infrequently (2.2%), with higher rates of first occurrence of non-insomnia NPs (23%).
Conclusions: In this meta-analysis including 3,353 participants, the rate of NPs was similar between DTG and non-DTG treated patients. Variables associated with increased NPs in the DTG vs nonDTG analysis were past psychiatric history, non-EU residence and, in contrast with previous findings, younger age. Within the DTG vs DTG+ABC analysis, past psychiatric history and country of residence showed significant association. Concomitant ABC use was not a variable associated with NPs. There was no indication that insomnia was associated with subsequent CNS


 DTG (N=1,672) n (%)nonDTG (N=1,681) n (%)Difference, % (95%CI)
Patients without NPs1,242 (74.3%)1,273 (75.7%)-1.45 (-4.4, 1.5)
First insomnia event with subsequent non-insomnia NPs37 (2.2%)25 (1.5%)0.73 (-0.2, 1.6)
Non-insomnia NPs without prior insomnia event384 (23.0%)378 (22.5%)0.48 (-2.4, 3.3)
Only one NPs event310 (18.5%)278 (16.5%)2.00 (-0.6, 4.6)

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