The mothers' mean age at delivery was 33 years (range, 23 to 43); 54% were African, 43% were European, and 3% were Asian; and 80% were infected through sexual exposure. The median (range) maternal plasma HIV RNA level at delivery was <50 copies/ml (<50 to 36,572 copies/ml), and the proportion of women with a detectable viral load at delivery was 34% (28 of 83). The median (range) CD4 lymphocyte count was 473 × 106/liter (98 × 106 to 1,580× 106/liter). The mode of delivery was cesarean section in 78% of the cases. None of the infants was HIV infected.
The NRTIs received by the 100 women included intravenous zidovudine (n = 100), oral zidovudine (n = 60), lamivudine (n = 67), stavudine (n = 32), didanosine (n = 24), and abacavir (n = 4). The majority of these women (83 of 100) received antiretroviral regimens with two NRTIs, with the most frequently prescribed combination (n = 20) being zidovudine with lamivudine and nelfinavir. Twelve patients were taking a regimen with only one NRTI; these regimens included zidovudine alone (n = 6), one NRTI and nevirapine (n = 5), and one NRTI and two protease inhibitors (n = 1).
Maternal antiretroviral therapy was initiated before the beginning of pregnancy in 27% of cases, during the first trimester in 14% of cases, during second trimester in 25% of cases, and during third trimester in 34% of cases. The median time on treatment with the current NRTI was 3 months (range, 0.23 to 81.7 months) for zidovudine, 4.78 months (range, 0.23 to 81.7 months) for lamivudine, 5.63 months (range, 0.53 to 45.8 months) for stavudine, 4.23 months (range, 0.53 to 37.3 months) for didanosine, and 21.2 months (range, 7.1 to 35 months) for abacavir. The median time elapsed between the last NRTI oral dose and delivery was 5.0 h (range, 0.4 to 22.0 h) for zidovudine, 5.0 h (range, 0.4 to 22 h) for lamivudine, 13.0 h (range, 1.2 to 20 h) for stavudine, 9.0 h (range, 2.1 to 33 h) for didanosine, and 3.5 h (range, 0.4 to 9.0 h) for abacavir.
Median drug concentrations in maternal and cord plasma samples are displayed in Table . Cord blood drug concentrations were below the assay limit of detection in 14 of 32 samples (44%) for stavudine and in 15 of 24 samples (62%) for didanosine but were detectable in all samples for zidovudine, zidovudine G, lamivudine, and abacavir.
Drug concentrations in maternal and cord plasma samples
For paired samples with concentrations in maternal samples above the assay limit of quantification, cord-to-maternal plasma drug concentration ratios was determined in order to assess placental transfer. Among the 160 measurable maternal-cord blood sample pairs, transplacental passage was assessed for zidovudine (n = 75), zidovudine G (n = 90), lamivudine (n = 59), stavudine (n = 12), didanosine (n = 10), and abacavir (n = 4). The median cord-to-maternal plasma drug concentration ratio was close to one for zidovudine (R = 1.22; range, 0.18 to 17.2), zidovudine G (R = 1.01; range, 0.36 to 12.1), stavudine (R = 1.32; range, 0.36 to 2.81), lamivudine (R = 0.93; range, 0.21 to 4.03), and abacavir (R = 1.03; range, 0.92 to 1.42) and was small for didanosine (R = 0.38; range, 0.00 to 2.00). There was a significant correlation between maternal and cord plasma drug concentrations for zidovudine (r2 = 0.10; P < 0.01), zidovudine G (r2 = 0.38; P < 0.01), lamivudine (r2 = 0.65; P < 0.01), stavudine (r2 = 0.7; P < 0.01), and didanosine (r2 = 0.88; P < 0.01) (Fig. ). For abacavir, no significant correlation between maternal and cord plasma drug concentrations was seen. Furthermore, for lamivudine, a significant relationship between cord/maternal drug concentration ratios and postdosing intervals was seen (Fig. ). For the other drugs, the cord/maternal ratios were not affected by postdosing time intervals.
Relationship between concentrations of zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI) in cord and maternal plasma samples.
Relationship between cord/maternal lamivudine (3TC) concentration ratios in plasma and postdosing intervals.
There were 46 amniotic fluid samples available for zidovudine, 45 for zidovudine G, 27 for lamivudine, 15 for stavudine, 8 for didanosine, and 1 for abacavir. Among these amniotic fluid samples, the proportions with drug concentrations below the detection limit were 1 of 27 for lamivudine, 1 of 15 for stavudine, and 4 of 8 for didanosine, but drug was detectable in all samples for zidovudine (46 of 46), zidovudine G (45 of 45), and abacavir (1 of 1).
Median drug concentrations and ratios in amniotic fluid are displayed in Table . Median concentrations in amniotic fluid were higher than those in maternal and cord plasma samples for lamivudine (0.45 and 0.41 mg/liter, respectively), zidovudine (0.59 and 0.7 mg/liter, respectively), zidovudine G (1.60 and 1.62 mg/liter, respectively), and stavudine (0.0 and 0.04 mg/liter, respectively). Concentrations of zidovudine and its metabolite in amniotic fluid were higher in mothers receiving oral zidovudine prior to delivery than in mothers received only intrapartum intravenous zidovudine; the median zidovudine and zidovudine G concentrations were, respectively, 1.68 mg/liter (range, 0.89 to 4.33 mg/liter) versus 1.31 mg/liter (range, 0.15 to 2.67 mg/liter) (P < 0.01) and 8.8 mg/liter (range, 3.8 to 26.0 mg/liter) versus 2.9 mg/liter (range, 0.1 to 4.4 mg/liter) (P < 0.01). Median (range) amniotic fluid/cord plasma drug concentration ratios, in samples with cord plasma drug concentrations above the assay limit of detection, were as follows: zidovudine, 2.25 (0.08 to 8.38); zidovudine G, 2.83 (0.06 to 19.6); stavudine, 4.87 (0.98 to 11.9); lamivudine, 3.99 (1.62 to 17.1); and didanosine, 1.14 (1.02 to 3.16). There was only one such ratio for abacavir, 0.89. A significant relationship between amniotic fluid and cord plasma drug concentrations was seen for zidovudine G (r2 = 0.10; P < 0.01), lamivudine (r2 = 0.10; P < 0.01), and stavudine (r2 = 0.22; P < 0.01). The ratio of the amniotic fluid drug concentration to the maternal plasma drug concentration was significantly related to the time elapsed since the last maternal dose for lamivudine but not for stavudine, didanosine, and abacavir.
Drug concentrations in amniotic fluid and relationship to concentrations in plasma