738a 
Transplacental Passage of Tenofovir and other Antiretrovirals at Delivery
Stefano Bonora*1, D Gonzalez de Requena1, E Chiesa2, A Maccabruni3, M Forleo4, F Vichi5, S Fiore6, T Bini6, E Ferrazzi6, A d'Arminio Monforte6, and TARGET Study Group
1Univ of Turin, Italy; 2Hosp di Circolo, Busto Arsizio, Italy; 3Univ of Pavia, Italy; 4Univ of Brescia, Italy; 5SM Annunziata Hosp, Florence, Italy; and 6Univ of Milan, Italy
Background: Knowledge of the magnitude of
the ART transfer across the placenta is essential for management of efficacy
and safety of HAART in pregnancy. Nucleoside reverse transcriptase inhibitors
(NRTI) have been shown to cross the placenta by simple diffusion and to
concentrate in amniotic fluid. Tenofovir (TDF) has
been found to cross the placenta in animal models, while human placental
transfer has not yet been investigated. Therefore, the aim of our study was to
evaluate placental transfer of TDF and other ART in the clinical setting.
Methods: In a
substudy of TARGET (an observational, multicenter Italian study of HAART in
pregnancy), we obtained paired samples of maternal and cordal blood at delivery
of 30 HIV+ women taking HAART. Samples were simultaneously collected
from a peripheral maternal vein and from the umbilical vein. Drugs administered
were TDF (n = 5), zidovudine (AZT, n = 30), lamivudine (3TC, n
= 27), abacavir (ABV, n = 3), nevirapine (NVP, n = 14),
nelfinavir (NFV, n = 8), lopinavir/ritonavir (LPV/RTV, n = 2),
and amprenavir/ritonavir (APV/RTV, n = 1). Plasma concentrations of all
ART administered was measured by a validated high-performance liquid
chromatography (HPLC) method. Placental transfer was determined as a ratio of
cordal-to-maternal drug concentrations.
Results: Median
cordal versus maternal plasma concentrations and median (range) ratios (R)
of cordal-to-maternal drug plasma concentration were the following: TDF 48 vs 47.5 ng/mL, R 0.99 (0.94 to 1.05); AZT 955 vs 664 ng/mL, R 1.85 (0.17 to 3.66); 3TC 206 vs 147 ng/mL, R 1.41 (0.5 to 2.18); ABV
216 vs 144 ng/mL, R 1.50 (1.05 to 2.24);
NVP 2611 vs 3653 ng/mL, R 0.79 (0.60
to 0.91); NFV 69 vs 468 ng/mL, R 0.14
(0 to 0.27); LPV 358 vs 6396 ng/mL, R
0.06 (0 to 0.11); APV 2534 vs 6839 ng/mL, R
0.37 (only 1 case); and RTV 14 vs 292 ng/mL, R 0 (0 to 0.003).
Conclusions: To the
best of our knowledge, this is the first clinical report of TDF passage across
placenta. This drug appeared to have an efficient transplacental passage, showing
equivalent concentration in cordal and maternal blood at delivery. However,
opposite to NRTI with confirmed median ratio values of >1, TDF ratios were
around 1 in all patients, suggesting simple diffusion without drug accumulation
in fetal blood. A high transfer was
confirmed also for NVP, while protease inhibitors were shown to cross the
placenta poorly, as previously reported. These data indicate that the pharmacology
of ART in the fetal compartment warrants further clinical evaluation.
|
