PACTG 394: TENOFOVIR DF IN HIV-1 INFECTED PREGNANT WOMEN AND THEIR INFANTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究的主要目的如下：1）评价单剂量富马酸替诺福韦酯（DF）在HIV感染孕妇及其婴儿中的药代动力学、安全性和耐受性，当在活跃分娩开始时或通过选择性剖腹产分娩前给药时。2)评价婴幼儿单剂量替诺福韦DF的药代动力学、安全性和耐受性。次要目的如下：1）描述单剂量替诺福韦DF对母体HIV-1 RNA水平的影响。2)探讨在单次分娩时给药后的妇女中，在产后1、6和12周时是否存在对替诺福韦的病毒耐药性。如果在第1、6或12周检测到病毒耐药性，则将确定表达的持续时间。3)确定婴儿的感染状况，并评估从HIV感染婴儿分离的病毒中是否存在对替诺福韦的耐药性。 这是一项I期、多中心、开放标签、非对照研究，旨在评价替诺福韦DF在活跃分娩或择期剖腹产分娩前的HIV-1感染孕妇及其婴儿中的安全性、耐受性和药代动力学。PACTG 394将包括通过临床评价和实验室监测替诺福韦DF在所有研究受试者组中的仔细毒性监测，特别注意可能发生的肾损害和骨骼疾病。 将在妊娠晚期（大于或等于34周）筛选入组女性。研究设计包括两个队列;每个队列将入组10对母亲/婴儿。预计每个队列中至少有5名妇女将通过阴道分娩。 在队列1中，女性将在主动分娩开始时（根据临床医生的最佳判断，当女性预计将在24小时内分娩时，应进行研究药物给药）或通过选择性剖腹产分娩前4小时接受单次口服替诺福韦DF 600 mg。所有妇女将接受标准的静脉注射齐多夫定（ZDV）预防。使用其他FDA批准的抗逆转录病毒药物治疗将由女性及其护理提供者自行决定。婴儿将接受标准ZDV预防，直到6周龄。 将在给药前和给药后1、2、4、8、12和24小时以及分娩时采集女性的药代动力学样本。还将收集脐带血用于测量替诺福韦浓度。替诺福韦DF在婴儿中的药代动力学将根据母体治疗后在队列1婴儿中测量的出生后血液浓度来确定。将从出生后12、24和36小时的婴儿中采集样本。 从队列1中获得的数据将解决在妊娠约38-40周的孕妇中替诺福韦DF的安全性、耐受性和药代动力学的目标。将根据分娩时母体和脐带血样本的数据确定母胎转运。基于脐带血水平和安全性特征，队列2中替诺福韦DF的母体剂量可保持不变或增加至900 mg。只有在队列1中满足所有以下标准时，队列2中的替诺福韦DF的母体剂量（900 mg）的剂量递增才会发生：（a）分娩和分娩时的中位脐带血替诺福韦浓度为1，000拷贝/mL），产后1、6和/或12周将进行病毒耐药性测试。如果在第1、6或12周发现替诺福韦耐药突变，将每隔12周对妇女进行随访，直到产后两年。如果在第1、6或12周未检测到病毒耐药性，则女性将在第12周退出研究。将在产后第20周联系受试者，告知其母亲病毒耐药性以及需要额外门诊预约或完成研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary objectives of this study are as follows: 1) To evaluate the pharmacokinetics, safety, and tolerance of a single dose of tenofovir disoproxil fumarate (DF) in HIV-infected pregnant women and their infants, when administered at the onset of active labor or prior to delivery by elective C-section. 2) To evaluate the pharmacokinetics, safety, and tolerance of a single dose of tenofovir DF in infants. The secondary objectives are as follows: 1) To describe the effect of a single dose of tenofovir DF on maternal HIV-1 RNA levels. 2) To explore if there is viral resistance to tenofovir at 1, 6, and 12 weeks post partum in women following single intrapartum dosing. If viral resistance is detected at week 1, 6, or 12 the duration of expression will be determined. 3) To determine the infection status of infants and evaluate if there is any viral resistance to tenofovir in viral isolates from HIV-infected infants. This is a Phase I, multicenter, open-label, uncontrolled study to evaluate the safety, tolerance, and pharmacokinetics of tenofovir DF in HIV-1 infected pregnant women in active labor or prior to delivery by elective C-section and in their infants. PACTG 394 will include careful toxicity monitoring through clinical evaluation and laboratory monitoring of tenofovir DF in all groups of study subjects with special attention to possible development of renal compromise and bone disease. Women will be screened for enrollment in their third trimester of pregnancy at greater than or equal to 34 weeks gestation. The study design includes two cohorts; 10 mother/infant pairs will be enrolled in each cohort. A minimum of five women, in each cohort, is expected to deliver vaginally. In Cohort 1, women will receive a single oral dose of tenofovir DF 600 mg at the onset of active labor (dosing with study drug should proceed when, in the clinician's best judgment, the woman is expected to deliver within 24 hours) or four hours prior to delivery by elective C-section. All women will receive standard intravenous zidovudine (ZDV) prophylaxis. Treatment with other FDA-approved antiretrovirals will be at the discretion of the woman and her care provider. Infants will receive standard ZDV prophylaxis until six weeks of age. Women will have pharmacokinetic samples obtained pre-dose and at 1, 2, 4, 8, 12, and 24 hours post dose and at the time of delivery. Cord blood will also be collected for measurement of tenofovir concentrations. Pharmacokinetics of tenofovir DF in infants will be determined from postnatal blood concentrations measured in Cohort 1 babies after maternal therapy. Samples will be obtained from the infant at 12, 24, and 36 hours of life. The data obtained from Cohort 1 will address the objectives of safety, tolerance, and pharmacokinetics of tenofovir DF in pregnant women at approximately 38-40 weeks gestation. Maternal-fetal transport will be determined from the data of maternal and cord blood samples at delivery. Based on cord blood levels and safety profile, the maternal dose of tenofovir DF may either remain the same or be increased to 900 mg in Cohort 2. Dose escalation to a maternal dose of tenofovir DF, 900 mg, in Cohort 2 will only occur if all of the following criteria are met in Cohort 1: (a) median cord blood tenofovir concentration is 1,000 copies/mL) at labor and delivery, 1, 6, and/or 12 weeks post-partum will have viral resistance testing performed. Should tenofovir resistance mutations be identified at week 1, 6, or 12, women will be followed at 12 week intervals until two years postpartum. If no viral resistance is detected at week 1, 6, or 12, women will come off study at Week 12. Subject contact will be made at week 20 postpartum to inform the mother of viral resistance and the need for additional clinic appointments or completion of the study.