BACKGROUND & AIMS:Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.METHODS:Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).RESULTS:Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.CONCLUSIONS:Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

in NHERF-1 F355R infected cells.FRET was observed in wild type and T564A YFP-radixin-CFP constructs, indicating molecular (N-C)-terminal binding.No significant FRET was detected in T564D YFP-radixin-CFP.In Vitro FRET analysis and actin binding binding assay demonstrated that Thr564 phosphorylation opens the (N-C)-terminal interaction and the opened phosphorylated form of radixin more readily cosediments with F-actin and binds to membrane.In addition, we have characterized of NHERF1 as a binding partner of Mrp-2.We identified the presence of radixin and NHERF-1 in hepatocytes and our data strongly implicate that radixin and NHERF-1 are essential for maintaining the polarized targeting and retaining of canalicular transporters and is a critical determinant of the overall structure and function of the canalicular membrane of hepatocytes.

Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb] <10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had 1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P < 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. (HEPATOLOGY 2013)

BACKGROUNDMyelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy.METHODSA total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0.RESULTSA total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection.CONCLUSIONSNadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

BACKGROUND:Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.METHODS:We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.RESULTS:A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.CONCLUSIONS:The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

A factor of 4 dimensionless collisionality scan of H-mode plasmas in MAST shows that the thermal energy confinement time scales as B tau(E,th) alpha v(*e)(-0.82 +/- 0.1) Local heat transport is dominated by electrons and is consistent with the global scaling. The neutron rate is in good agreement with the nu(*) dependence of tau(E,th). The gyrokinetic code GYRO indicates that micro-tearing turbulence might explain such a trend. A factor of 1.4 dimensionless safety factor scan shows that the energy confinement time scales as B tau(E,th) alpha q(eng)(-0.82 +/- 0.2) eng. These two scalings are consistent with the dependence of energy confinement time on plasma current and magnetic field. Weaker q(eng) and stronger. dependences compared with the IPB98y2 scaling could be favourable for an ST-CTF device, in that it would allow operation at lower plasma current.

trended toward increased improvement with treatment duration >2.5 years.Since all subjects participated in the retreatment study, carryover effects from full-dose PEG/RBV may have obscured MT treatment effects.These data suggest PEG decreases hepatic inflammation, but impact on MFS may not be demonstrated with 3 years of MT.

Previous studies of chronic hepatitis C virus (HCV) treatment have demonstrated variations in response among racial and ethnic groups including poorer efficacy rates among African American and Hispanic patients. The individualized dosing efficacy vs flat dosing to assess optimaL pegylated interferon therapy (IDEAL) trial enrolled 3070 patients from 118 United States centres to compare treatment with peginterferon (PEG-IFN) alfa-2a and ribavirin (RBV) and two doses of PEG-IFN alfa-2b and RBV. This analysis examines treatment response among the major racial and ethnic groups in the trial. Overall, sustained virologic response (SVR) rates were 44% for white, 22% for African American, 38% for Hispanic and 59% for Asian American patients. For patients with undetectable HCV RNA at treatment week 4, the positive predictive value of SVR was 86% for white, 92% for African American, 83% for Hispanic and 89% for Asian American patients. The positive predictive values of SVR in those with undetectable HCV RNA at treatment week 12 ranged from 72% to 81%. Multivariate regression analysis using baseline characteristics demonstrated that treatment regimen was not a predictor of SVR. Despite wide-ranging SVR rates among the different racial and ethnic groups, white and Hispanic patients had similar SVR rates. In all groups, treatment response was largely determined by antiviral activity in the first 12 weeks of treatment. Therefore, decisions regarding HCV treatment should consider the predictive value of the early on-treatment response, not just baseline characteristics, such as race and ethnicity.

Background and Aims: Chronic hepatitis C (CHC) patients with failure to antiviral therapy are a challenge.Reports of retreatment have included nonresponders and relapsers mostly previously treated with conventional IFN and ribavirin (RBV).We evaluated the efficacy and factors related to sustained virological response (SVR) in CHC patients who have relapsed after a prior treatment with PEG-IFN plus RBV.Methods: Out of 1,228 CHC patients treated with PEG-IFN/RBV, 165 (13%) had a relapse.Among these, 62 patients were retreated between April 2003 and June 2008 with PEG-IFN-a-2a or -2b and RBV at a dose of 800 to 1200 mg/day.Clinical, biological, virological and histological data were collected.Type of PEG-IFN, initial doses and modifications of therapy were analyzed.The efficacy was evaluated with a qualitative HCV RNA assay (<15 IU/mL).Factors associated with SVR were analyzed.Results: SVR was achieved in 26 of the 62 (42%) patients; 69% received PEG-IFN-a2a.Median duration of therapy was 48 weeks (16-72 weeks).Retreatment was at least 24 weeks longer than the previous course in 51%.SVR was higher in young (<50 years) (61%) than old patients (27%) (p = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) (p = 0.023).Lengthening therapy for at least 24 weeks than previous course was associated with higher SVR (53% vs 28%, p = 0.04).Also, among 16% of patients who received a high ribavirin dose per weight (>15.2 mg/kg/day), a better SVR rate was observed when compared to lower dose/weight (70% vs 35%, p = 0.04).All patients without complete EVR (undetectable HCV RNA at W12) did not achieve SVR (Negative Predictive Value, NPV = 100%).In the logistic regression, independent predictors of response were: age (p = 0.018), genotype (p = 0.048) and initial ribavirin dose/weight (p = 0.022). Conclusion:Retreatment with PEG-IFN plus ribavirin is effective in genotype 2 or 3 relapsers after a first course of PEG-IFN plus RBV, especially in young patients.High RBV dose per weight seems to be an important factor for the retreatment response.Furthermore, the presence of detectable HCV RNA at W12 should be considered a stopping rule in the retreatment of relapsers.

Several improvements to the MAST plant and diagnostics have facilitated new studies advancing the physics basis for ITER and DEMO, as well as for future spherical tokamaks (STs). Using the increased heating capabilities P NBI ⩽ 3.8 MW H-mode at I p = 1.2 MA was accessed showing that the energy confinement on MAST scales more weakly with I p and more strongly with B t than in the ITER IPB98(y, 2) scaling. Measurements of the fuel retention of shallow pellets extrapolate to an ITER particle throughput of 70% of its original designed total throughput capacity. The anomalous momentum diffusion, χϕ, is linked to the ion diffusion, χi, with a Prandtl number close to P ϕ ≈ χϕ/χi ≈ 1, although χi approaches neoclassical values. New high spatial resolution measurements of the edge radial electric field, E r , show that the position of steepest gradients in electron pressure and E r (i.e. shearing rate) are coincident, but their magnitudes are not linked. The T e pedestal width on MAST scales with rather than ρpol. The edge localized mode (ELM) frequency for type-IV ELMs, new in MAST, was almost doubled using n = 2 resonant magnetic perturbations from a set of four external coils (n = 1, 2). A new internal 12 coil set (n ⩽ 3) has been commissioned. The filaments in the inter-ELM and L-mode phase are different from ELM filaments, and the characteristics in L-mode agree well with turbulence calculations. A variety of fast particle driven instabilities were studied from 10 kHz saturated fishbone like activity up to 3.8 MHz compressional Alfvén eigenmodes. Fast particle instabilities also affect the off-axis NBI current drive, leading to fast ion diffusion of the order of 0.5 m2 s−1 and a reduction in the driven current fraction from 40% to 30%. EBW current drive start-up is demonstrated for the first time in a ST generating plasma currents up to 55 kA. Many of these studies contributed to the physics basis of a planned upgrade to MAST.

Neo-classical tokamak plasma theory predicts poloidal rotation driven by the temperature gradient of a few km s(-1). In conventional aspect-ratio tokamak plasmas, e.g. on JET and DIII-D, apparent poloidal velocities considerably in excess of the neo-classical values have been measured, particularly in the presence of internal transport barriers, by means of charge-exchange recombination spectroscopy (CXRS) on the fully ionized C6+ impurity ions. Comparison between such measurements and theoretical predictions requires careful corrections to be made for apparent 'pseudo' velocities, which can arise from the finite lifetime of the excited atoms in the magnetized plasma and the energy dependence of the charge-exchange excitation process. In present day spherical tokamak plasmas this correction is an order of magnitude smaller than on large conventional tokamaks, which operate at higher temperature and magnetic field, hence reducing any associated systematic uncertainties. On MAST measurements of toroidal and poloidal flows of the C6+ impurities are available from high-resolution Doppler CXRS measurements, including appropriate corrections for the pseudo-velocities. Comparison of the measured C6+ velocities with neo-classical theory requires calculation of the impurity flow, which differs from that of the bulk ions due to the respective diamagnetic contributions for each species and inter-species friction forces. Comparisons are made with the predictions of a recent neo-classical theory (Newton 2007 Collisional transport in a low collisionality plasma with strong rotation PhD Thesis University of Bristol, Newton and Helander 2006 Phys. Plasmas 13 102505), which calculates the full neo-classical transport matrix for bulk ions and a single impurity species for a strongly rotating plasma, as well as those of

Background: High maternal serum HBV DNA is a risk factor for vertical transmission of HBV.Lamivudine (LAM; US pregnancy category C) and tenofovir disoproxil fumarate (TDF; US pregnancy category B) are licensed for the treatment of both HIV-1 and chronic HBV infection.The use of LAM and TDF to prevent HBV vertical transmission is of interest, but efficacy and safety data are limited.Methods: The Antiretroviral Pregnancy Registry (APR) is a prospective international registry of voluntary reports to detect major teratogenic effects involving antiretrovirals (ARVs) and HBV drugs administered in pregnancy.Founded in 1989, the APR enrolls ~1300 pregnant women/year in the US (~20% of live births to HIV-1 infected women).Results: Cumulative APR data on HBV drug exposure in pregnancy for LAM, TDF, adefovir, entecavir and telbivudine (7,720, 942, 30, 2, and 1 live births, respectively) were reviewed from 11,950 prospective cases (9,948 live births) reported to the APR through July 31, 2008.Most cases were in HIV-1-infected women, typically exposed to combination ARVs; 107 cases were HIV-1/HBV co-infected and 99 had HBV mono-infection.Congenital anomaly rates with LAM and TDF are comparable to those in the CDC population-based birth defects surveillance system in the US (2.72/100 live births) and to rates of other ARVs in the APR.

S51 PEG-IFNa-2a (40KD) 360 mg/week (N = 433) n (%) PEG-IFNa-2a (40KD) 180 mg/week (N = 438) n (%) Efficacy (as HCV RNA <15 IU/mL) Week 4 RVR 156 (35.0)* 115 (26.3)Week 12 complete EVR 322 (74.4)** 270 (61.6)Week 24 325 (75.1) # 297 (67.8)Week 48 EOT 301 (70.0) 287 (66.0)Week 72 SVR 230 (53.0) 219 (50.0)Safety Overall Tx discontinuations 115 (27) 136 (31) Tx discontinuations due to AEs or lab abnormalities 41 (9) 32 (7) SAEs 46 (11) 45 (10) Dose modifications (Peg-IFNa-2a (40KD)) 119 (27) 78 (18) Neutropenia (<0.5×10 9 /L) 34 (8) 16 (4) Thrombocytopenia (<50×10 9 /L) 18 (4) 11 (3) Anaemia (<10 g/dL) 72 (17) 65 (15) Cochran-Mantel-Haenszel test: *p < 0.

Background: Liver cancer is the third leading cause of cancer death and the incidence of hepatocellular carcinoma (HCC) is increasing globally.Effective therapy for advanced HCC was an unmet need until a recent phase III trial [Sorafenib HCC Assessment Randomized Protocol (SHARP)], which demonstrated that sorafenib, a multi-kinase inhibitor blocking Raf-1, VEGFR and PDGFR, significantly improves overall survival (OS) versus placebo.Recently, sorafenib gained approval by the regulatory agencies for the treatment of HCC.Patients who failed previous loco-regional therapies were permitted in the SHARP trial; here we report results of a subgroup analysis, which evaluated the effect of patients' prior therapies on their outcomes.Methods: 602 patients with advanced, measurable HCC, ECOG PS0-2 and CP-A, received either sorafenib (400 mg bid) or placebo.Endpoints included OS, time to progression (TTP; based on independent tumor assessment), and safety.This subgroup analysis evaluates 270 patients from SHARP who received prior curative treatments (resection/local ablation, PEI, RFA) (n = 158) and patients who received previous chemoembolization (TACE) therapy (n = 176).Results: Among 158 patients previously treated with curative treatments, 81 received sorafenib and 77 placebo; while among 176 patients progressing after TACE, 86 received sorafenib and 90 placebo.Median TTP was significantly better in the sorafenib group compared with placebo for patients progressing after curative treatments: TTP was 5.5 vs 2.7 months (HR: 0.62; 95%CI: 0.39-0.98)and after chemoembolization: median TTP 5.8 vs 4.0 months (HR: 0.57; 95%CI: 0.36-0.91).Median OS showed a favorable trend towards sorafenib benefit for curative treatments group [11.9 vs 8.8 months (HR: 0.79; 95%CI: 0.51-1.22)]and chemoembolization group [11.9 vs 9.9 months (HR:0.75;95%CI: 0.49-1.14)].Most common grade 3 drug-related treatment-emergent adverse events for sorafenib were diarrhea (9.9 vs 7.0%) and hand-foot skin reaction (8.6 vs 7.0%) for curative treatments vs TACE, respectively.No grade 4 drug-related diarrhea or hand-foot skin reaction was reported.Conclusions: Sorafenib improved clinical outcomes compared with placebo in patients with unresectable HCC irrespective of prior therapy.These data are consistent with those in the overall SHARP population and support sorafenib as the new standard of care in HCC patients progressing after loco-regional therapies.

Background: Peginterferon (PEG-IFN) plus ribavirin is the treatment of choice for chronic liver disease due to hepatitis C virus (HCV).Since two types of PEG-IFN are available, the aim of this study was to compare their efficacy and safety.Methods: 320 consecutive treatment-naive patients, HCV-RNA positive chronic hepatitis/cirrhosis, were randomised to receive either PEG-IFN alpha-2a 180mg/week (Group A) or PEG-IFN alpha-2b 1.5 mg/kg/week (Group B) plus ribavirin 1000 (<75 kg) or 1200 mg/d ( 75 kg).Patients (pts) affected by genotypes 1/4 received 48 weeks of treatment, while those affected by genotypes 2/3 were treated for 24 weeks.Analysis was done by intention-to-treat strategy.Results: Overall the SVR (undetectable serum HCV-RNA 24 weeks after the end of treatment) was obtained by 197 pts (61.6%): 110 (68.7%) in Group A and 87 (54.4%) in Group B (p = 0.008).In genotype 1/4, the SVR was obtained by 88 pts (47.3%): 51 (54.8%) in Group A and 37 (39.8%) in Group B (p = 0.04); in genotype 2/3, the SVR was obtained by 109 pts (81.3%): 59 (88.1%) in Group A and 50 (74.6%) in Group B (p = 0.046).In pts with chronic hepatitis the SVR occurred in 171 (65.5%): 96 (75.6%) in Group A and 75 (56%) in Group B (p = 0.0009); in cirrhotic pts the SVR was obtained by 26 (44.1%): 14 (42.4%) in Group A and 12 (46.2%) in Group B (p = 0.7).The SVR, according to the basal viral load, was similar in the two groups if HCV-RNA was equal or less than 500,000 IU/mL.In pts with viral load of more than 500,000 IU/mL, the SVR in Group A was 69%, while in Group B was 46.2%: this difference was statistically significant (p = 0.002).At multivariate analysis the variables independently related to the SVR were: male sex; absence of cirrhosis; Genotype 2/3; treatment with PEG-IFN alpha-2a.As far as the side effects are concerned they were similar, although there were more withdrawals for side effects in the group treated with PEG-IFN alpha-2b. Conclusion:In HCV chronic hepatitis, patients treated with PEG-IFN alpha-2a plus ribavirin obtained significantly more SVR than those treated with PEG-IFN alpha-2b.

Radial profiles of electron temperature and density through type I ELM filaments have been obtained from a new edge Thomson scattering diagnostic at MAST. The lasers were fired in burst mode, 5 µs apart, to study profile evolution of a single filament as it moves toroidally past the laser beams. The plasma particle and energy loss due to each filament can be deduced from these profiles. As the filaments move out of the plasma, the ne pedestal is seen to collapse locally inwards by as much as 7.5% of the plasma minor radius. Insight into the toroidal structure of the perturbation has been obtained from high time resolution interferometry data. The interferometer data show excursions in line integral density through the midplane of the plasma occurring from 150 µs before the onset of the ELM particle loss. These excursions are due to the evolution of the spatial structure of the plasma during the ELM and indicate that the filaments may develop from broader structures. By combining the toroidal structure information from the interferometer and the radial structure information from the TS system with other diagnostic data on MAST, a two dimensional picture of the ELM phenomenon is obtained.