Search

Background: The impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown., Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL., Results: Twenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported., Conclusions: Changes in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

Placental cytokine balance may be critical for the control of mother-to-child transmission (MTCT) of HIV. We assessed whether the type and duration of antiretrovirals used for prevention of HIV-1-MTCT modified the inflammatory cytokine profile. We investigated the levels of cytokine expression in the placentas of 61 HIV-1-infected women who received zidovudine (ZDV) plus single dose nevirapine (SD-NVP) or ZDV only for prevention of MTCT. Placentas of 38 HIV-1-uninfected women were included as controls. All placentas were obtained after vaginal delivery. Levels of mRNA and cytokine expression were quantified using real-time PCR and ELISA, respectively, in placental explants and 24-hour culture supernatants and analyzed in relation to the women's characteristics and the type and duration of antiretroviral prophylaxis. HIV-1-infected and uninfected women did not show any differences in the expression of placental cytokine secretion except for a trend toward lower TNF-alpha mRNA levels in HIV-1-infected women. Within the HIV-1-infected group, women who were exposed to a long duration of ZDV (>72 days) or received SD-NVP less than 5h prior to delivery, more frequently expressed detectable levels of IL-10 in their placentas (32% versus 7% (p = 0.01) and 32% versus 5% (p = 0.02), respectively). No infant was found to be HIV-1-infected. Our results showed a normalization of the placental cytokine balance in HIV-1-infected women receiving antiretroviral prophylaxis. Furthermore, the type and duration of antiretroviral prophylaxis have an impact on the placental anti-inflammatory IL-10 expression level, which may contribute to controlling HIV replication at the placental level, thus reducing MTCT of HIV-1.

Antiretroviral treatment with zidovudine (ZDV) from the 14th week until the end of pregnancy has markedly reduced the vertical transmission rate of HIV-1 in Europe and North America. A shorter duration of treatment has reduced this rate in Africa and Southeast Asia to a lesser degree. In Southeast Asia, subtype E is the major subtype rather than subtype B as in Western countries. The goals of this study were to determine the optimal duration of ZDV prophylaxis for subtype E and to confirm its effectiveness at the histologic level. Fifty pregnant women seropositive for HIV-1 subtype E were given ZDV prophylaxis consisting of 300 mg administered twice daily, switching to 300 mg administered every 3 hours from the onset of labor until delivery. Twenty-seven received "short-term" ZDV lasting 14 to 35 days before delivery, whereas the other 23 received "long-term" ZDV lasting 62 to 92 days. The effectiveness of ZDV prophylaxis was assessed by detection of HIV-1 in the placenta using in situ polymerase chain reaction (PCR). All babies in this study were tested up to one year of age. Three were not positive until after one month of age, but one was positive as a neonate. Four neonates were positive for HIV-1 as detected by PCR on peripheral blood, including one in the neonatal period. All cases were from the short-term prophylaxis group. Decidual glandular epithelial cells were the only cell type in the placenta that expressed HIV proviral DNA under ZDV prophylaxis. Sixty-seven percent of placentas in the short-term ZDV group showed more than occasional positive cells compared with 22% in the group receiving long-term ZDV prophylaxis (P < 0.02). This is first study to compare the effectiveness of short-term and long-term ZDV prophylaxis with respect to the presence of HIV in the placenta. Our study shows that longer (at least 60 days) prophylaxis is more effective in reducing HIV expression in the placenta and is associated with reduced transmission to neonates.