Project: Safety and efficacy of Dolutegravir and EFV400 for pregnant and breast feeding women: a randomized non-inferiority clinical trial

Acronym PREGART (Reference Number: RIA2017MC-2009)
Duration 01/06/2019 - 31/05/2024
Project Topic Elimination of mother to child transmission of HIV is considered as one of the priorities for the World Health Organization (WHO) and national programs. Safe and effective antiretroviral drugs during pregnancy and breastfeeding are key to achieving the elimination strategy in 2020. Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor-based antiretroviral therapy(ART) regimen demonstrated minimum drug interaction, lower risk of treatment discontinuation and superior virological suppression against other first-line agents, including efavirenz and boosted protease inhibitors. DTG and low dose EFV 400mg/day (EFV400) are recommended by WHO as an alternative first-line regimen for adults. Safety and efficacy data on the use of DTG and EFV400 in pregnant and breastfeeding women are not yet available. Given the recent evidence that the standard dose of EFV600 might be associated with higher toxicity during pregnancy, DTG and low dose EFV 400mg/day (EFV400) are promising alternatives for pregnant and breastfeeding women pending safety and efficacy data. Both DTG and EFV are metabolized by genetically polymorphic enzymes UGT1A1 and CYP2B6 respectively. Investigating the pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx) of DTG in resource-limited genetically diverse African populations is an important step towards optimizing antiretroviral therapy during pregnancy and breastfeeding. We propose a multi-national, three-arm clinical trial to identify the optimal ART regimen for pregnant and breastfeeding women by comparing three alternative ART regimens. The specific objectives are: 1) To show that [TDF, 3TC, DTG] is non-inferior to [TDF, 3TC, EFV600]; 2) To show that [TDF, 3TC, EFV400] is non-inferior to [TDF, 3TC, EFV600]; 3) To compare safety and efficacy of [TDF, 3TC, DTG] with [TDF, 3TC, EFV400]. As a substudy, using population PK/PD/PGx modelling and simulation, we will identify optimal doses of DTG for pregnant and breastfeeding women. We plan to enrol 915 HIV infected pregnant mothers in Ethiopia and Uganda in a three-arm randomized non- inferiority trial with an equal allocation ratio. A subset of the subjects will also be followed to undergo PK/PD/PGx study to determine the optimized doses for pregnant and breastfeeding women. Expected outcomes include generating scientific evidence to support the use of EFV400 and DTG for pregnant and breastfeeding women, generating evidence on the safety of EFV400 and DTG for pregnant and breastfeeding women. PK/PD/PGx data will also be generated to further support the dosing of EFV and DTG during pregnancy and breastfeeding.
Network EDCTP2
Call Clinical trials and operational research studies to optimise the use of products for poverty-related diseases in mothers, newborns, children and/or adolescents

Project partner

Number Name Role Country
1 Hawassa University Coordinator Ethiopia
3 Istituto Superiore Di Sanita Partner Italy
5 Karolinska Institutet Partner Sweden
7 Makerere University Partner Uganda