Background: Zidovudine (ZDV) has markedly reduced HIV perinatal transmission, but some patients (pts) do not tolerate/refuse it. PACTG 332 studied d4T (Stavudine) pharmacokinetics (pks) and safety to explore d4T potential use as an alternative to ZDV.

Subjects: Fourteen (14) HIV-infected pregnant pts, unable/unwilling to take ZDV. Entry median (range) maternal parameters: age 24 yrs (21–37); %CD4 34.3 (5.5–54); 13/14 had CD4 > 200, 10/14 on d4T at entry (3 had d4T before entry); 11/14 had HIV RNA viral load (VL) < 400 c/ml, others had 26, 430, 6610, 2550 c/ml.

Methods: Pts took open-label 40 mg d4T PO bid (30 mg if < 60 kg) and 150 mg 3TC (Lamivudine) PO bid from entry to labor. In labor, 4 pts had IV d4T (0.05 mg/kg 30 min, then 0.05 mg/kg/hr) and 10 had PO d4T; all had PO 3TC. On study, 2 pts took only d4T/3TC, 12 took additional ARVs: 6 protease inhibitor; 4 nevirapine; 2 abacavir. All infants took PO 2 mg ZDV/kg qid and 2 mg 3 TC/kg bid for 6 wks; a single 1 mg d4T/kg dose was given at 1 and 6 wks. d4T levels were assayed by RIA (Sigma) and/or by LC/MS/MS, d4T concentration-time data by WinNonLin 3.0; and VL by Roche Amplicor Monitor (LLD 400 c/ml) in an ACTG certified lab.

Results: No serious/life threatening d4T or 3TC laboratory or clinical toxicities seen in women or infants. Delivery maternal VL was < 400 c/ml in 9/13 evaluable pts (other 4 < 10,000 c/ml). Median (range) infant parameters: gestational age (GA) 38 wks (35–40); 2 were < 37 wks; birth weight (BW) 3.2 kg (2.2–3.9); 13/14 had appropriate BW for GA. Antenatal and labor maternal d4T pk measures were similar (t_1/2 79.9 ± 12.5 vs 87.3 ±24.7 min; Cl/F 6.7 ±1.5 vs. 5.7 ±1.2 ml/min/kg; AUC 79.9 ±18.9 vs 88.1 ±16.6 ug.min/mL); and approximated historical values of non-pregnant adults. Mean cord blood levels in 3 (moms had IV d4T) were 144 ± 48 ng/mL and in 7 (moms had PO d4T) were 101 ±88 ng/mL; cord:maternal d4T ratio: 1.3 ±0.3. Infant d4T pks showed a longer half-life and lower clearance at 7d vs 38d (t_1/2 134.9 ±26.5 vs 91.6 ±25.7min; CL/F 5.6 ±1.2 vs 6.8 ±1.0 ml/min/kg; AUC 187.4 ±46.3 vs 148.3 ±28.2 ug.min/ml). Infant pks at 6 wks approached maternal values. Twelve (12) infants followed 24 wks were HIV-uninfected; 2 infants had neg HIVDNA PCR at 1 and 6 wks, but were lost at 24 wks.

Conclusions: d4T, in combination with 3TC, as part of an antenatal ARV regimen was well tolerated, safe, and had excellent transplacental transfer with IVor PO dosing. These data suggest d4T may be a reasonable alternative for HIV-infected pregnant women who cannot receive ZDV.