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

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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.