Dolutegravir superior to standard-of-care in young children: results from the ODYSSEY trial
Polly Clayden, HIV i-Base
Dolutegravir (DTG)-based ART was superior to standard-of-care in children weighing 3 to 14 kg, starting first- or second-line treatment.
These 96 week results from the younger cohort of the ODYSSEY trial were presented at the 13th International Workshop on HIV Paediatrics 2021. 
ODYSSEY, a multi-country randomised trial, showed superior efficacy for DTG plus two NRTIs vs standard-of-care in 707 children and adolescents weighing 14 kg or more (median age 12 years), starting first- or second-line ART. These results were presented earlier this year at CROI 2021. 
Late breaking results, shown at the workshop, were for an additional cohort of 85 younger children weighing less than 14 kg, who completed 96 weeks follow-up on 28 June 2021.
The children were randomised: 42 to DTG and 43 to standard-of-care (Uganda 43, Zimbabwe 22, South Africa 20).
Their median age was 1.4 years (IQR 0.6 to 2.0); 23 were 3 to <6 kg, 40 were 6 to <10 kg and 22 were 10 to <14 kg. Seventy two children started first-line and 13 started second-line ART; 74% in the standard-of-care arm received boosted lopinavir.
Median follow-up was 120 (IQR 97 to 132) weeks; 5 (6%) children were lost to follow-up.
The investigators performed three analyses to estimate the difference in the probability of clinical/virological failure by 96 weeks between DTG-based ART and standard-of-care in children weighing <14 kg:
- Stand-alone analysis, using data only from children <14 kg.
- Pooled analysis, assuming the treatment difference is identical in children <14 kg and >14 kg, and combining the two data sets (they allocated a weight of approximately 90% to data from children >14 kg).
- Bayesian analysis, using information from the 707 children as a prior distribution and clinical opinion todetermine how much weight is given to the that (based on interviews with paediatricians they assigned a weight of 78% to data from the older children).
There were 11 children in the DTG arm with virological or clinical failure by 96 weeks (26%) vs 21 (49%) in standard-of-care; 8 (19%) vs 16 (37%) failures were virological. Of 6 deaths, 2 (5%) were in the DTG and 4 (9%) in the standard-of-care arms.
The investigators found that there was less probability of failing in the DTG vs standard-of-care arm, p=0.05.
For the difference in proportion with virological or clinical failure by 96 weeks <14 kg, the Bayesian analysis gave an 11% difference in favour of DTG: -0.106 (95% CI -0.192 to -0.020). The other analyses also favoured DTG vs standard-of-care: stand-alone -0.196 (95% CI -0.379 to -0.005) and pooled -0.094 (95% CI -0.146 to -0.038). Test of heterogeneity of treatment effect between >14kg and <14kg: p=0.24.
At 96 weeks, 76% of children in the DTG arm had viral load <50 copies/mL compared with 50% in standard-of-care, p=0.02. The corresponding proportions with cut-off <400 copies/mL were 91% vs. 71%, p=0.03.
At 48 weeks, these proportions were 44% and 49% for <50 copies/mL, p=0.69. And 74% vs 69% for <400 copies/mL, p=0.69.
There were a total of 34 serious adverse events: 15 (11 children) in the DTG arm vs 19 (11 children) in standard of care, p=0.92. This included the 2 vs 4 deaths. And 36 (19 children) had grade 3 and above adverse events in DTG vs 34 (21 children) in standard-of-care, p=0.79. There were 2 ART-modifying events in the standard-of-care arm: 1 raised liver enzymes and 1 vomiting.
At 96 weeks there was a significant difference in mean change in total cholesterol (mg/dL) from baseline in children <14 kg also favoring DTG: -26 (95% CI -42 to -9), p=0.003.
Presenting author, Pauline Amuge from Uganda, noted that these results support WHO guidelines and roll-out of DTG-based regimens for younger children starting first- or second-line ART and she added: “procurement of dispersible DTG for children <20 kg should be expedited”.
These results provide good evidence for rapid global rollout of DTG for children aged four weeks and above using the new dispersible 10 mg tablets. 
Following this ODYSSEY late breaker, WHO released a statement.  This applauded the results and emphasised the grim reality that children living with HIV still continue to be left behind by the global HIV response.
In 2020, only 54% of the 1.7 million children living with HIV received ART compared to 74% of adults. Among WHO focus countries, only 40% of children (or 74% of children receiving ART) achieved viral suppression.
WHO has recommended DTG-based ART for all infants and children since 2018 and provided dosing recommendations for those over four weeks old and weighing more than 3 kg in July 2020.
New WHO 2021 consolidated guidelines on HIV  and the newly released policy brief on transitioning to the 2021 optimal formulary for antiretroviral drugs for children  give further guidance on how to transition to DTG-containing regimens as well as how to best dose it when co-treatment for TB is needed.
Two generic formulations of DTG 10 mg dispersible tablets have been tentatively approved by the US FDA.  The cost for children in low- and middle-income countries where these are available is $4.50 for a 90-tablet bottle.
- Amuge P et al Dolutegravir-based ART is superior to standard of care in young children living with HIV. 13th International Workshop on HIV Paediatrics 2021(virtual workshop).16–17 July 2021. Late breaker oral abstract 124.
- Clayden P. Dolutegravir superior to standard of care in children and adolescents: results from the ODYSSEY trial. 1 June 2021.
- Clayden P. New formulation of dolutegravir will make modern ART available for babies and young children at less than $120 a year. 9 December 2020.
- WHO statement. New findings from the ODYSSEY trial confirm superiority of dolutegravir-based ART in young children. 16 July 2021.
- WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 16 July 2021.
- WHO. Transitioning to the 2021 optimal formulary for antiretroviral drugs for children: implementation considerations.16 July 2021.
This report was first posted on 17 July 2021.