Eleni Aklillu

Africa’s regulatory authorities lack the resources and infrastructure to oversee clinical trials effectively. To address these challenges and improve oversight systems, collaboration between academia, international organisations, national ethics committees, and regulatory authorities is essential. The EU-funded RER-CTO project aims to enhance ethical and regulatory standards for trial oversight (CTO) in sub-Saharan Africa. It focuses on identifying gaps in the legal and policy framework, improving regulatory and research ethics oversight capacity through the digitalisation of CTO systems, developing training programmes, and fostering collaboration among NECs and NRAs to create joint clinical trial review guidelines. The project involves clinical trial researchers, regulatory authorities, ethics committees, universities, and research institutes from Ethiopia, Tanzania, Norway, and Sweden.

Elimination of mother to child transmission of HIV is one of the priorities for World Health Organization (WHO) and national programs. Safe and effective antiretroviral drugs during pregnancy and breastfeeding is key to achieving the elimination strategy by 2030. 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. Low dose of efavirenz (EFV 400 mg) displayed non-inferior virologic suppression but better tolerability than EFV 600mg. Recently DTG and low dose EFV 400mg/day (EFV400) are recommended by WHO as first line and an alternative first line regimen for adults including pregnant women in 2021. Safety and efficacy data on the use of DTG and EFV400 in pregnant and breastfeeding women including rates of mother to child transmission (MTCT), adverse pregnancy, maternal and neonatal outcomes, and impact of intrauterine ARV exposure on infant neurocognitive development are not yet available. . 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, two arm Phase-4 non-inferiority randomized clinical trial to identify the optimal ART regimen for pregnant and breastfeeding women by comparing the efficacy and safety of the two newly introduced first-line ART regimens in mother-infant pairs. The specific objectives are: 1) To compare the rates of PMTCT, virological suppression at delivery in mothers receiving DTG- versus EFV400mg- based ART regimen and 2) To compare safety outcomes including the rate of composite adverse pregnancy, maternal and neonatal outcomes, metabolic derangements and infant neurocognitive development. As a sub study, using population PK/PD/PGx modeling and simulation, we will identify optimal doses of DTG for pregnant and breastfeeding women. We plan to enroll 1156 HIV infected pregnant mothers in Ethiopia and Uganda in a two-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 on the use of EFV400 and DTG for pregnant and breastfeeding women, generating evidence on the safety and efficacy 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.