RESUMO
The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter · h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/106 cells (interquartile range [IQR], 53 to 430 fmol/106 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/106 cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adenina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , HIV-1 , Recém-Nascido/metabolismo , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Organofosfonatos/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adenina/farmacocinética , Feminino , Humanos , Gravidez , TenofovirRESUMO
OBJECTIVE: Viral resistance occurs with a high frequency after single-dose nevirapine. We aimed to evaluate the tolerance and resistance profiles of a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) given to HIV-1-infected delivering women and their newborns. DESIGN: An open-label phase I/II trial in Cambodia, Côte d'Ivoire and South Africa. METHODS: HIV-1-infected pregnant women received zidovudine from the enrollment until the beginning of labor, when single-dose nevirapine and two tablets of TDF/FTC were given. One daily tablet of TDF/FTC was then administered for 7 days postpartum. All infants received single-dose nevirapine with single-dose TDF (13 mg/kg) and single-dose FTC (2 mg/kg) and 1 week of zidovudine. Mothers and infants were followed for 2 months. Serious adverse events, kinetic of maternal plasma HIV-1 RNA, pediatric HIV infection and genotypic resistance and viral subtype were assessed. RESULTS: Thirty-six HIV-1-infected pregnant women were enrolled: median age 28 years (interquartile range: 26-31 years), median CD4 cell count 462 cells/µl (interquartile range: 376-632) and median HIV-1 RNA 3.7 log10 copies/ml (interquartile range: 2.95-4.11). Two infants had clinical serious adverse events, including one who died (neonatal sepsis). One transient grade 3 neutropenia and two grade 3/4 hyperbilirubinemia were also reported in neonates. One HIV pediatric in-utero infection was diagnosed (2.8%; 95% confidence interval 0-15.4%). Genotypic viral resistance to nevirapine was detected in one mother out of 34 (2.9%) at one month postpartum, but was also detectable at enrollment. CONCLUSION: The combination of TDF/FTC to delivering women and their neonates appears well tolerated and to minimize the occurrence of nevirapine viral resistance.