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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究的主要目标如下：1)评估单剂量替诺福韦富马酸二异丙酯(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，该药在活跃期开始或选择性剖腹产前服用。2)评价婴儿单剂替诺福韦DF的药代动力学、安全性和耐受性。次要目标如下：1)描述单剂量替诺福韦DF对母亲HIV-1RNA水平的影响。2)探讨产后1周、6周和12周单次给药后妇女对替诺福韦是否存在病毒耐药性。如果在第1周、第6周或第12周检测到病毒耐药性，将确定表达的持续时间。3)确定婴儿的感染状况，并评估HIV感染婴儿的病毒分离株是否对替诺福韦具有病毒耐药性。这是一项I期、多中心、开放标签、非对照研究，旨在评估替诺福韦DF在活跃期或择期剖腹产前感染HIV-1的孕妇及其婴儿中的安全性、耐受性和药代动力学。PACTG 394将包括通过临床评估和实验室监测对所有研究对象组的替诺福韦DF进行仔细的毒性监测，特别注意可能发生的肾脏损害和骨骼疾病。怀孕大于或等于34周的妇女将在怀孕第三个月进行筛查。研究设计包括两个队列；每个队列将有10对母婴。预计每个队列中至少有五名女性将通过阴道分娩。在第1组中，妇女将在分娩开始时(当临床医生认为妇女有望在24小时内分娩时，继续服用研究药物剂量)或在分娩前4小时通过选择性剖腹产接受单剂替诺福韦DF 600毫克。所有妇女都将接受标准的静脉注射齐多夫定(ZDV)预防。FDA批准的其他抗逆转录病毒药物的治疗将由妇女和她的护理提供者自行决定。婴儿将接受标准的ZDV预防，直到六周大。妇女将在服药前、服药后1、2、4、8、12和24小时以及分娩时获得药代动力学样本。脐带血也将被采集用于测量替诺福韦的浓度。替诺福韦DF在婴儿体内的药代动力学将根据产妇治疗后第1组婴儿出生后的血药浓度来确定。样本将在婴儿出生12、24和36小时时从婴儿身上获取。从第1组获得的数据将针对怀孕约38-40周的孕妇使用替诺福韦DF的安全性、耐受性和药代动力学目标。将根据分娩时的产妇和脐带血样本的数据来确定母婴转运。根据脐血水平和安全性情况，在队列2中，孕妇服用替诺福韦DF的剂量可能保持不变，也可能增加到900毫克。在队列2中，只有当队列1满足以下所有标准时，才会发生剂量升级至孕妇剂量900毫克的替诺福韦DF：(A)脐血替诺福韦浓度中位数为1,000拷贝/毫升；(B)在分娩和分娩时，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，妇女将每隔12周进行一次跟踪调查，直到产后两年。如果在第1、6或12周没有检测到病毒耐药性，妇女将在第12周停止研究。受试者将在产后第20周接触受试者，告知母亲病毒耐药性，以及需要额外的诊所预约或完成研究。

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.