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

Abstract

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB.

Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (C_trough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC_{0-24 h}), and maximum plasma concentration (C_max) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin C_max on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014-002632-14), and the ISRCTN registry (ISRCTN91737921).

Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4-17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08-2·11) for C_trough, 1·23 (0·99-1·53) for AUC_{0-24 h}, and 0·94 (0·76-1·16) for C_max. Individual dolutegravir C_trough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a C_max of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean C_max was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30-40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir.

Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB.

Funding: Penta Foundation, ViiV Healthcare, UK Medical Research Council.

Figure 1

Study profile Dolutegravir doses were protocol-approved doses at the time of pharmacokinetic assessment. Non-adherence to trial medication was predefined as a dolutegravir plasma concentration 24 h after dolutegravir intake (C_trough) of more than 15 times higher than the baseline concentration. PK=pharmacokinetic. TB=tuberculosis. PK day 1=dolutegravir administered twice daily plus rifampicin. PK day 2=dolutegravir administered once daily. *Both not included in analysis because no data on PK day 1 with rifampicin due to non-adherence for one participant and samples not shipped to laboratory for the other participant; PK day 2 samples not included in linear mixed model analysis because there were no PK day 1 data for this dose and formulation. †PK day 1 unevaluable as the participant took dolutegravir on previous day outside of dosing window and did not return for PK day 2. ‡One participant was non-adherent to trial medication on both PK days; the second participant changed dolutegravir dose from 35 mg film-coated tablet at PK day 1 to 50 mg film-coated tablet on PK day 2 assessment and was non-adherent to trial medication on both PK days; the third participant was non-adherent to trial medication on PK day 1 and did not return for PK day 2. ¶PK day 2 not evaluable due to non-adherence; PK day 1 was evaluable and included in linear mixed model analysis. ||Missing samples on PK day 1 resulting in insufficient number of samples to perform analysis, PK day 2 was evaluable and included in linear mixed model analysis.

Figure 2

Geometric mean dolutegravir plasma concentration time curves (A) Children receiving dolutegravir 25 mg dispersible tablet once daily (n=1, black solid line) or twice daily with rifampicin (n=1, grey line). (B) Children receiving dolutegravir 25 mg film-coated tablet once daily (n=5, black solid line) or twice daily with rifampicin (n=5, grey line). (C) Children receiving dolutegravir 50 mg film-coated tablet once daily (n=7, black solid line) or twice daily with rifampicin (n=7, grey line). Solid lines in the twice-daily curves indicate observed concentrations; grey dotted lines indicate imputed values by repeating the first 12 h. Geometric mean dolutegravir plasma concentration time curves with adult reference parameters of maximum plasma concentration (C_max) in adults receiving dolutegravir 50 mg twice daily (blue dotted line), trough plasma concentration (C_trough) in adults receiving dolutegravir 50 mg once daily (green dotted line), and dolutegravir 90% effective concentration (EC₉₀) in the adult dolutegravir 10-day monotherapy study (Min and colleagues, 2011; red dotted line).