Authors: Violari A, Kekitiinwa A, White E, Mumbiro V, Rutebarika D, Dobbels E, Kataike H, Moloantoa T, Atwine L, Nazzinda R, Mbabazi R, Kanjanavanit S, Mosia N, Na-Rajsimax S, Techakunakorn P, Nakabuye S, Puthanakit T, Smit T, Kobbe R, Fortuny C, Chidziva E, Nansamba W, Kakayi B, Bbuye D, Sarfati T, Shakeshaft C, Coelho A, Saïdi Y, Lugemwa A, Klein N, Mujuru H, Bwakura- Dangarembizi M, Musiime V, Cotton M, Giaquinto C, Rojo P, Gibb D, Ford D, Turkova A
Published in: International workshop on HIV pediatrics 2021
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, ARTmodifying events and suicidality-related events, and patient/carer mood-and-sleep questionnaire responses in DTG versus SOC.
Results: 707 children ≥14kg were randomised (subSaharan 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) years; 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; hazard ratio for time to first NPAE (DTG vs SOC) was 1.87 (95%CI: 0.79, 4.41). 12 AEs were neurological: 6(6) in DTG vs 6(5) in SOC. 19 AEs were psychiatric: 12(10) in DTG vs 7(4) in SOC. Median(IQR) age and time from enrolment to 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 numbers 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 moodand-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.
Conclusion: 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.
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