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.
Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
EBioMedicine. 2021 Jan;63:103167. doi: 10.1016/j.ebiom.2020.103167. Epub 2020 Dec 18.
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.
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.
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.
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.
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.
多替拉韦（DTG）是所有 HIV 感染者（包括孕妇）的首选方案，但它对胎儿的影响尚不完全清楚。虽然目前还不清楚这是否是一种因果关系，但围孕期接触 DTG 与神经管缺陷（NTD）发生率增加有关。这导致了人们对在有生育能力的妇女中使用 DTG 的不确定性。
C57BL/6J 孕鼠随机分为对照组（水）、1x-DTG（2.5mg/kg-峰值血浆浓度3000ng/ml-治疗水平）或 5x-DTG（12.5mg/kg-峰值血浆浓度12000ng/ml-超治疗水平），每日一次，从妊娠第 0.5 天到处死。DTG 与 50mg/kg 替诺福韦+33.3mg/kg 恩曲他滨联合使用。确定胎儿表型，并通过质谱法定量检测母鼠和胎鼠的叶酸水平。
352 窝（91 只对照组，150 只 1x-DTG，111 只 5x-DTG）共 2776 只胎鼠（747 只对照组，1174 只 1x-DTG，855 只 5x-DTG）被评估。各组的窝仔数和存活率相似。1x-DTG 组的胎儿和胎盘重量均低于对照组。5x-DTG 组的胎盘重量高于对照组。1x-DTG 组观察到 5 例 NTD ，均为 NTD。1x-DTG 组胎儿缺陷（包括小眼球、严重水肿和血管/出血缺陷）更为常见。相比之下，5x-DTG 组的缺陷率与对照组相似。对照组和 1x-DTG 组的胎儿叶酸水平相似，但 5x-DTG 组的叶酸水平明显更高。
我们的研究结果支持 DTG 在治疗剂量下与胎儿畸形风险增加之间存在因果关系，包括与 Tsepamo 研究中报告的女性从受孕开始接受 DTG 为基础的 ART 接触时类似的 NTD 发生率。DTG 与胎儿异常之间的非单调剂量反应关系可以解释以前临床前 DTG 研究中未发现胎儿毒性的原因。胎儿叶酸水平提示 DTG 不太可能是叶酸摄取的抑制剂。
本项目由美国国立卫生研究院（NIH）下属的美国国立儿童健康与人类发育研究所（Eunice Kennedy Shriver National Institute of Child Health and Human Development）、美国国立卫生研究院（NIH）、美国卫生与公众服务部（Department of Health and Human Services）用联邦资金资助，合同号为 HHSN275201800001I。
