Treatment optimisation with dolutegravir-based antiretroviral treatment for children and adolescents with HIV

As of 2024, an estimated 2.4 million children and adolescents were living with HIV. While new infections and AIDS-related mortality have declined, paediatric virological suppression still lags behind adults, partly due to delays in evaluating and rolling out optimised antiretroviral formulations. With improved survival, treatment optimisation increasingly focuses on ensuring long-term safety and tolerability while maintaining efficacy. Dolutegravir (DTG), a potent, well-tolerated and low-cost integrase inhibitor, has transformed adult HIV treatment, but paediatric evidence was limited when my doctoral research began. Using data from ODYSSEY, a phase II/III randomised controlled trial in 792 children across Africa, Europe and Thailand, I examined the safety of DTG-based ART, focusing on neuropsychiatric symptoms, weight gain and metabolic outcomes. A nested pharmacokinetic (PK) substudy, which I co-led, assessed the safety and efficacy of twice-daily DTG with rifampicin-based TB treatment. Neuropsychiatric events were infrequent; however, suicidal ideation was more commonly reported in the DTG arm. Reassuringly, most participants reported this once. There were no group differences in other mood symptoms or sleep outcomes. In the ≥14 kg cohort, weight gain was modestly higher with DTG versus SOC (mean difference 1.0 kg over 240 weeks), particularly in first-line participants, alongside greater increases in height and body circumferences but no excess in height-adjusted measures of overweight/obesity. No differences in weight gain were observed in the <14 kg cohort. Lipid profiles were more favourable with DTG and DTG was not associated with hyperglycaemia. The TB-PK substudy demonstrated that twice-daily DTG overcame rifampicin-related enzyme induction, achieving target exposures with no adverse events attributed to DTG and nearly all participants achieving virological suppression. Overall, the findings of my research supported continued DTG use in paediatric ART and informed clinical care and treatment guidelines. Building on this work, I designed and initiated the D3/Penta 21 trial, the first paediatric RCT evaluating DTG/lamivudine dual therapy for maintenance of virological suppression. This trial, ongoing at thesis submission, aims to generate evidence for the simplified regimen for children.