Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
EBioMedicine. 2023 Sep;95:104762. doi: 10.1016/j.ebiom.2023.104762. Epub 2023 Aug 14.
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.
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.
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.
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.
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.
多拉韦林（DTG）是所有人类免疫缺陷病毒（HIV）感染者的一线推荐治疗方案。博茨瓦纳是一个没有叶酸强化计划的国家，最初的研究结果表明，在接触多拉韦林的围孕期，神经管缺陷（NTD）的发病率升高。在这里，我们探讨了在叶酸缺乏的饮食环境下，DTG 是否会影响小鼠模型中与胎儿相关的畸形风险。
2 周内，C57BL/6 小鼠食用叶酸缺乏饮食，然后交配并随机分为对照组（水）、1xDTG（2.5mg/kg）或 5xDTG（12.5mg/kg）组，均经口给予 50mg/kg 替诺福韦二吡呋酯和 33.3mg/kg 恩曲他滨。治疗从妊娠第 0.5 天（GD）至处死（GD15.5）每日进行一次。评估胎儿的大体畸形。定量检测母体和胎儿的叶酸水平。
评估了 313 窝（103 窝对照、106 窝 1xDTG、104 窝 5xDTG）。各组的存活率、胎盘重量和胎儿重量无差异。仅在 DTG 组观察到 NTD（发生率：0%对照组；1.0%1xDTG；1.3%5xDTG）。尾部、腹壁、肢体、颅面和出血缺陷在 DTG 组的发生率均高于对照组。与我们之前在叶酸充足的小鼠妊娠中使用 DTG 的研究结果相比，叶酸缺乏与包括 NTD 在内的多种缺陷的发生率增加有关，但仅在 DTG 组观察到。我们观察到一种严重的左右不对称表型，在 DTG 组比对照组更常见。
母体叶酸缺乏可能会增加 DTG 相关胎儿缺陷的风险。在服用 DTG 的 HIV 妇女怀孕期间，尤其是在缺乏叶酸强化计划的国家，应考虑使用围孕期叶酸补充剂。
本项目由美国国立卫生研究院下属国立儿童健康与人类发育研究所、美国国立卫生研究院、美国卫生与公众服务部，通过合同号 HHSN275201800001I 和拨款号 R01HD104553 提供联邦资金资助。LS 由加拿大母婴健康和 HIV 一级研究主席资助。HM 由安大略省 HIV 治疗网络的初级研究员奖资助。
