Therapeutic drug monitoring of dolutegravir in children and adolescents living with HIV: A retrospective study

3 Background: Dolutegravir (DTG)-based antiretroviral regimens are recommended as first-line and salvage therapy for HIV in all populations. Achieving therapeutic DTG plasma concentrations in paediatric patients, however, may be challenging due to interindividual variability and adherence challenges. The utility of therapeutic drug monitoring (TDM), particularly in paediatrics, remains understudied. This study aimed to describe the use and usefulness of DTG TDM in paediatric patients. Materials and methods: TDM data were collected retrospectively from the Québec Antiretroviral Therapeutic Drug Monitoring Program between 1 January 2011 and 31 March 2022. Inclusion criteria were subjects under 18 years old with at least one DTG TDM. We excluded subjects if all their samples' time post-dose were unknown or in the first half of the dosing interval. For samples not drawn exactly at the end of the dosing interval, trough concentrations (Ctau) were estimated with mean population half-lives for specific age or weight groups. The efficacy and toxicity Ctau thresholds were ≥0.32 and ≥1.47 mg/L, respectively. Viral suppression was defined as a viral load <50 copies/mL. Interindividual and intra-individual coefficients of variation (CV) were calculated. An independent t-test was used to compare mean Ctau in subjects with and without viral suppression. Results: Fifty-three subjects (55% female) contributed 249 DTG samples (mean (SD) 8.6 (4.5) samples per subject). At the time of first DTG TDM, the mean (SD) age and weight were 11.1 (4.2) years and 43.6 (18.8) kg, respectively, and 86% of subjects had viral suppression. TDM was prescribed for the indication 'paediatrics' or 'control' in 90.8% of cases. The mean (SD) Ctau was 2.07 (1.65) mg/L, with 21% Ctau results being therapeutic, 4.8% subtherapeutic and 55% supratherapeutic (19% were unknown due to missing or absorption-phase time post-dose). Pharmacists recommended DTG intake without food in 17.3% of TDM reports and recommended a dose decrease if the presence of bothersome central nervous system side effects in 45.8% of reports. Following these recommendations, no dose decreases were done. All Ctau (n = 6) in children weighing 6 to <14 kg were supratherapeutic. This proportion was also high in patients weighing 30 to <40 kg (64%) and >40 kg (56%). Interindividual variability was high (CV 65.4%), while intra-individual variability was lower (median CV 25.6%). No significant difference in mean Ctau was found between patients with and without viral suppression (p > 0.05). Proportions of viral suppression increased from 86% to 93% across the first four TDMs, despite relatively stable proportions of Ctau above the efficacy threshold. Proportions of Ctau within the therapeutic window increased from 18.2% to 36.8%. The proportion of supratherapeutic Ctau decreased from 60.4% to 39.3%. Among seven subjects with at least one subtherapeutic Ctau, 85.7% reached therapeutic levels by their last TDM. Conclusions: A large DTG Ctau interindividual variability and proportion of supratherapeutic levels were seen in paediatric patients. It remains unclear if these high DTG Ctau are clinically relevant in this population. Improved virologic outcomes over successive TDMs suggest some potential benefit. Current DTG weight-band dosing recommendations could be optimized to limit unnecessarily high concentrations.