A Phase I/II, Open-Label Study to Evaluate the Safety, Tolerance and Pharmacokinetics of Stavudine (d4T) in Combination With Lamivudine (3TC) in HIV-Infected Pregnant Women and Their Infants

New antiretroviral agents or combinations are sought that are as efficacious as ZDV and that would be effective in reducing the rate of vertical transmission of HIV in women who have been long-term recipients of ZDV. d4T is a good candidate drug. It is a thymidine nucleoside analogue that inhibits replication of HIV at concentrations similar to those of ZDV which have anti-HIV activity. The demonstrated safety profile of d4T, the ease of administration, and, most importantly, preliminary efficacy data, especially in combination with 3TC, make this an excellent candidate combination for a Phase I perinatal trial. Two cohorts of women and infants are enrolled in this study. The first five mother/infant pairs enrolled comprise Group I. Mothers enrolled in this group must allow their infants to receive ZDV. Eight mother/infant pairs are then enrolled in Group II; Group II infants are allocated into two groups: those whose mothers allow the administration of ZDV (Group IIA) and those whose mothers do not (Group IIB). Group I: Women: Beginning at a minimum of 14 weeks gestation: Oral d4T until the start of active labor. Oral 3TC. At the start of active labor (defined as regular uterine contractions resulting in cervical dilation [3-4 cm] and effacement [50-60%]) and during delivery: d4T administered IV as a loading dose followed by a continuous infusion until the umbilical cord is clamped. Oral 3TC if patient's previous dose of 3TC was administered at least 0.5h prior to onset of labor and additional dose of 3TC is administered and the time until next dose is scheduled accordingly. Infants: d4T as a single oral dose on Day 6 (+/- 2 days) and on Day 42 (this dose can be given between Days 35 and 42, inclusive). Oral ZDV (or IV if unable to take oral dosing) for 6 weeks, beginning a maximum of 12 hours after birth. 3TC for 6 weeks, beginning a maximum of 12 hours after birth. Group II: Women: Beginning at a minimum of 14 weeks gestation: Oral d4T until the umbilical cord is clamped. Oral 3TC. At the start of active labor and through delivery: Oral d4T and 3TC as above. If the last doses of d4T and 3TC were given at least 0.5 hours prior to onset of active labor, an additional dose of d4T and 3TC is given and repeated every 12 hours. Infant Group IIA: d4T as a single oral dose on Day 6 (+/- 2 days) and on Day 42 (this dose can be given between Days 35 and 42, inclusive). Oral ZDV (or IV if unable to tolerate oral dosing) for 6 weeks, beginning a maximum of 12 hours after birth. 3TC for 6 weeks, beginning a maximum of 12 hours after birth. Infant Group IIB: Beginning a maximum of 12 hours after birth: d4T for 6 weeks. 3TC for 6 weeks. [AS PER AMENDMENT 9/15/97: If tolerated, infants continue on protocol treatment to 6 weeks of age. At 6 weeks, infants should receive standard care, including PCP prophylaxis, from an HIV specialist/pediatrician. HIV-infected infants are offered ACTG trial enrollment or open-label treatment based on best clinical judgment of their physician.] [AS PER AMENDMENT 2/19/99: Patients who prematurely discontinue study treatment should continue to be followed on study for the duration of the study.]