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 (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0-24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax 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 Ctrough, 1·23 (0·99-1·53) for AUC0-24 h, and 0·94 (0·76-1·16) for Cmax. Individual dolutegravir Ctrough 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 Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax 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.

Conflict of interest statement

Declaration of interests AT, DF, DMG, and MKC received support from core funding to the Medical Research Council Clinical Trials Unit (grant numbers MCUU_00004/03 and MCUU_00004/07). AC received grants for pregnancy research from Gilead Sciences, ViiV Healthcare, and Merck Group. AT received funding for serving on ViiV Healthcare advisory board. AV served on a Data Safety Monitoring Board for Janssen Pharmaceuticals. DMB received grants from ViiV Healthcare, Gilead Sciences, and Merck Group for the PANNA network; served on the advisory board for Merck Group; participated in the work of the Data Safety Monitoring Board for Janssen Pharmaceuticals; and received funding from ViiV Healthcare and Pfizer for lectures. RAF received Senior fellowship in Clinical Science from Wellcome Trust. AT, AC, DMB, DMG, MA, and PA are members of the WHO-led Paediatric Antiretroviral Working Group (PAWG) and Paediatric Drug Optimisation Group (PADO). AT and PA are members of the WHO-led Child and Adolescent TB Technical Working Group. MA and AC served as PAWG Co-Chairs. MA served as a Vice Chair of the Treatment Scientific Committee of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT). All other authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

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 (Ctrough) 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 (Cmax) in adults receiving dolutegravir 50 mg twice daily (blue dotted line), trough plasma concentration (Ctrough) 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).