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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的主要目的如下：1)评估单剂量富马酸替诺福韦二氧吡酯（DF）在hiv感染孕妇及其婴儿的药代动力学、安全性和耐受性，在主动分娩开始时或择期剖腹产分娩前给药。2)评估婴儿单剂量替诺福韦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)探讨产后1周、6周和12周妇女在分娩时单次给药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，将确定表达的持续时间。3)确定婴儿感染状况，评估hiv感染婴儿病毒分离株中是否存在对替诺福韦的病毒耐药性。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HIV-1感染孕妇、主动分娩或择期剖腹产前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替诺福韦DF对所有研究对象进行仔细的毒性监测，特别注意肾脏损害和骨病的可能发展。妇女将在怀孕第三个月大于或等于34周时进行筛选。研究设计包括两个队列；每组10对母亲/婴儿将被纳入。在每个队列中，预计至少有五名妇女通过阴道分娩。在队列1中，妇女将在主动分娩开始时接受单次口服替诺福韦DF 600毫克（临床医生的最佳判断是，当妇女预计在24小时内分娩时，应继续服用研究药物）或在分娩前4小时通过择期剖腹产。所有妇女将接受标准静脉注射齐多夫定（ZDV）预防。使用其他fda批准的抗逆转录病毒药物治疗将由妇女和她的护理人员自行决定。婴儿将接受标准的ZDV预防，直到6周龄。妇女将在给药前、给药后1、2、4、8、12和24小时以及分娩时获得药代动力学样本。还将收集脐带血以测量替诺福韦的浓度。替诺福韦DF在婴儿中的药代动力学将通过在母体治疗后对队列1婴儿进行的产后血药浓度测定来确定。将在婴儿出生后12、24和36小时采集样本。从队列1获得的数据将解决替诺福韦DF在妊娠约38-40周的孕妇中的安全性、耐受性和药代动力学的目标。母胎运输将根据分娩时母体和脐带血样本的数据来确定。根据脐带血水平和安全性，在队列2中，母亲的替诺福韦DF剂量可能保持不变或增加到900 mg。只有在队列1中满足以下所有标准的情况下，才会在队列2中将剂量增加到替诺福韦DF 900 mg: (a)分娩和分娩时，产后1、6和/或12周脐带血替诺福韦中位浓度为1000拷贝/mL)，进行病毒耐药性测试。如果在第1周、第6周或第12周发现替诺福韦耐药突变，妇女将每隔12周随访一次，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，女性将在第12周退出研究。将在产后20周与受试者联系，告知母亲病毒耐药性情况，以及是否需要进行额外的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.