Publications

12

Aug, 2021

Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2

 

Authors: E Molteni, CH Sudre, LS Canas, SS Bhopal, RC Hughes, M Antonelli, B Murray, K Kläser, E Kerfoot, L Chen, J Deng, C Hu, Somesh Selvachandran, Kenneth Read, Joan Capdevila Pujol, Prof Alexander Hammers, Prof Tim D Spector, Prof Sebastien Ourselin, Claire J Steves, Marc Modat, Michael Absoud, Prof Emma L Duncan

Published in: The Lancet

 

Abstract 

Background In children, SARS-CoV-2 infection is usually asymptomatic or causes a mild illness of short duration. Persistent illness has been reported; however, its prevalence and characteristics are unclear. We aimed to determine illness duration and characteristics in symptomatic UK school-aged children tested for SARS-CoV-2 using data from the COVID Symptom Study, one of the largest UK citizen participatory epidemiological studies to date.

Methods In this prospective cohort study, data from UK school-aged children (age 5–17 years) were reported by an adult proxy. Participants were voluntary, and used a mobile application (app) launched jointly by Zoe Limited and King’s College London. Illness duration and symptom prevalence, duration, and burden were analysed for children testing positive for SARS-CoV-2 for whom illness duration could be determined, and were assessed overall and for younger (age 5–11 years) and older (age 12–17 years) groups. Children with longer than 1 week between symptomatic reports on the app were excluded from analysis. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed.

Findings 258 790 children aged 5–17 years were reported by an adult proxy between March 24, 2020, and Feb 22, 2021, of whom 75 529 had valid test results for SARS-CoV-2. 1734 children (588 younger and 1146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study timeframe (illness onset between Sept 1, 2021, and Jan 24, 2021). The most common symptoms were headache (1079 [62·2%] of 1734 children), and fatigue (954 [55·0%] of 1734 children). Median illness duration was 6 days (IQR 3–11) versus 3 days (2–7) in children testing negative, and was positively associated with age (Spearman’s rank-order rs 0·19, p<0·0001). Median illness duration was longer for older children (7 days, IQR 3–12) than younger children (5 days, 2–9). 77 (4·4%) of 1734 children had illness duration of at least 28 days, more commonly in older than younger children (59 [5·1%] of 1146 older children vs 18 [3·1%] of 588 younger children; p=0·046). The commonest symptoms experienced by these children during the first 4 weeks of illness were fatigue (65 [84·4%] of 77), headache (60 [77·9%] of 77), and anosmia (60 [77·9%] of 77); however, after day 28 the symptom burden was low (median 2 symptoms, IQR 1–4) compared with the first week of illness (median 6 symptoms, 4–8). Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2.

Interpretation Although COVID-19 in children is usually of short duration with low symptom burden, some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.

 

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9

Aug, 2021

Risk of infection and transmission of SARSCoV-2 among children and adolescents in households, communities and educational settings: A systematic review and meta-analysis

 

Authors: O Irfan, J Li, K Tang, Z Wang, ZA Bhuta

Published in: Journal of global health

 

Abstract

Background There is uncertainty with respect to SARS-CoV-2 transmission in children (0-19 years) with controversy on effectiveness of school-closures in controlling the pandemic. It is of equal importance to evaluate the risk of transmission in children who are often asymptomatic or mildly symptomatic carriers that may incidentally transmit SARS-CoV-2 in different settings. We conducted this review to assess transmission and risks for SARS-CoV-2 in children (by age groups or grades) in community and educational-settings compared to adults.

Methods Data for the review were retrieved from PubMed, EMBASE, Cochrane Library, WHO COVID-19 Database, China National Knowledge Infrastructure (CNKI) Database, WanFang Database, Latin American and Caribbean Health Sciences Literature (LILACS), Google Scholar, and preprints from medRixv and bioRixv) covering a timeline from December 1, 2019 to April 1, 2021. Population-screening, contact-tracing and cohort studies reporting prevalence and transmission of SARS-CoV-2 in children were included. Data were extracted according to PRISMA guidelines. Meta-analyses were performed using Review Manager 5.3.

Results Ninety studies were included. Compared to adults, children showed comparable national (risk ratio (RR)=0.87, 95% confidence interval (CI)=0.71-1.060 and subnational (RR=0.81, 95% CI=0.66-1.01) prevalence in population-screening studies, and lower odds of infection in community/household contact-tracing studies (odds ratio (OR) =0.62, 95% CI=0.46-0.84). On disaggregation, adolescents observed comparable risk (OR=1.22, 95% CI=0.74-2.04) with adults. In educational-settings, children attending daycare/preschools (OR=0.53, 95% CI=0.38-0.72) were observed to be at lower-risk when compared to adults, with odds of infection among primary (OR=0.85, 95% CI=0.55-1.31) and high-schoolers (OR=1.30, 95% CI=0.71-2.38) comparable to adults. Overall, children and adolescents had lower odds of infection in educational-settings compared to community and household clusters.

Conclusions Children (<10 years) showed lower susceptibility to COVID-19 compared to adults, whereas adolescents in communities and high-schoolers had comparable risk. Risks of infection among children in educational-settings was lower than in communities. Evidence from school-based studies demonstrate it is largely safe for children (<10 years) to be at schools, however older children (10-19 years) might facilitate transmission. Despite this evidence, studies focusing on the effectiveness of mitigation measures in educational settings are urgently needed to support both public health and educational policy-making for school reopening.

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6

Aug, 2021

Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection

 

Authors: D Buonsenso, DD Giuda, L Sigfrid, DA Pizzuto, GD Sante, CD Rose, I Lazzareschi, M Sali, F Baldi, DPR Chieffo, D Munblit, P Valentini

Published in: The Lancet

 

Introduction

Although more patients are surviving COVID-19, there are emerging data on a substantial proportion of patients with persisting, and often debilitating, symptoms and sequelae for months following acute COVID-19. This scenario is commonly referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or long COVID. Some of the most commonly reported symptoms are fatigue, weakness, breathlessness, chest pain, and concentration impairment. Several independent studies have shown the existence of PASC, with chronic inflammation and chronic endothelial disease suggested among the possible pathophysiological mechanisms of this multifaceted condition. Although the course of acute SARS-CoV-2 infection in children is normally milder and can present with less typical symptoms compared with adults, emerging evidence from Sweden, Italy, the UK, and Russia suggests that children can also have persisting symptoms more than 3 months after acute COVID-19, with a similar pattern of symptoms as reported by adults. In light of an increasing number of parents and clinicians asking for guidance and support for children with PASC in our centre, we have set up a post-COVID Paediatric Unit. Children with a microbiologically confirmed diagnosis of COVID-19 are assessed in our post-COVID Paediatric Unit at least 5 weeks after the onset of acute infection (see the appendix for our post-COVID paediatric follow-up protocol).

 

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5

Aug, 2021

COVID-19 vaccines for children in LMICs: another equity issue

 

Authors: B Kampmann U Okomo

Published in: The Lancet

 

Introduction

Given the success of COVID-19 vaccines in preventing death and severe disease in adults  and their impact on community transmission, use in children and young people (CYP) inevitably requires consideration. Although severe COVID-19 is rare in CYP, they are affected by SARS-CoV-2 infection and the impacts of the COVID-19 pandemic, including education, mental health, and general wellbeing.
As of late July, 2021, no COVID-19 vaccine is recommended for children younger than 12 years and safety and efficacy data from phase 3 clinical trials are so far limited: 1131 CYP aged 12–15 years received the Pfizer–BioNTech mRNA vaccine and safety data are available from phase 1 and 2 trials of Sinovac’s inactivated CoronaVac vaccine in 438 children aged 3–17 years.
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2

Aug, 2021

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe—results from the PED-MERMAIDS multicentre case–control study

 

Authors: MK Vasconcelos, K Loens, L Sigfrid, E Iosifidis, C Epalza, D Donà, V Matheeussen, S Papachristou, E Roilides, M Gijon, P Rojo, C Minotti, L Da Dalt, S Islam, J Jarvis, A Syggelou, M Tsolia, MN Nyang’wa, S Keers, H Renk, AL Gemmel, C D’Amore, MC degli Atti, CRT Sánchez, F Martinón-Torres, S Burokienė, T Goetghebuer, V Spoulou, A Riordan, C Calvo, D Gkentzi, M Hufnagel, PJ Openshaw, MD de Jong, M Koopmans, H Goossens, M Ieven, PLA Fraaij, CGiaquinto, JA Bielicki, P Horby, M Sharland

Published in: BMJ Journals

 

Abstract

Background Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation.

Methods 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets.

Results RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses.

Conclusion RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.

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29

Jul, 2021

No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial

 

Authors: T.G Jacobs, A. Colbers, H. Waalewijn, P. Amuge, D. Bbuye, E. Kaudha, A. Nanduudu, S. Makumbi, L. Atwine, S. Mudzingwa, K. Nathoo, J. Hakim, A. Liberty, A.J. Van Rensburg, M. Archary, D.M Gibb, D. Ford, A. Turkova, D.M Burger, ODYSSEY trial team

Published in: IAS 2021

 

Abstract

Background: ODYSSEY and IMPAACT-P1093 found lower and more variable dolutegravir (DTG) exposure in children compared to adults based on mg/kg dose. Investigating the main metabolic pathway (UGT1A1) for DTG could help to explain these findings. Estimates of DTG glucuronide/DTG molar metabolic ratio (DTG-MR) are 0.05-0.08 in adults but this has not been studied in children.

Methods: A subset of children was selected from PK substudies within the ODYSSEY trial, including all children aged <2 years and a random sample of older children receiving DTG film-coated tablets (FCT; >=20kg) or dispersible tablets (DT; 3-<25kg). DTG and DTG-glucuronide concentrations were measured with a validated UPLC-MS/MS assay and geometric mean (GM) DTG-MR was determined using 3 plasma samples per PK curve (t=2, 6 and 24h).   We assessed correlation between DTG-MR and DTG clearance in children, as clearance adjusted for formulation is independent of DTG dose, and it is associated with DTG exposure. Pearson’s correlation coefficient was used on log-transformed data to assess the relationships between DTG-MR and DTG clearance/kg (corrected for higher bioavailability of DT), and DTG-MR and age (not logtransformed).

Results: In total, 37 children (age 3 months – 18 years) were included in this study. There was positive relationship between DTG-MR and DTG clearance/kg in children (r(37)=0.64, p<.001) (Figure). No association was found between DTG-MR and age (r(37)=-0.12, p=0.50). GM(CV%) DTG-MR in children was 0.051(66%), in line with adult values.

Conclusions: Intersubject variability in DTG-MR was high in children and as the ratio correlates with clearance, this may explain high variability of DTG exposure between children. DTG-MR was similar to adult values and did not change with age, hence increased glucuronidation does not appear to explain the relatively low DTG exposure observed in children aged >3 months. Further studies are needed to assess the role other factors contributing to differences in DTG exposure in children.

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29

Jul, 2021

Effect of dolutegravir on folate and vitamin B12 status among HIV- infected children and adolescents in the ODYSSEY trial

 

Authors: L. Barlow-Mosha, G. Ahimbisibwe, E. Chappell, P.M. Amuge, A. Nanduudu, E. Kaudha, T. Amukele, D. Balamusani, B. Kafufu, A. Nimwesiga, C. Kityo, A.R Kekitiinwa, R. Namwanje, G. Kasangaki, A. Mulindwa, G.A. Muzorah, D. Bbuye, M. Nolan, C. Giaquinto, D.M Gibb, D. Ford, P. Musoke, A. Turkova, The ODYSSEY Trial Team

Published in: International workshop on HIV pediatrics 2021

 

Abstract

Background: Neural tube defects (NTDs) are known to be associated with maternal folate and vitamin B12 deficiency, and initial surveillance studies suggested an increased risk of NTDs among infants conceived by women taking dolutegravir (DTG). We, therefore, compared folate and vitamin B12 levels among HIV-infected children aged 6-<18 years starting first- or second-line DTG-based antiretroviral treatment (ART) versus Standard of Care (SOC) at 3 Ugandan sites in the ODYSSEY trial.

Methods: Plasma folate was measured on stored samples at baseline and 4 weeks. Red blood cell (RBC) folate and vitamin B12 levels were measured using samples collected prospectively at ≥96 weeks. Samples were analysed in one laboratory using Elecys assays. Normal regression was used to compare change in plasma folate from baseline to 4 weeks (adjusted for baseline) and cross-sectional RBC folate and vitamin B12 between randomised arms, adjusting for site, sample date, first-/ second-line ART and randomisation stratification factors

Results: 229 children ≥6 years were randomised; 51% female, median(IQR) age was 12.3 years (9.0,14.7), CD4  501cells/mm3  (228,795); 67% started second-line ART; 114 started DTG, 115 started SOC (40% lopinavir/ritonavir-, 37% efavarinez-, 23% atazanavir/ritonavir-based ART). By 4 weeks, mean plasma folate was higher in DTG arm versus SOC (difference (DTG-SOC) 1.6 ng/mL; 95%CI 0.8, 2.3; p<0.01). At week ≥96, mean RBC folate was higher in the DTG arm vs SOC (difference 73 ng/mL; 95%CI 3, 143; p=0.04). Plasma and RBC folate levels varied by site, but there was no evidence for heterogeneity of treatment effects (Table). Vitamin B12 levels were similar between arms (p=0.42). 

Conclusions: We found no evidence that DTG-based ART was associated with decreased levels of plasma folate or RBC folate; levels were higher than on NNRTI-/PI-based ART though the mechanism is unclear. Vitamin B12 levels were similar in both arms. These results suggest any increased risk of NTDs in infants conceived on DTG is unlikely to be due to DTG causing decreased folate and vitamin B12 levels.   

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29

Jul, 2021

Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir-based ART vs. standard-of-care in the ODYSSEY trial

 

Authors: E White, A Turkova, HA Mujuru, I Nankya, B Wynne, S Ali, A Kekitiinwa, A Lugemwa, E Kaudha, A Liberty, H Cassim, M Archary, M Cotton, L Barlow-Mosha, TR Cressey, C Ngampiyasakul, U Srirompotong, O Behuhuma, Y Saidi, A Bamford, R Kobbe, P Rojo, C Giaquinto, DM Gibb, D Ford on behalf of the ODYSSEY trial team

Published in: International Workshop on HIV pediatrics

 

Abstract

Background: ODYSSEY, a multi-country randomised trial, demonstrated superior treatment efficacy for dolutegravir (DTG) plus two NRTIs versus standard-ofcare (SOC) in children ≥14kg (median age 12 years [range:3-18]) starting first- and second-line ART. We describe virological and drug resistance outcomes by 96 weeks.

Methods: Virological failure (VF) was defined as confirmed viral load (VL)≥400c/mL after week 36 or lack of virological response by week 24 with ART switch. Participants with VF were retrospectively tested for post-failure resistance up to week 96, using the latest sample with VL≥1000c/mL after failure and prior to treatment change; the corresponding baseline sample was sequenced if ≥1 major IAS mutation was identified

Results: 311 children started first-line ART (154 DTG, 157 SOC [92% efavirenz]) and 396 started second-line (196 DTG, 200 SOC [72% lopinavir/r, 25% atazanavir/r]). NRTI backbones were ABC/3TC (80% first-line, 54% second-line), TDF/XTC (19%, 26%), ZDV/3TC (1%, 19%), and ABC/TDF (0%, 0.8%). On firstline, 11(7%) DTG vs. 30(19%) SOC experienced VF by 96 weeks, and on second-line, 31(16%) DTG vs. 40(20%) SOC. Samples were tested for all 112 failures: median time from VF to resistance test was 24[IQR:12-47] weeks. 47(42%) had post-failure resistance test at week 96, 60(54%) were tested earlier (16 due to treatment change, 44 no later sample available with VL≥1000c/mL or later sample failed to amplify); the remaining 5(4%) failed to amplify on all samples. On first-line, post-failure resistance tests were available as follows: reverse transcriptase (RT)/protease (PR) (11 DTG, 29 SOC), integrase (IN) (10 DTG); on second-line: RT/PR (28 DTG, 39 SOC), IN (22 DTG). First line ART: No participants on first-line DTG had a major IAS drug resistance mutation post-failure (0/11 NRTI/NNRTI/PI; 0/10 INSTI). On SOC, 18/29(62%) participants had NRTI resistance post-failure (DTG vs. SOC p<0.001), 27/29(93%) NNRTI resistance (p<0.001) and 0/29 PI resistance. Of 13 with NRTI resistance post-failure and a baseline resistance test, all developed at least one new NRTI mutation; 18/19(95%) developed new NNRTI resistance. Second line ART: 20/28(71%) DTG vs. 28/39(72%) SOC had at least one NRTI mutation post-failure; 21/28(75%) vs. 35/39(90%) had NNRTI resistance; and 2/28(7%) vs. 2/39(5%) had PI resistance. Among DTG vs. SOC participants with a major resistance mutation post-failure and baseline result, 0/16 DTG vs. 3/23 SOC (p=0.26) developed new NRTI resistance, 0/18 vs. 3/26 (p=0.26) new NNRTI resistance and 1/2 vs. 1/1 new PI resistance. On DTG, 4/22(18%) on second-line developed INSTI resistance (2 Q148R/K, 1 G118R, 1 G118R+R263K); 3/4 were on ZDV/3TC.

Conclusion: ODYSSEY demonstrated that DTG has a high genetic resistance barrier in children, preventing emergent resistance to NRTIs. We identified no postfailure resistance to any drug class amongst children initiating first-line DTG, significantly less than first-line SOC. Among those on second-line DTG, there was no new NRTI resistance, however 4 children developed new INSTI resistance. These results support using DTG-containing regimens for children starting firstline or second-line ART, but ongoing adherence support is required for children on second-line.

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29

Jul, 2021

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

 

Authors: A Turkova, A Kekitiinwa, E White, V Mumbiro, E Khauda, A Liberty, E Dobbels, GM Ahimbisibwe, T Moloantoa, L Atwine, S Kanjanavanit, NR Mosia, T Puthanakit, T Smit, R Kobbe, C Fortuny, E Chidziva, RC Kyambadde, D Bbuye, T Sarfati, A Coelho, Y Saïdi, A Lugemwa, N Klein, M Bwakura-Dangarembizi, C Kityo, M Cotton, C Giaquinto, P Rojo, DM Gibb, D Ford, the ODYSSEY trial team

Published in: IAS 2021

 

Abstract

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% efavirenzbased 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.

 

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29

Jul, 2021

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

 

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

 

Abstract

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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