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NIH grant 75N94023D00001-0-759402600001-1: IMPAACT 2050 / CREATE - Phase IV Study of the Pharmacokinetics of Long-Acting Injectable Cabotegravir and Rilpivirine in Pregnant and Postpartum Women with HIV in the United States
Institute: {'code': 'OD', 'abbreviation': 'OD', 'name': 'NIH Office of the Director', 'admin_org_id': '12500055', 'admin_funding_url': ''}. PI: ISA TREJOS. Award: $2502640.
Start: 2026-09-28T00:00:00.
Background:The introduction of long-acting injectable (LAI) antiretroviral therapy (ART) combining cabotegravir (CAB), an integrase strand transfer inhibitor, and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, represents a paradigm shift in the management of HIV-1 infection. By replacing daily oral regimens with bimonthly intramuscular injections, LAI CAB/RPV overcomes critical adherence barriers, reduces pill fatigue, and mitigates HIV-related stigma. However, significant physiological alterations during pregnancy—including expanded plasma volume, altered drug-metabolizing cytochrome P450 and UDP-glucuronosyltransferase activity, changes in plasma protein binding, and increased renal blood flow—frequently result in subtherapeutic exposures for many antiretroviral agents. Due to the historic exclusion of pregnant individuals from registrational clinical trials, robust prospective pharmacokinetic (PK), safety, and efficacy data for LAI CAB and RPV during pregnancy and the postpartum period remain critically limited. This knowledge gap poses clinical dilemmas regarding the continuation or initiation of LAI ART during gestation and risks perinatal transmission or virologic breakthrough.
Objective and Design:IMPAACT 2050 / CREATE is a prospective, multi-center, Phase IV clinical trial conducted across 10 U.S.-based clinical research sites within the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The primary objective is to characterize the longitudinal pharmacokinetics, safety, tolerability, and virologic outcomes of LAI CAB and RPV administered in routine clinical care to pregnant women living with HIV-1 and their infants. The study will enroll up to 24 evaluable mother-infant pairs. Maternal participants will be followed prospectively through pregnancy (up to 8 study visits, spanning approximately six months of gestation) and paired with their infants through six weeks postpartum (up to 3 infant visits).
Methods:Intensive and sparse pharmacokinetic sampling will quantify maternal plasma trough concentrations ($C_{trough}$), maximum concentrations ($C_{max}$), and area under the concentration-time curve (AUC) of CAB and RPV across each trimester and postpartum. Transplacental drug passage will be determined via paired maternal plasma and umbilical cord blood at delivery. Infant washout pharmacokinetics and safety monitoring will evaluate drug elimination kinetics and potential in utero drug-related toxicities through six weeks of life. Secondary endpoints include virologic suppression maintenance (), prevention of perinatal HIV transmission, maternal injection site reactions, and maternal and infant adverse events.
Significance:IMPAACT 2050 will provide crucial, high-priority pharmacokinetic and safety benchmarks to inform evidence-based clinical dosing guidelines, regulatory product labeling, and national perinatal HIV treatment guidelines (e.g., HHS Perinatal Guidelines). Ultimately, this research will support equitable access to innovative, long-acting HIV therapeutics for pregnant and breastfeeding women while ensuring optimal maternal virologic suppression and perinatal transmission prevention.document fetched 2026-10-04 02:43