Real-life 3D therapy failure: Analysis of NS5A 93H RAS plus 108 K polymorphism in complex with ombitasvir by molecular modeling.

We report a real-life 3D therapy failure in a patient treated with ombitasvir (OMV)/paritaprevir/ritonavir and dasabuvir without ribavirin (3D-R). He had therapy failure at week 12 after the end of treatment. We detected resistance-associated substitutions (RASs) plus polymorphisms on NS3, NS5A, and NS5B target regions by population sequencing (15% cut-off) at baseline, at relapse and during follow-up. About this, NS5A RASs generally persist longer than resistances in the other target genes and may impact treatment outcome. Therefore, to evaluate OMV drug-resistance mechanism, we studied the acquired RAS plus polymorphisms on NS5A phosphoprotein by computational studies. OMV showed a higher affinity towards baseline and 93H/108 K mutant structure (follow-up) with respect to 93H/R108 mutant structure (relapse) on phosphoprotein. By Molecular Dynamics simulations (MDs), structural information about the protein stability in presence of OMV were observed. According to our data, molecular modeling approach has proved to be a powerful method to evaluate the impact of these RASs plus specific amino acid (AA) changes on phosphoprotein.

Boceprevir or telaprevir in hepatitis C virus chronic infection: The Italian real life experience.

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.

Biphasic hemodynamic effects of LDL-apheresis in common carotid artery.

OBJECTIVE: Heparin-induced Extracorporeal Low Density Lipoprotein Precipitation (HELP) Apheresis gives beneficial reductions in Low Density Lipoprotein (LDL) cholesterol levels; otherwise, extracorporeal circulation settings might elicit inflammation and platelet aggregation. The net effect of these variations on carotid hemodynamic has not been established. Aim of the present study was to investigate periprocedural variations of common carotid artery wall shear stress, circumferential wall tension, and Peterson's elastic modulus. METHODS: Measurements were sequentially performed on 22 procedures: immediately before apheresis (T1), within one hour after (T2), after 24 (T3) and 48 hours (T4). In order to confirm acute effects, in additional 30 procedures measurements were performed at T1 and T2. RESULTS: Mean shear stress was decreased at T2, with an improvement at T4. Mean circumferential wall tension showed an improvement at T4; arterial stiffness showed the same trend, but only close to statistical significance. The following 30 procedures, where measurements were performed at T1 and T2 only, confirmed previous results, showing a deep wall shear stress decrease at T2 (-21%). CONCLUSION: LDL apheresis seems to have a biphasic effect on common carotid hemodynamics: the acute worsening of shear stress, probably mediated by extracorporeal circulation, was followed by its improvement, possibly driven by LDL cholesterol reduction.