Antiretroviral therapy with twice-daily dolutegravir coadministered with rifampicin was found to be safe and overcame the enzyme-inducing effects of rifampicin in children with HIV-associated tuberculosis (TB) infection, according to results of a study published in The Lancet HIV.
Researchers conducted a study to assess the safety and pharmacokinetics of twice-daily dolutegravir dosing for the treatment of children (age range, 4 weeks to 18 years) with HIV-associated TB infection receiving rifampicin. Patients who developed TB infection during the study period were switched from once- to twice-daily dolutegravir dosing at the time of rifampicin initiation, and those who were infected before the study period initiated twice-daily dosing at enrollment. Dolutegravir was administered in either dispersible or film-coated tablets and via weight-band dosing. All children receiving twice-daily dolutegravir were switched back to once-daily dosing 2 weeks after rifampicin was discontinued.
A 12-hour pharmacokinetic profile was performed for rifampicin plus twice-daily dolutegravir dosing, and a 24-hour profile was performed for once-daily dolutegravir dosing. The researchers used linear mixed-effect models with dose as the fixed effect and patient as the random effect to estimate geometric mean ratios (GMRs) and calculate 90% CIs. Comparisons between sub-study days were made by evaluating GMRs for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 to 24 hours after dosing (AUC0–24 h), and maximum plasma concentration (Cmax).
A total of 37 children were included in the safety analysis, of whom 24 were diagnosed with TB infection prior to enrollment and 13 were diagnosed after enrollment. Of these patients, the median age was 11.9 (range, 0.4-17.6) years, 51% were women or girls, and 97% resided in sub-Saharan Africa.
Among all patients, 20 (54%) were included in the pharmacokinetic substudy. Of these patients, 12 had at least 1 evaluable pharmacokinetic curve for dolutegravir and available data for within-participant comparisons of pharmacokinetic parameters for dolutegravir. Comparisons of geometric mean ratios (GMRs) between rifampicin and twice- vs once-daily dolutegravir were 1.51 (90% CI, 1.08-2.11) for Ctrough, 1.23 (90% CI, 0.99-1.53) for AUC0-24h, and 0.94 (90% CI, 0.76-1.16) for Cmax.
For all children receiving rifampicin plus twice-daily dolutegravir, individual Ctrough concentrations were higher than the 90% effective concentration. In addition, twice-daily dolutegravir was associated with increased clearance (GMR, 1.63; 90% CI, 1.30-2.04) and a lower elimination half-life (GMR, 0.59; 90% CI, 0.49-0.70) compared with once-daily dulutegravir. Of 18 children with evaluable rifampicin concentrations, a Cmax concentration below the optimal target of 8 mg/L was noted in 15 (83%). The rifampicin geometric mean Cmax was 5.1 mg/L, with a coefficient of variation of 71%.
During a median follow-up period of 31 weeks, 15 adverse events (AEs) of grade 3 or higher occurred in 11 (30%) patients. There were also 10 severe AEs noted in 8 (22%) patients, 2 (5%) of whom died. Of note, none of the reported AEs or deaths were deemed related to dolutegravir, and there was no evidence that increasing the dose of dolutegravir was associated with an increased risk for an AE.
This study was limited by the small number of children weighing between 20 and 39 kg, as the licensed dose of dolutegravir was recently increased for those in this weight range.
According to the researchers, a “…dolutegravir twice-daily dosing strategy can overcome a rifampicin drug interaction and can be given safely to children, providing a practical, effective, and readily available treatment option for children with HIV-associated TB.”
Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Turkova A, Waalewijn H, Chan MK, et al. Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. Lancet HIV. Published online July 19, 2022. doi:10.1016/S2352-3018(22)00160-6