P3 Prevalence of the hepatitis C virus polymorphism Q80K in a pooled analysis of G1 patients from telaprevir and simeprevir phase II/III clinical trials C Sarrazin, E Lathouwers, M Peeters, B Daems, A Buelens, J Witek, Y Wyckmans, B Fevery, T Verbinnen, A Ghys, M Schlag, A Baldini, S De Meyer and O Lenz Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany, Janssen Infectious Diseases BVBA, Beerse, Belgium, Janssen Research & Development LLC, Titusville, USA, Janssen, Beerse, Belgium, Janssen-Cilag, Vienna, Austria, Janssen, Paris, France

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8-h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV-infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR-resistant variants were classified by fold change in inhibitory concentration (IC50 ). Baseline TVR-resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR-resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR-resistant variants in non-SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR-based treatment arms in non-SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.

Background: In the Phase 3 study REALIZE, genotype 1 HCVinfected patients, who failed prior treatment with pegylatedinterferon (P) and ribavirin (R) (including relapsers, partial-and null-responders), received placebo (Pbo) or telaprevir (T) 750 mg q8 h for 12 weeks, with or without a Lead-in (i.e., 4 weeks of PR prior to starting telaprevir), in combination with 48 weeks of PR.Overall SVR rates were 64%, 66% and 17% (P < 0.001) in T12/PR48, Lead-in T12/PR48 and Pbo/PR48, respectively, with no significant difference with or without Lead-in.Viral variants emerging in patients who did not achieve SVR were characterised.Methods: HCV NS3-4A population sequencing was performed at baseline, during treatment, and at follow-up visits.Telaprevirresistant variants were classified into lower-level resistance (V36A/M, T54A/S, R155K/T, and A156S) and higher-level resistance (V36M+R155K and A156T/V).On-treatment virological failure (VF) was defined as discontinuation due to a virological stopping rule and/or having viral breakthrough.Relapse was evaluated in patients that completed their assigned treatment regimen.Results: In total, 97/530 (18%) patients receiving telaprevir had VF, with no significant difference in VF rate with or without Lead-in: 52/266 (20%) in T12/PR48 and 45/264 (17%) in Lead-in T12/PR48.The majority of patients who experienced VF were prior null-responders (78%) and had genotype 1a (71%).VF during the telaprevir/Pbo treatment phase (47/530, 9%) was predominantly associated with higher-level resistant variants, while VF during the PR treatment phase (50/530, 9%) was associated with both higherlevel (genotype 1a) and lower-level (genotype 1a/1b) resistant, or wild-type variants (genotype 1b).The overall relapse rate in the telaprevir treatment groups was 8% (32/414).A similar proportion of patients in T12/PR48 (7%) and Lead-in T12/PR48 (9%) relapsed.Relapse was generally associated with lower-level resistant or wildtype variants.In 60/104 (58%) patients who failed treatment and had resistant variants, variants were no longer detected at end of study (median follow-up = 11 months).Conclusions: The variants emerging in patients not achieving SVR in the REALIZE study were similar irrespective of the use of a Leadin and are consistent with those previously observed in treatmentnaive patients.Resistant variants became undetectable over time during follow-up in the majority of patients.

Einleitung/Ziele: In der REALIZE-Studie erhielten behandlungserfahrene Patienten mit HCV Genotyp 1 Infektion, bei denen die Therapie mit pegyliertem Interferon (P) und Ribavirin (R) versagt hat (einschl. Relapser, Partial Responder und Null Responder) Placebo (Pbo) oder Telaprevir (T) 750mg q8h über 12 Wochen mit oder ohne Lead-in Phase (LI, d.h. 4 Wochen PR vor Beginn mit T) in Kombination mit 48 Wochen PR. SVR-Raten betrugen 64%, 66% und 17% (P<0,001) in T12/PR48, Lead-in T12/PR48 und Pbo/PR48, respektive, ohne signifikante Differenz mit oder ohne LI. Virale Varianten in Patienten ohne SVR wurden charakterisiert.

Impulsivity is a psychological phenomenon that has not been extensively studied in headache patients. We aim to assess the presence of impulsivity in patients with chronic migraine (CM) and medication overuse (MO).All patients examined in an outpatient headache clinic between January 2013 and March 2014 were included. Episodic migraine, CM, and MO were diagnosed according to ICHD-III beta criteria. We prospectively gathered demographic and clinical characteristics. Mood disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and impulsiveness was assessed with the Plutchik Impulsivity Scale.A total of 155 patients were included (22 men, 133 women). The mean age (SD) was 38.2 (11.7) years (range, 18-70); 104 patients (67.1%) presented CM and, among them, 74 (71.1%) had MO. Of the patient total, 28.4% met criteria for anxiety, 7.1% for depression and 16.1% for impulsivity. The CM group showed higher scores for HADS-anxiety (8.5 [SD 4.5] vs 6.4 [SD 3.6], P = .003) and HADS-depression (4.4 [4.3] vs 1.9 [2.3], P < .001). Among CM cases only, scores for HADS-anxiety (9.3 [4.4] vs 6.8 [4.3], P = .01) and HADS-Depression (5.1 [4.6] vs 2.7 [2.9], P = .002) were higher in patients who also had MO. We found no associations between Plutchik scale scores or presence of impulsivity with either CM or MO.Impulsivity is a common trait in our population of migraine patients, but unlike mood disorders, it is not correlated with either CM or MO.La impulsividad es una dimensión psicológica no estudiada en profundidad en pacientes con cefalea. Pretendemos evaluar su influencia en la presencia de una migraña crónica (MC) o uso excesivo de medicación (UEM).Pacientes atendidos consecutivamente en una consulta de cefaleas (enero de 2013-marzo de 2014). Diagnosticamos migraña episódica, MC o UEM de acuerdo con la Clasificación Internacional de Cefaleas, versión beta de la III edición (CIC-III). Recogimos prospectivamente características demográficas y clínicas. Evaluamos trastornos del ánimo mediante la Escala de Ansiedad y Depresión Hospitalaria (HADS) y la impulsividad con la Escala de Plutchik.Ciento cincuenta y cinco pacientes (22 varones, 133 mujeres), edad 38,2 ± 11,7 años (18-70); 104 (67,1%) con MC y entre ellos 74 (71,1%) con UEM. El 28,4% de los 155 pacientes incluidos en la serie cumplía criterios de ansiedad, el 7,1% de depresión, y el 16,1% de impulsividad. Las puntuaciones de las subescalas HADS-ansiedad (8,5 ± 4,5 vs. 6.4 ± 3.6, p: 0.003) y HADS-depresión (4,4 ± 4,3 vs. 1,9 ± 2,3, p < 0,001), eran mayores en los casos con MC. Entre los pacientes con MC, HADS-ansiedad (9,3 ± 4,4 vs. 6,8 ± 4,3, p: 0,01) y HADS-depression (5,1 ± 4,6 vs. 2,7 ± 2,9, p: 0,002) eran más altas en aquellos con UEM. No encontramos relación entre la presencia de impulsividad o la puntuación en la Escala de Plutchik y la MC o UEM.En nuestra población de migrañosos la impulsividad es frecuente, pero, a diferencia de los estados de ánimo, no se correlaciona con MC o UEM.

Removal of dye compounds from colour baths used in the textile industry is a possible application of nanofiltration. However, the mechanisms involved in this process are not clearly understood and the practical application of the process is facing many problems such as fouling and flux decline. The mechanisms of retention and flux decline were examined using two different approaches. Firstly, synthetic dye baths were prepared according to manufacterer's recipes. Retention of two reactive dyes (reactive blue 2 and reactive orange 16) was studied in separate baths and with different concentrations of Na2SO4, Na2CO3, NaOH and a surfactant. Different nanofiltration membranes (UTC-60, NF70 and NTR 7450) were used. The water flux in each of the experiments was monitored. It was found that the retention of ions decreased with the ion concentration due to a decrease of the Donnan potential. The retention of the dyes was high and was not influenced by the dye concentration or the ionic strength. The water flux was dependent of the ion concentration in the feed solution: high ion concentrations caused a dramatic decrease of the water flux. The dye concentration in the bath was found to have only a minor influence, whereas surfactants did not change water flux or dye retention. A theoretical explanation for these effects is given. The phenomenon of flux decline limits strongly the applicability of nanofiltration for direct treatment of dye baths. In a second step, an industrial wastewater from a textile factory was treated biologically in an active sludge system. The effluent was used as feed for nanofiltration with the same membranes as in the first step. The overall results for these experiments were satisfactory. The ion concentration was much lower than in the earlier experiments due to mixing of different feed streams. Therefore, the water fluxes were not considerably lower compared with the clean water fluxes. The retentions were sufficiently high to make recirculation of the treated water possible, thereby providing a considerable saving of water.