Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels
Haneesha Mohan,
Monica Guzman Lenis,
Evelyn Y. Laurette,
Oscar Tejada,
Tanvi Sanghvi,
Kit-Yi Leung,
Lindsay S. Cahill,
John G. Sled,
Paul Delgado-Olguín,
Nicholas D.E. Greene,
Andrew J. Copp,
Lena Serghides
Affiliations
Haneesha Mohan
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada
Monica Guzman Lenis
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada
Evelyn Y. Laurette
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada
Oscar Tejada
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada
Tanvi Sanghvi
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada
Kit-Yi Leung
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Lindsay S. Cahill
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Chemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada
John G. Sled
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
Paul Delgado-Olguín
Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Heart & Stroke Richard Lewar Centre of Excellence, Toronto, Ontario M5S 3H2, Canada
Nicholas D.E. Greene
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Andrew J. Copp
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Lena Serghides
Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada; Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada; Corresponding author at: Toronto General Hospital Research Institute, Princess Margaret Cancer Research Tower (PMCRT), University Health Network, 101 College Street, 10th Floor, Room 359, Toronto, Ontario M5G 1L7, Canada.
Background: Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential. Methods: Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5 mg/kg-peak plasma concentration ~3000 ng/ml – therapeutic level), or 5x-DTG (12.5 mg/kg-peak plasma concentration ~12,000 ng/ml – supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50 mg/kg tenofovir+33.3 mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry. Findings: 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group. Interpretation: Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake. Funding: This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I.
