The project

Safety and efficacy of Dolutegravir and EFV400 for pregnant and breastfeeding women: a randomised non-inferiority clinical trial

PREGART is a Phase 4, multicentre, randomised clinical trial comparing the two first-line antiretroviral therapy (ART) regimens currently recommended by the World Health Organization (WHO) for HIV-infected pregnant and breastfeeding women. The trial involves 1,156 mother-infant pairs in Ethiopia and Uganda.

The project runs from January 2026 to December 2028, and is funded by the Global Health EDCTP3 Joint Undertaking under Horizon Europe (Grant Agreement No. 101145768), and is coordinated by Karolinska Institutet (Stockholm, Sweden) in partnership with Hawassa University (Ethiopia), Makerere University (Uganda), and Istituto Superiore di Sanità (Italy).

PREGART will provide evidence-based recommendations for national, regional, and international policymakers, including WHO, on optimal ART regimen for pregnant and breastfeeding women living with HIV.

Background

The use of safe and effective antiretroviral drugs during pregnancy and breastfeeding is key to achieving the elimination of mother-to-child transmission (MTCT) by 2030.

Pregnant and breastfeeding women are routinely excluded from clinical trials due to ethical considerations and regulatory complexity. As a result, data on the safety and efficacy of antiretroviral drugs during pregnancy remain scarce. Policymakers and prescribers must extrapolate findings from studies conducted in adult men and non-pregnant women — a significant limitation, since pregnancy-related physiological changes profoundly alter the pharmacokinetics and pharmacodynamics of drugs.

In 2021, WHO updated its HIV treatment guidelines and recommended two new first-line combination ART (cART) regimens for all adults, including pregnant and breastfeeding women:

• Preferred regimen: Dolutegravir (DTG) + Tenofovir (TDF) + Lamivudine (3TC)
• Alternative regimen: Low-dose Efavirenz 400 mg (EFV400) + TDF + 3TC

Both drugs cross the placental barrier and are excreted in breast milk, raising important questions about their comparative safety and efficacy for the mother and her infant — in particular, regarding infant neurocognitive development and the risk of mother-to-child transmission (MTCT) of HIV.

While several related trials have been published — including NAMSAL (DTG vs. EFV400 in adult non-pregnant women, Cameroon), DolPHIN-2 (DTG vs. EFV600 in late pregnancy), and IMPAACT 2010/VESTED (three ART regimens in pregnancy, excluding EFV400) — none has directly compared DTG and EFV400 in pregnant women with MTCT and infant neurocognitive development as outcomes.

PREGART is the only registered clinical trial in the world investigating the safety and efficacy of both newly recommended first-line ART regimens in mother–infant pairs with a long-term follow-up.

Objectives

Primary Objectives

   1. Efficacy — Prevention of mother-to-child transmission (PMTCT): To compare the proportion of HIV-infected infants at 12 months of age between the two treatment arms.
   2. Efficacy — Virological suppression: To compare the proportion of mothers achieving virological suppression (HIV-RNA < 50 copies/mL) at delivery.
   3. Safety: To compare the rate of composite adverse pregnancy, maternal and neonatal outcomes — including spontaneous abortion, stillbirth, preterm delivery, and infant born small for gestational age — between the two treatment arms.

Secondary Objectives

   • Compare virological suppression during pregnancy and breastfeeding.
   • Compare infant and child growth and neurocognitive development up to 96 weeks after birth.
   • Compare the occurrence of severe adverse events in mothers during pregnancy and breastfeeding.
   • Assess the type, frequency, and severity of treatment-associated adverse events in mothers (including dyslipidaemia, hepatotoxicity, neuropsychiatric events, glucose metabolism disorders, and drug resistance).
   • Investigate the impact of pharmacokinetics (PK)

Trial Design

PREGART is a multi-national, multicenter, interventional, open-label, parallel assignment, and controlled two-arm non-inferiority randomized clinical trial.

HIV-infected pregnant women in their first or second trimester (≤ 28 weeks of gestation), aged ≥ 18 years and ART-naïve or on a first-line regimen, are randomised 1:1 to one of two treatment arms:

   • Arm 1: TDF + 3TC + DTG (preferred regimen)
   • Arm 2: TDF + 3TC + EFV400 (alternative regimen)

The target sample size is 1,156 participants (578 per arm, accounting for 20% loss to follow-up), with 90% power to detect non-inferiority on the primary efficacy endpoint.

Participants and their infants are followed from enrolment through delivery and up to 96 weeks post-partum. Key assessment points include delivery, and 6, 24, 48, 72, and 96 weeks after birth. Infant outcomes assessed include HIV status (by DNA PCR), growth parameters, and neurocognitive development (Bayley Scales of Infant and Toddler Development, 4th edition).

A nested pharmacokinetics and pharmacogenetics (PK/PG/PD) sub-study measures plasma drug concentrations of EFV400 and DTG during pregnancy and post-delivery, with cord blood collected at delivery and whole-blood samples collected for genotyping of drug-metabolising enzymes.

The trial is registered in the Pan African Clinical Trials Registry (Registry No.: PACTR201909810587438).

Study Sites

The trial is conducted across two countries in sub-Saharan Africa:

Ethiopia — 20 trial sites in three regions:
   • Southern Nations, Nationalities and Peoples Region (SNNPR) / Sidama
   • Oromia Region
   • Addis Ababa City Administration

Uganda — Centres of excellence for HIV care and public hospitals, including:
   • Mildmay Hospital Uganda
   • TASO Entebbe
   • China-Uganda Partnership Hospital (Kisenyi)
   • Kawaala Health Centres

Project History

The PREGART trial was originally launched in 2019 with funding from EDCTP2 (Grant RIA2017MC-2009). Its implementation was severely disrupted by three successive crises: the COVID-19 pandemic (which forced an 18-month suspension of all trial activities and a further 6-month recruitment halt in Uganda), the civil war in Northern Ethiopia (which led to the closure of three trial sites and the loss of 39 enrolled mother–infant pairs), and the Ebola outbreak in Uganda (which imposed a further 4-month halt). Following a 36-month no-cost extension granted by EDCTP2, the trial has continued under a new EDCTP3 cost extension (2026–2028), which provides 1.8 million euros to complete enrolment and all follow-up activities.

As of June 2025, 608 of 1,156 participants have been enrolled (53% of target), and recruitment is ongoing.

Capacity Building

Beyond its clinical objectives, PREGART is committed to strengthening research capacity in sub-Saharan Africa. The project supports a PhD training programme for four doctoral students enrolled at Karolinska Institutet, working on research questions directly embedded in the trial.

Consortium

Istituto Superiore di Sanità – Italy
Coordinator

Funding

PREGART is funded by the Global Health EDCTP3 Joint Undertaking under Horizon Europe (Grant Agreement No. 101145768).

The Global Health EDCTP3 Joint Undertaking is supported by the European Union’s Horizon Europe research and innovation programme, participating African and European countries, and the Bill & Melinda Gates Foundation.