Recent work has demonstrated the existence of a systemic interaction between didanosine (ddI) and tenofovir disoproxyl fumarate (TDF) that leads to a significant increase in plasma ddI levels when coadministered with TDF (40 to 50% increase). These two drugs are, respectively, nucleoside and nucleotide analogues of adenosine and efficiently inhibit the human immunodeficiency virus (HIV) reverse transcriptase when transformed to their triphosphate moieties in the intracellular (IC) medium (ddA-TP and TFV-DP, respectively). Since ddI and TDF partly share the same IC metabolic pathway leading to the active triphosphates, we investigated a putative IC interaction. We used high-performance liquid chromatography-tandem mass spectrometry techniques to determine ddA-TP and TFV-DP IC levels in HIV-infected patients cotreated with both drugs, in comparison with patients treated with just one of the two drugs. These measurements revealed no significant differences in IC levels of the corresponding triphosphates when ddI (250 mg, once a day [QD]) was coadministered with TDF (300 mg, QD) compared to ddI 400 mg (QD) administered without TDF, thus supporting the dose adaptation proposed for this combination. However, we observed that both ddA-TP and TFV-DP have very long IC half-lives, resulting in unusual IC pharmacokinetic profiles with no significant changes in triphosphate concentrations between two dosings. In the case of TFV-DP, this t 1/2 of elimination was roughly estimated to be 180 h (7.5 days). This characteristic is certainly interesting in terms of efficacy but could have some drawbacks in terms of virus resistance for patients discontinuing these drugs.Nucleoside reverse transcriptase inhibitors (NRTIs) were the first antiretroviral class shown to be effective against human immunodeficiency virus (HIV) infection and still play a critical role as major components of highly active antiretroviral therapy. The first generation of NRTIs comprised 2Ј,3Ј-dideoxynucleosides which have to undergo three phosphorylation reactions within cells and work both as competitive inhibitors and as chain terminators with regards to HIV reverse transcriptase.Closely related drugs, i.e., acyclic phosphonate analogues of nucleotides (NtRTIs), have recently been approved for clinical applications and are now given as part of combination antiretroviral regimens. This new strategy consists of directly providing the cell with the monophosphate analogue, thus bypassing the first phosphorylation step, which proved to be rate limiting for many NRTIs. The first approved drug of this category is tenofovir disoproxyl fumarate (TDF), which provides high intracellular (IC) levels of tenofovir diphosphate (TFV-DP, equivalent to NRTI triphosphate) with very low mitochondrial toxicity (7).However, the issue of drug-drug interactions between NRTIs and also between NRTIs and NtRTIs is of major concern and should be addressed with all the analytical and chemical tools available. NRTIs and NtRTIs might interact not only at the systemic level (absorption, ...

The aim was to evaluate emtricitabine (FTC) and tenofovir (TFV) neonatal ingestion through breast milk. Median TFV and FTC breast milk doses represented 0.03% and 2%, respectively, of the proposed oral infant doses. Neonatal simulated plasma concentrations were extremely low for TFV but between the half-maximal inhibitory concentration and the adult minimal expected concentration for FTC. The rare children who will acquire HIV despite TDF-FTC therapy will need to be monitored for viral resistance acquisition.For prevention of mother-to-child transmission (PMTCT) of HIV in resource-limited settings, single-dose nevirapine (sd-NVP) has been commonly administered at the start of labor up to now according to previous World Health Organization (WHO) guidelines. However, the use of sdNVP results in resistance mutations in 15 to 70% of women, at 4 to 6 weeks postpartum, compromising the success of subsequent treatments with NVP in mothers and children (1, 7). Adding a single dose of tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) reduced these resistance mutations by half (2, 10). TDF and FTC placental transfer has already been studied (4, 5), but no data were reported so far on the transfer of these drugs after birth through breast-feeding. Breast-feeding cessation or replacement feeding introduced under routine circumstances is no longer recommended by WHO, as these interventions are often associated with increased mortality and morbidity (13). Thus, it is important to assess to what extent maternal TDF and FTC are transmitted through breast milk to infants. Furthermore, TDF-FTC-based fully suppressive antiretroviral regimens represent now a recommended approach for PMTCT in pregnant, delivering, and breast-feeding women (14).Five Ivorian mothers included in the ANRS 12109 TEmAA (Tenofovir/Emtricitabine in Africa and Asia) study and who chose to exclusively breast-feed their infant were administered one tablet of NVP (200 mg) plus two tablets of TDF (300 mg)-FTC (200 mg) at the start of labor and one TDF-FTC daily tablet for 7 days postpartum. The protocol was approved by the Ethics Committee of the country (Cote d'Ivoire). The women and the children's fathers were asked to sign an informed consent form. Maternal blood and milk samples were collected concomitantly after drug administration on days 1, 2, 3, and 7 after delivery. A liquid-liquid extraction procedure was performed using 300 l of methanol-dichloromethane (10/16, vol/vol) containing 0.1% hydrochloric acid added to 100 l of milk samples. After vortexing and centrifugation at 20,000 ϫ g at ϩ4°C for 20 min, the upper phase was withdrawn and evaporated under nitrogen to dryness. The sample was then reconstituted with 100 l of mobile phase, and 40 l of the extract was injected in the analytical system. TFV and FTC concentrations were measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method previously described (9) and adapted for FTC. Limits of quantitation were 4.9 and 9.5 ng/ml for TFV and FTC, respectively. Maximal and minim...