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Neuropsychiatric manifestations and sleep disturbances in children and adolescents randomised to dolutegravir-based ART vs standard-of-care in the ODYSSEY trial

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BACKGROUND: Dolutegravir is associated with neuropsychiatric adverse events (NPAEs) in adults. We present first randomised data in children and adolescents.
METHODS: ODYSSEY is an open-label, multi-centre, randomised trial, comparing efficacy and safety of dolutegravir-based ART(DTG) with standard of care (SOC) in children initiating first- or second-line therapy. We compared NPAEs, including serious adverse events(SAEs), grade '¥3 events, ART-modifying events and suicidality-related events, and patient/carer mood-and-sleep questionnaire responses in DTG versus SOC.
RESULTS: 707 children '¥14kg were randomised (sub-Saharan Africa 88%, Thailand 9%, Europe 4%); 311 children started first-line(92% efavirenz-based in SOC); 396 second-line(98% PI-based). Median(IQR) age was 12.2(9.1,14.9); 362(51%) were male; median follow-up 142(124,159) weeks.
There were 31 NPAEs (in 23 children): 18(15) in DTG vs 13(8) in SOC (Table). Median(IQR) age and time from enrolment at first event were 15.9(10.4,17.5) years and 72(47,124) weeks respectively. Most NPAEs (23) were in children starting first-line; and most (22) occurred in males. Ten participants(5 DTG;5 SOC) had 13 SAEs: 7 DTG(3 epilepsy/convulsions, 1 headache/hypertension, 1 depression, 1 parasuicide, 1 psychosis) vs 6 SOC(3 epilepsy/convulsions, 1 dizziness, 2 parasuicide). 12 children(8 DTG;4 SOC) experienced 15 suicidality events: 10 suicidality ideation(6 DTG;4 SOC) and 5 parasuicide(2 DTG;3 SOC). ART-modifying NPAE(s) included 3 DTG(2 depression, 1 psychosis) and 2 SOC(1 parasuicide, 1 dizziness).
Small number of participants/carers reported symptoms of self-harm(8 DTG;1 SOC,p=0.04), "life was not worth living"(17 DTG;5 SOC,p=0.009) or suicidal thoughts(13 DTG;0 SOC,p<0.001) in mood-and-sleep questionnaires; the reported symptoms were transient and did not lead to treatment change. There were no differences between treatment groups in low mood/feeling sad, problems concentrating, feeling worried or feeling angry/aggressive, time to fall asleep, nightmares/vivid dreams or sleep quality.
CONCLUSIONS: Numbers of NPAEs and reported neuropsychiatric symptoms were low. More participants reported neuropsychiatric symptoms in the DTG arm vs SOC, however this difference should be interpreted with caution in an open-label trial.

Table. Summary of neuropsychiatric adverse events in ODYSSEY

DTG, N=350
SOC, N=357
Total, N=707
P-value
All neuropsychiatric adverse events,
N [N participants]
18[15]13[8]31[23]0.125*
-Neurological adverse events
6[6]6[5]12[11]0.736*
-Psychiatric adverse events
12[10]7[4]19[14]0.112*
Serious adverse events
7[5]6[5]13[10]
Grade '¥3 adverse events
12[9]8[7]20[16]
ART-modifying events
3[3]2[2]5[5]
Hazard Ratio for time to first NPAE (95% CI)
1.87 (0.79, 4.41)1(ref)

0.154
NPAE= neuropsychiatric adverse events. *Comparing number of participants with at least 1 event. Adjusted for ODYSSEY A and B.