A Phase 1 Pharmacokinetic Trial of Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination in Pregnant Women with Chronic Hepatitis C Virus Infection

项目总结 在美国，有320万人慢性感染丙型肝炎病毒(丙型肝炎病毒)，携带1- 妊娠期患病率为2.4%。最近2014年10月批准了固定剂量组合， 含有NS5B聚合酶抑制剂索莫布韦(SOF)90毫克和NS5A抑制剂来地帕韦(LDV) 400 mg，标志着无干扰素和利巴韦林的新时代，直接作用于丙型肝炎病毒的抗病毒治疗。A 12周 口服LDV/SOF一天一次，治愈率达99%。基于 提交给FDA的动物模型数据，这种药物组合被给予B类怀孕 指定，尽管目前还没有孕妇接受LDV/SOF的经验。 怀孕是一段特殊的时期，女性会有独特的动机去参与那些 改善自己的健康，并确保未出生的孩子的健康。因此，孕妇有 经常进行产前检查；以及诸如抗病毒治疗和监测等保健干预措施 轻松整合到现有的产前保健基础设施中。丙型肝炎病毒治疗的好处是 许多，包括预防严重肝病、肝细胞癌和肝移植，如 以及改善身体、情感和社会健康。《传染病》杂志的最新指南 美国疾病协会建议所有丙型肝炎病毒感染者接受治疗。产前阶段 是孕期治疗丙型肝炎病毒的理想时机，因为产前健康状况的改善 丙型肝炎病毒围产期传播给婴儿的护理、利用和预防 怀孕期间安全用药可能需要调整剂量，因为由怀孕引起的 生理变化。因此，仔细的药代动力学(PK)评估是确保 给母亲和发育中的胎儿安全的给药。在此R21应用程序中，我们提出了一个 单臂、单中心、开放标签的PK和12周治疗丙型肝炎安全性的第一阶段评估 15例丙型肝炎孕妇LDV/SOF病程分析治疗将在大约24周后开始 怀孕的感觉。在这项研究中，我们将确定：1)妊娠期间LDV和SOF的PK是否类似于 与未怀孕妇女相比，2)如果怀孕期间对LDV/SOF治疗的病毒应答是 类似于在非怀孕妇女中观察到的情况，以及3)是否有任何最初的产妇或新生儿安全 产前LDV/SOF注射与丙型肝炎病毒感染历史对照检测到的问题 在我们的机构交付。从这项研究的结果来看，未来的研究将寻求优化剂量， 孕期LDV/SOF的孕龄、时机和治疗时间。产前丙型肝炎治疗将 改善孕产妇健康，防止丙型肝炎病毒在社区和围产期的进一步传播 给孩子，从而增强两代人的长期健康。

PROJECT SUMMARY There are 3.2 million persons in the United States chronically infected with hepatitis C virus (HCV) with a 1- 2.4% prevalence during pregnancy. The recent October 2014 approval of the fixed dose combination, containing the NS5B polymerase inhibitor sofosbuvir (SOF) 90 mg and the NS5A inhibitor ledipasvir (LDV) 400mg, marked a new era of IFN and ribavirin free, directly acting antiviral treatment for HCV. A 12 week treatment course of LDV/SOF resulted in a 99% cure rate when given as a once-a-day oral pill. Based on the animal model data submitted to the FDA, this drug combination was given a pregnancy category B designation, even though there is currently no experience with LDV/SOF in pregnant women. Pregnancy is a time when women are uniquely motivated to engage in activities which are geared toward improvement of their own health and ensuring the health of their unborn child. As such, pregnant women have frequent prenatal care visits; and health care interventions, such as antiviral therapy and monitoring, can be easily integrated into the existing healthcare infrastructure of prenatal care. The benefits of HCV treatment are numerous, including prevention of severe liver disease, hepatocellular carcinoma, and liver transplantation, as well as improvements physical, emotional and social health. The most recent guidelines by the Infectious Disease Society of America recommend that all HCV-infected persons receive treatment. The antenatal period represents an ideal window of opportunity for treatment of HCV in pregnancy due to increased antenatal health care utilization and prevention of perinatal transmission of HCV to the infant. Safe administration of drugs in pregnancy may require dose adjustment due to the pregnancy-induced physiologic alternations. Therefore, careful pharmacokinetic (PK) evaluation is a critical first step to ensure safe administration of drugs to both the mother and the developing fetus. In this R21 application, we propose a single-arm, single-center, open label Phase 1 evaluation of the PK and safety of treating HCV with a 12 week course of LDV/SOF in 15 HCV-infected pregnant women. Therapy will be initiated at approximately 24 weeks of gestation. In this study we will determine: 1) if the PK of the LDV and SOF are similar in pregnancy as compared to those in nonpregnant women, 2) if the viral response to LDV/SOF treatment in pregnancy is similar to that observed in nonpregnant women, and 3) if there are any initial maternal or neonatal safety concerns detected with antenatal LDV/SOF administration compared with HCV-infected historical controls delivered at our institution. From the findings of this study, future studies will seek to optimize the dose, gestational age timing and treatment duration of LDV/SOF during pregnancy. Antenatal HCV treatment will improve maternal health, prevent further HCV transmission in the community and perinatal HCV transmission to the child, and thus enhance the long-term health of two generations.