Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy modelResearch in context
Haneesha Mohan,
Jessica Nguyen,
Ben MacKenzie,
Audrey Yee,
Evelyn Yukino Laurette,
Tanvi Sanghvi,
Oscar Tejada,
Valeriya Dontsova,
Kit-Yi Leung,
Cameron Goddard,
Taylor De Young,
John G. Sled,
Nicholas D.E. Greene,
Andrew J. Copp,
Lena Serghides
Affiliations
Haneesha Mohan
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Jessica Nguyen
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Ben MacKenzie
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Audrey Yee
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Evelyn Yukino Laurette
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Tanvi Sanghvi
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Oscar Tejada
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Valeriya Dontsova
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Kit-Yi Leung
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
Cameron Goddard
Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada
Taylor De Young
Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada
John G. Sled
Mouse Imaging Center, 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, 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, University Health Network, Toronto, Ontario, Canada; Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Corresponding author. 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.
Summary: Background: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. Methods: C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. Findings: 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. Interpretation: Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. Funding: This project has been funded by 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 and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.
