First paediatric pharmacokinetic data of dolutegravir in combination with a TAF-based NRTI backbone

Dolutegravir (DTG) exposure in children was 20–30% lower when combined in ART regimens with tenofovir alafenamide (TAF) compared with standard of care. These data from a sub study of CHAPAS-4 were presented at the International Workshop on HIV & Pediatrics 2022. 

DTG plus two NRTI, is the preferred treatment for children living with HIV. TAF is under investigation in this population but there are currently no pharmacokinetic (PK) data on DTG exposure when these drugs are given in combination. There are also limited data in children taking DTG with food.

CHAPAS-4 (Children with HIV in Africa: Pharmacokinetics and Acceptability of Simple novel second-line antiretroviral regimens) is a 96 week, randomised controlled trial in children aged 3–13 years (n=690) failing first-line ART. It compares TAF versus standard of care (SOC; abacavir or zidovudine) and DTG versus ritonavir-boosted protease inhibitors in a factorial design. The data presented were from a nested PK sub study.

DTG dosing is according to WHO weight bands: children weighing 14–19.9 kg, 25 mg as dispersible tablets and children >20 kg, 50 mg film-coated tablets with food. DTG concentrations were measured (LC-MS/MS method). Samples were at t=per-dose (0.5), 1, 2, 4, 6, 8, 12, 24 hours post DTG dose. The target C-trough was 0.32 mg/L.

Forty-one children taking DTG were included in this PK sub study: 21 (median 10.8 years and 28.5 kg) taking DTG plus SOC and 20 (median 10.9 years and 25.9 kg) taking DTG plus TAF.

Those taking DTG with SOC had (mean with coefficient of variation %): AUC0–24h 63.2 (32.6) h.mg/L and C-trough 0.9 (50.6) mg/L. Those taking DTG with TAF:  AUC0–24h 48.5 (41.9) h.mg/L and Ctrough 0.7 (77.6) mg/L.  

To evaluate the effect of food the investigators compared these data with that from the fasting ODYSSEY trial. They noted that DTG exposure increases 30–60% when taken with food. Also, that this sub study of CHAPAS-4 is the first DTG evaluation of fed children   

They reported an AUC GM ratio (fed/fasted) of 1.02 (90% CI: 0.9 to 1.16 ).  There was no difference in Cmax and Ctrough.

comment

This sub-study shows exposure of DTG in combination with TAF in children to be 20–30% lower than with abacavir or AZT (SOC).   These evaluations are important as TAF has been highlighted (including by Paediatric Antiretroviral Working Group [PAWG] of the WHO) as a possible NRTI option for children.

The investigators noted that the clinical relevance of this sub study has yet to be determined.

As the main CHAPAS-4 study has still to be completed, viral load and safety data are not presently available. They also noted that the mechanism for the reduced DTG exposure with TAF is not clear.

The extra PK comparison of fed DTG in CHAPAS-4 versus fasted in ODYSSEY had several limitations including different trial schedule, not a randomised comparison and different sample schedule. The investigators concluded that they could not confirm a food effect in children on DTG exposure.     

Reference

Bevers L et al. First pharmacokinetic data of dolutegravir in combination with a TAF containing backbone in children living with HIV. International Workshop on HIV & Pediatrics 2022. Hybrid Meeting Montreal, Canada.  27–28 July 2022. Oral abstract 1.