Transmitted drug resistance to rilpivirine in newly diagnosed antiretroviral naive adults.

We characterized transmitted drug resistance to rilpivirine and the predicted efficacy of first-line rilpivirine-containing regimens in antiretroviral-naive Spanish patients. International Antiviral Society-USA mutations were detected in 138 of 2781 patients (4.9%), E138A (3.4%) being the most prevalent. Using the Stanford Algorithm, 121 patients (4.4%) showed low-level or intermediate resistance. No differences in the predicted efficacy of first-line non-nucleoside reverse transcriptase inhibitor-based regimens were observed. As rilpivirine becomes more widely used in clinical practice, the evolution of its transmitted drug resistance will need to be monitored. In addition, the exact role of E138A singletons on rilpivirine activity as part of first-line regimens merits further evaluation.

Use of cohort data to estimate national prevalence of transmitted drug resistance to antiretroviral drugs in Spain (2007-2012).

Prevalence of transmitted drug resistance (pTDR) to antiretroviral drugs in Spain (2007-2012) was estimated using the CoRIS cohort, adjusting its territorial distribution and transmission route to the reference population from the Spanish Information System on New human immunodeficiency virus diagnoses. A total of 2702 patients from ten autonomous communities and with naive FASTA sequence within 6 months of human immunodeficiency virus diagnosis were selected. Weighted pTDR, estimated using the inverse probability of selection in the sample by autonomous communities and transmission group, was 8.12% (95% CI 6.44-9.80), not significantly different from unweighted pTDR. We illustrate how proportional weighting can maximize representativeness of cohort-based data, and its value to monitor pTDR at country level.

Analysis of transmitted drug resistance in Spain in the years 2007-2010 documents a decline in mutations to the non-nucleoside drug class.

We have studied transmitted drug resistance (TDR) in 1.864 antiretroviral-naïve patients entering CoRIS (Spain) during 2007-2010. An overall 8.58% TDR was observed (3.92%, nucleoside reverse transcriptase inhibitors (NRTIs); 3.86%, non-nucleoside reverse transcriptase inhibitors (NNRTIs); 2.31%, protease inhibitors), with a significant decreasing trend over time for NNRTIs (5.53%, 2007; 2.45%, 2010; p for trend = 0.044). Non-B subtype prevalence was 15.93%, with a significant increase (11.95%, 2007; 18.14%, 2010; p for trend = 0.018), mainly related to immigration. Having no formal education increased the risk of TDR to NNRTIs (OR, 7.26), and carrying a non-B subtype reduced the risk of TDR to NRTIs (OR, 0.27). These findings may have important implications for treatment guidelines and laboratory testing recommendations.

Synthesis, ligand pK(a), and Fe(III) complexation constants for a series of bipodal dihydroxamic acids.

The synthesis of four bipodal dihydroxamic acids containing an apical C atom and amide linkages is described, where Ia,b represent "normal" and "retro" hydroxamate isomers: (R)CH[C(=O)NH(CH(2))(2)NHC(=O)(CH(2))(n)()R'](2) (Ia, R = CH(3), R' = N(OH)(C=O)CH(3), n = 2; Ib, R = CH(3), R' = (C=O)N(OH)CH(3), n = 2; Ic, R = CH(3), R' = (C=O)N(OH)CH(3), n = 3; Id, R = C(4)H(9), R' = (C=O)N(OH)CH(3), n = 2.). The pK(a1) and pK(a2) values in aqueous solution are reported, and some degree of cooperativity is noted. Complexation equilibria with Fe(aq)(3+) are described, and values for stepwise and overall equilibrium constants are reported. log beta(230) values for Ia-d are 59.22, 59.45, 58.91, and 58.46, slightly lower than for rhodotorulic acid, although the pFe values for the synthetic siderophores are comparable to that for rhodotorulic acid.

Cytoprotection and iron mobilization in rat hepatocyte cultures by a new synthetic dihydroxamate chelator.

The cytoprotection and iron mobilization effect of a new dihydroxamate chelator 1,1 bis [(11-N-hydroxy)-2,5,11-triaza-1,6,10-trioxo dodecanyl] ethane or KD was studied in primary rat hepatocyte cultures exposed to iron-citrate. Lactate dehydrogenase (LDH) release and malondialdehyde (MDA) production were measured as indexes of cytotoxicity. Cell viability was evaluated using the [3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide] (MTT) reduction test. To demonstrate that this chelator was able to decrease iron uptake or increase iron release from the hepatocytes, labelled cells were obtained by maintaining the cultures in the presence of 0.02 microM 55Fe-citrate. The efficacy of KD was compared to desferrioxamine B (DFO) at stoechiometry concentrations. After 24 h of exposure to 50 microM of iron-citrate, a significant release of LDH and MDA was observed. Cell viability was also significantly decreased. When 100 microM of KD were added at the same time as iron, LDH and MDA release was decreased and cell viability was improved. In the presence of the same chelator concentration, a net decrease of iron uptake by the cells was observed as attested by the low intracellular 55Fe level. Moreover, in the 55Fe loaded hepatocytes, the chelator increased the iron extracellular level indicating its iron release effect from the cells. In all tested experimental conditions, the efficacy of 100 microM of the dihydroxamate chelator KD was close to that of 50 microM of the trihydroxamate chelator DFO. In conclusion, KD is effective at a level comparable to DFO in protecting rat hepatocytes against the toxic effect of iron-citrate by decreasing the uptake of the metal and increasing its release from the cells. This synthetic compound appears to have some potential therapeutical interest and the results obtained encourage the synthesis of new hydroxamate ligands.