Open-label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1-infected patients who failed placebo plus peginterferon and ribavirin.

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥ 800,000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥ 2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.

Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.

Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.

Early response to antidepressant treatment in bulimia nervosa.

BACKGROUND: Bulimia nervosa (BN) is a serious psychiatric disorder characterized by frequent episodes of binge eating and inappropriate compensatory behavior. Numerous trials have found that antidepressant medications are efficacious for the treatment of BN. Early response to antidepressant treatment, in the first few weeks after medication is initiated, may provide clinically useful information about an individual's likelihood of ultimately benefitting or not responding to such treatment. The purpose of this study was to examine the relationship between initial and later response to fluoxetine, the only antidepressant medication approved by the US Food and Drug Administration (FDA) for the treatment of BN, with the goal of developing guidelines to aid clinicians in deciding when to alter the course of treatment. METHOD: Data from the two largest medication trials conducted in BN (n=785) were used. Receiver operating characteristic (ROC) curves were constructed to assess whether symptom change during the first several weeks of treatment was associated with eventual non-response to fluoxetine at the end of the trial. RESULTS: Eventual non-responders to fluoxetine could be reliably identified by the third week of treatment. CONCLUSIONS: Patients with BN who fail to report a 60% decrease in the frequency of binge eating or vomiting at week 3 are unlikely to respond to fluoxetine. As no reliable relationships between pretreatment characteristics and eventual response to pharmacotherapy have been identified for BN, early response is one of the only available indicators to guide clinical management.

The effect of the impedance of a thin hydrogel electrode on sensation during functional electrical stimulation.

Surface functional electrical stimulation results in stimulation of cutaneous receptors and discomfort. The degree of non-uniformity of current distribution in the cutaneous layers in the vicinity of the electrode may influence the sensation experienced. This paper describes the effects on sensation of a thin, high impedance electrode designed to reduce the non-uniformity of current distribution. Sensation associated with stimulation via a self-adhesive electrode with much higher impedance than conventional electrodes was compared with a low impedance electrode in a single-blinded, crossover study. The high impedance electrode does not alter either the current at which sensation is first registered. However, at higher currents, the high impedance electrode allows 9% more current to be passed for an equivalent sensation to that experienced with the conventional electrode. A 28% decrease in discomfort with the use of the high impedance electrode was also reported.