Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

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 ⅐ 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/10 6 cells (interquartile range [IQR], 53 to 430 fmol/10 6 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/10 6 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.The combination tenofovir (TFV) disoproxil fumarate (TDF)-emtricitabine (FTC) has been considered during the perinatal period to prevent mother-to-child transmission (PMTCT) and/or to reduce viral resistance to nevirapine (NVP) (3, 8); its administration to pregnant women at the onset of labor followed by a single dose to the neonate was thus proposed. The TEmAA (Tenofovir/Emtricitabine in Africa and Asia) ANRS 12109 Trial study was an open, phase I/II trial built in two steps. In the first step, the TDF-FTC combination was administered to HIV-infected pregnant women, and the pharmacokinetics, safety, and toxicity were evaluated for mothers and their newborns (2). After estimation of the maternal and fetal FTC-tenofovir (TFV) pharmacokinetic profiles, the mother was proposed to renew the dose after 12 h if she had not delivered yet in order to maintain effective TFV fetal concentrations. Then, a 13-mg/kg of body weight TDF dose (at birth) was proposed for neonates to obtain similar exposure to that in adults (16). In the second step of the TEmAA study, the TDF-FTC combination was administered to HIV-infected pregnant women and to their newborns, allowing evaluation of these dose propositions based on the results obtained in the first step of the study. Tolerance and virological results have been reported elsewhere (24).TFV, like other nucleoside analogues, undergoes intracellular phosphorylation by various cellular kinases to an active diphosphate (TFV-DP), which competiti...