Substudies from the ODYSSEY trial: results July 2021
Polly Clayden, HIV i-Base
Findings from several sub studies of the ODYSSEY trial – presented at the 13th International Workshop on HIV Paediatrics 2021 and 11th IAS Conference on HIV Science – provided valuable insights into a number of issues previously observed with adult ART.
ODYSSEY is a multi-country randomised trial, that demonstrated superior treatment efficacy for dolutegravir (DTG) plus two NRTIs vs standard-of-care in children weighing at least 14 kg starting first- and second-line ART.
Week 96 results from the main trial were presented earlier this year at CROI. 
The trial also included a cohort ofyoungerchildrenwho were evaluated separately. Late breaking results for these additional 85 children, weighing less than 14 kg, who completed 96 weeks follow-up on 28 June 2021, were also shown at the paediatric workshop. [2, 3]
ODYSSEY included a number of sub studies. As well as generating pharmacokinetic (PK) data, which contributed data for DTG’s approval, several of these took the opportunity to look at phenomena previously seen in adults. The following results were presented:
- The first randomised data in children and adolescents looking at weight gain with DTG-based ART, which was not associated with excessive weight gain in this population. [4, 5]
- The first randomised data in children and adolescents looking at DTG-associated with neuropsychiatric adverse events, which were infrequent. [6, 7]
- An evaluation of resistance that found DTG to have a high genetic resistance barrier in children and adolescents. [8, 9]
- An evaluation of folate that found no evidence that DTG-based ART was associated with decreased levels of plasma folate or red blood cells (RBC) folate. 
- PK data in children for paediatric formulations of DTG.
- Data on DTG glucuronide/DTG molar metabolic ratio (DTG-MR) and DTG clearance/kg in children and adolescents – also not previously studied in this population.
Main study summary and baseline characteristics
- DTG + 2NRTIs vs standard-of-care in children and adolescents starting first- or second-line ART.
- 707 children and adolescents randomised: 88% sub-Saharan Africa, 9% Thailand, 4% Europe.
- 311 started first-line (92% efavirenz [EFV]-based in standard-of-care); 396 second-line (72% lopinavir/ritonavir [LPV/r], 25% atazanavir/ritonavir [ATV/r] in standard-of-care).
- 65% started abacavir (ABC)/lamivudine (3TC), 23% tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or 3TC, 11% zidovudine (AZT)/3TC.
- At baseline, median age was 12.2 years (IQR 9.1 to 14.9; range 2.9 to18.0).
- 49% were girls.
- Median follow-up 142 weeks (IQR 124 to 159).
DTG-based ART was not associated with excessive weight gain in children and adolescents in ODYSSEY. But children grew better after starting DTG. Few participants became newly overweight or obese in either arm.
There were small differences between arms in weight, height and BMI that stabilised before two years, with few participants becoming newly overweight/obese in each arm. Differences between arms were similar by first- or second-line, sex, age and NRTI backbone.
This study compared weight, height and BMI-for-age Z-scores (BAZ) between treatment arms and described proportions becoming newly overweight (BAZ >1 to <2) or newly obese (BAZ >2).
At baseline, median weight 31 kg (IQR 24 to 43, range 14 to 85), height 138 cm (IQR 125 to 153, range 89 to 182), BMI 16.3 kg/m2 (IQR 14.9 to 18.5, range 9.8 to 34.5) and BAZ -0.6 (IQR -1.4 to 0.0, range -7.8 to 2.8).
And, 11% of participants had WHO-defined severe thinness/thinness, 5% were overweight and 1% obese.
Weight change from baseline was slightly more with DTG than standard-of care at week 96: 1 kg (95% CI 0.3 to 1.7), p=0.004. As was height change: 0.8 cm (95% CI 0.2 to 1.4), p=0.007.
Similar differences were reported with BMI and BAZ: 0.3 (95% CI 0.0 to 0.6), p=0.03 and 0.12 (95% CI -0.01 to 0.24), p=0.06, respectively.
These early differences between groups stabilised. At 96 weeks there were no differences in BAZ by sex, baseline age group or TDF at baseline.
Overall, 25 (4%) participants were newly overweight or obese at 96 weeks: 14 (4%) DTG and 9 (3%) in standard-of care, p=0.55.
Those that did become newly overweight or obese were a median age at enrolment of 13 years (IQR 10.3 to 15.4); 5% were on first-line and 3% second-line ART; 4% were girls vs 3% boys and 6% were on TDF vs 3% not on TDF.
Neuropsychiatric adverse events
Neuropsychiatric adverse events and participant-reported neuropsychiatric symptoms were infrequent.
There were no difference in the reported low mood or anxiety symptoms nor in sleep problems by trial arm.
Although there were more psychiatric events in the DTG arm, the numbers were small and the difference between trial arms was not significant.
More participants reported self-harm or suicidality ideation on mood questionnaires in the DTG arm but the investigators suggested: “This difference should be interpreted with caution in an open-label trial”.
This study compared neuropsychiatric adverse events, including serious adverse events grade 3 and above events, ART-modifying events and suicidality-related events, as well as participant/carer mood-and-sleep questionnaire responses between the two treatment groups.
Overall, there were 31 neuropsychiatric adverse events(in 23/707; 3% participants): 18 (15) in DTG vs 13 (8) in standard-of-care, p=0.125. Hazard ratio (HR) for time to first neuropsychiatric adverse event: 0.154 (95% CI 0.79 to 4.41). Of these events, 16/362 (4%) were in boys vs 7/345 (2%) in girls; 16/311 (5%) on first-line vs 7/396 (2%) on second-line.
Median age at first event was 15.9 years (IQR 10.4 to 17.5). Median time (IQR) from enrolment at first event was 72 weeks (IQR 47 to 124) weeks.
There were 12 neurological adverse events (in 11 participants): 6 (6) in DTG vs 6 (5) in standard of care, p=0.736. The most common were epilepsy/convulsions with 4 (4) events reported in each arm. There were 4 serious adverse events in 3 participants in each arm. None in the DTG and 1 in the standard of care arm required ART modification. HR for time to first event DTG vs standard of care was 1.18 (95% CI 0.36 to 3.87), p=0.784.
There were 19 psychiatric adverse events: 12 (10) in DTG vs 7(4) in standard of care, p=0.097. Suicidal ideation/behaviour was most common, with 8 (8) and 7 (4) events in the respective arms. There were 3 (2) vs 2 (1) serious adverse events. And 2 (1) vs 1 (1) ART-modifying events. HR for time to first event 2.48 (95% CI 0.78 to 7.90), p=0.125. Of note, 2 events in the DTG arm (depression and insomnia) occurred months after switching treatment.
The investigators noted that although DTG doses increased during the study – following PK substudies and subsequently approved by FDA and EMA – most neuropsychiatric adverse events occurred on the initial lower doses.
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.
In the mood-and-sleep questionnaires, small numbers of participants/carers reported symptoms of: self-harm (8 DTG vs 1 standard of care, p=0.038), “life was not worth living” (17 DTG vs 5 standard of care, p=0.009) or suicidal thoughts (13 DTG vs 0 standard of care, p<0.001). These symptoms were transient, rarely occurred more than once and did not lead to treatment modification.
Overall, the results on neuropsychiatric manifestations from ODYSSEY are reassuring but the investigators noted that clinicians should be aware of suicidality ideation among adolescents and screen appropriately.
The study found DTG to have a high genetic resistance barrier in children, preventing emergent resistance to NRTIs.
There was no post-failure resistance to any drug class in children starting first-line DTG – this was significantly less than for those on standard-of-care.
There was no new NRTI resistance in children on second-line DTG, but 4 developed new INSTI resistance (4 were on AZT).
Participants reaching virological failure by 96 weeks were included in the resistance analysis. Thiswas defined as confirmed viral load >400 copies/mL after week 36 or lack of virological response by week 24 and ART switch.
Those with virological failure were retrospectively tested for post-failure resistance up to week 96. The latest sample with viral load >1000 copies/mL after failure and before treatment change was used. Earlier samples, including baseline, were sequenced if one or more major IAS mutation was identified post-failure.
Among participants on first-line, 11 (7%) DTG vs 30 (19%) standard-of-care experienced viral failure by 96 weeks, and on second-line, 31(16%) DTG vs 40 (20%) standard-of-care.
The estimated proportion with emergent resistance was none on first-line DTG vs 20 major IAS drug resistance mutations post-failure in standard of care: 13 NRTI, 18 NNRTI. On first-line standard-of-care 62% of participants with virological failure had new NRTI resistance and 88% had new NNRTI resistance.
On second-line DTG, 4 participants had a major mutation (INSTI) vs 5 on standard of care: 3 NRTI, 2 NNRTI, 1 PI. There was no new resistance to NRTI on DTG vs 3 (10%) in standard-of care.
Of those exposed to PIs in standard-of-care, only 3% with virological failure developed PI resistance.
Both participants with virological failure on NNRTI-based second-line standard-of-care had emergent NNRTI resistance.
The investigators reported a variety of emergent mutations to NRTI and NNRTI among participants on first-line standard-of-care – M184 was most common NRTI mutation and K103 was most common NNRTI mutation.
There were 2 emergent PI mutations in one participant on second-line standard of care. The 4 children on second-line DTG had 3 different emergent INSTI mutations.
Post virological failure, participants on first-line DTG remained susceptible to most NRTI backbones. Those on first-line standard-of care and both second-line treatment groups had higher levels of resistance, particularly to ABC and 3TC (or FTC).
The cumulative probability of re-suppression/switch by 72 weeks after failure in the DTG vs standard of care arms respectively: 0.58 (95% CI 0.40 to 0.73) vs 0.42 (95% CI 0.28 to 0.55), p=0.047.
The investigators explained that these results support using DTG-containing regimens for children starting first-line or second-line ART, but ongoing adherence support is required for children on second-line.
There was no evidence that DTG-based ART was associated with decreased levels of plasma folate or red blood cells (RBC) folate in ODYSSEY.
Plasma folate levels at four weeks and RBC folate levels at week 96 and later were higher than on standard-of-care. But the investigators noted that the mechanism is unclear. Vitamin B12 levels were similar in both arms.
This study compared folate and vitamin B12 levels among participants at three Ugandan sites in the trial.
Plasma folate was measured on stored samples at baseline and 4 weeks. RBC folate and vitamin B12 levels were measured using samples collected prospectively at 96 weeks or more.
A total of 229 children were randomised: 51% female, at baseline and median age was 12.3 years (IQR 9.0 to 14.7).
Seventy-five (33%) started first-line (100% EFV in standard-of-care) and 154 second-line (99% PI in standard-of-care)
The mean change in plasma folate from baseline (mean 6.1 ng/mL) to week 4 was 0.4 ng/mL (SE 0.3) in the DTG arm (n=110) vs -1.1 ng/mL (SE 0.3) in the standard-of-care arm (n=107). Difference DTG/standard-of-care: 1.6 ng/mL (95% CI 0.8 to 2.4), p<0.01.
At week 96, mean RBC folate was 887 pg/mL (SE 29) in the DTG-arm (n=109) vs 855 pg/mL (SE 28) in the standard-of-care arm (n=105). Difference: 73 ng/mL (95% CI 3 to 143) p=0.04.
At week 96, vitamin B12 levels were similar: 478 pg/mL (SE 21) in the DTG arm and 504 pg/mL (SE 26) in standard-of-care, p=0.42.
The 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.
PK data were also shown on paediatric formulations of DTG.
DTG formulations for children include film-coated tablets (FCTs) of different strengths and dispersible tablets (DTs). A previous bioequivalence study in healthy adults showed a 1.6-fold higher area under the curve (AUC) with DTs compared to FCTs.
Similarly in children, DTG exposure for those receiving DTs was 1.76 times higher compared to FCTs of the same dose: 30 mg DTs gave equivalent exposure to 50mg FCTs.
The investigators compared DTG PK parameters between DTs and FCTs in children weighing 14 to <25kg.
There were 64 PK curves available: in 14 to <20 kg weight-band 19 children had 25 mg FCT and 13 children 25 mg DT; in 20 to <25 kg 14 children had 25 mg FCT, 9 children 50mg FCT and 9 children 30 mg DT.
Paired data were available for 11 children. DTG C24h was lower than in adults (0.83 mg/L) for children receiving 25 mg FCT: geometric mean C24h (CV%) was 0.44 mg/L (50%) in weight-band 14 to <20 kg and 0.32 mg/L (94%) in 20 to <25 kg.
DTG C24h was similar to adults for 25 mg DT in weight-band 14 to <20 kg and 50 mg FCT and 30 mg DT in weight-band 20 to <25kg: 0.85 mg/L (67%), 0.75 mg/L (44%) and 0.76 (73%) respectively.
GMR (90%CI) for DTG AUC0-24 25 mg DT vs 25 mg FCT was 1.76 (1.46 to 2.12) for children 14 to <20 kg. GMR (90%CI) for DTG AUC0-24 30 mg DT vs 50 mg FCT was 1.12 (0.86-1.46) for children 20 to <25kg.
There was positive relationship between DTG-MR and DTG clearance/kg in children in the trial. And there was no association between DTG-MR and age. DTG-MR in children was in line with adult values.
ODYSSEY (and IMPAACT-P1093) found lower and more variable DTG exposure in children compared to adults based on mg/kg dose. Estimates of DTG-MR are 0.05–0.08 in adults but this has not previously been studied in children.
A subset of children was selected from PK substudies within the trial, including all children less than 2 years of age and a random sample of older children receiving DTG FCT or DT. A total of 37 children (3 months to18 years of age) were included.
This evaluation found a positive relationship between DTG-MR and DTG clearance/kg in children: r(37)=0.64, p<0.001. And no association between DTG-MR and age: r(37)=-0.12, p=0.50. GM(CV%) DTG-MR in children was 0.051(66%), similar to adult values.
All references are to the programmes and abstracts of the 13th International Workshop on HIV Paediatrics 2021(virtual workshop),16–17 July 2021 and 11th IAS Conference on HIV Science, 18–21 July 2021 (virtual conference), unless otherwise specified.
- Clayden P. Dolutegravir superior to standard of care in children and adolescents: results from the ODYSSEY trial. HTB. 1 June 2021.
- Amuge P et al Dolutegravir-based ART is superior to standard of care in young children living with HIV. HIV Paediatrics 2021. Late breaker oral abstract 124.
- Clayden P. Dolutegravir superior to standard-of-care in young children: results from the ODYSSEY trial. HTB. 1 August 2021.
- Mujuru H et al.Weight gain in children and adolescents on dolutegravir vs standard-of-care in the ODYSSEY trial. HIV Paediatrics 2021. Oral abstract 7.
- Turkova A et al. Weight gain in children and adolescents on dolutegravir vs standard of care in the ODYSSEY trial. IAS 2021. Poster abstract PEB202.
- Turkova A et al. Neuropsychiatric manifestations and sleep disturbances in children and adolescents randomised to dolutegravir-based ART vs standard-of-care in the ODYSSEY trial. IAS 2021. Oral abstract OAB0505.
- Violari A et al. Neuropsychiatric manifestations and sleep disturbances in children and adolescents randomised to dolutegravir- based ART vs standard-of-care in the ODYSSEY trial. HIV Paediatrics 2021. Poster abstract 66.
- Kityo C et al. Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir- based ART vs standard-of-care in the ODYSSEY trial. HIV Paediatrics 2021. Oral abstract 10.
- Kityo C et al. Virological failures and genotypic resistance in children and adolescents randomised to dolutegravir-based ART vs. standard-of-care in the ODYSSEY trial. IAS 2021. PEBLB17.
- Barlow-Mosha L et al. Effect of dolutegravir on folate and vitamin B12 status among HIV-infected children and adolescents in the ODYSSEY trial. HIV Paediatrics 2021. Poster abstract 65.
- Waalewijn H et al.Exposure to two dolutegravir formulations in children in the ODYSSEY trial. HIV Paediatrics 2021. Poster abstract 60.
- Jacobs TG et al. No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial. IAS 2021. Poster abstract PEB194.
This article was first published on 30 August 2021.