Origin Of The Far Off-Axis GRB171205A

We show that observed properties of the low luminosity GRB171205A and its afterglow, like those of most other low-luminosity (LL) gamma ray bursts (GRBs) associate with a supernova (SN), indicate that it is an ordinary SN-GRB, which was produced by inverse Compton scattering of glory light by a highly relativistic narrowly collimated jet ejected in a supernova explosion and viewed from a far off-axis angle. As such, VLA/VLBI follow-up radio observations of a superluminal displacement of its bright radio afterglow from its parent supernova, will be able to test clearly whether it is an ordinary SN-GRB viewed from far off-axis or it belongs to a distinct class of GRBs, which are different from ordinary GRBs, and cannot be explained by standard fireball models of GRBs as ordinary GRBsComment: 5 pages, 6 figures, updated data in Fig. 3, Corrected GRB angular distance used in Fig.

Direct-acting antiviral therapy for chronic hepatitis C

Hepatitis C virus (HCV) infection was discovered in the late 1980s. Since then, tremendous progress has been made in understanding the pathophysiology of HCV infection together with the development of improved therapies for patients with chronic hepatitis C. The main focus of this thesis was to improve our understanding of new treatment strategies for chronic hepatitis C. Several direct-acting antivirals were investigated in multiple in vitro and in vivo studies. This thesis gives more insight into the pathogenesis of chronic HCV infection, its epidemiology, development of innovative treatments and upcoming viral resistance during therapy with direct-acting antivirals. The results of this thesis contribute to the impressive treatment progress, which will ultimately improve the prognosis of chronic hepatitis C patients

Controlled-release interferon alpha 2b, a new member of the interferon family for the treatment of chronic hepatitis C

Introduction: Combination therapy with pegylated interferon alpha (Peg-interferon) and ribavirin is currently the cornerstone of antiviral therapy for chronic hepatitis C. Monotherapy with Peg-interferon still is important for the treatment of chronic hepatitis B. With the advent of new therapies, protease inhibitors for chronic hepatitis C and nucleotide inhibitors for chronic hepatitis B, there remains a need for interferon-based therapies. The side effects of Peg-interferon are a main disadvantage and represent a stumbling block for many patients to enter and continue therapy. Areas covered: In this review, the authors will discuss controlled-release interferon alpha 2b (CR2b) (Locteron (R), Biolex Therapeutics, Pittsboro, NC, USA), a new slow-release interferon alpha 2b preparation for the treatment of chronic viral hepatitis. Other alternative interferons will also be discussed. Expert opinion: CR2b is a slow-release microsphere preparation for the administration of plant-derived recombinant human interferon alpha 2b. Compared with Peg-interferon, treatment with CR2b shows less flu-like reactions and less depression, and is at least as effective as conventional Peg-interferon-based therapy in patients with chronic hepatitis C. CR2b has the added advantage of biweekly instead of once weekly administration. CR2b appears to cause more neutropenia than Peg-interferon alpha 2b. This may be due to higher trough serum levels of CR2b at the end of a dosing interval. The bone marrow effects of CR2b closely resemble those published for the registered Peg-interferon alpha 2a. CR2b appears to have at least comparable efficacy with fewer side effects than current registered Peg-interferon

Dynamic changes in HCV RNA levels and viral quasispecies in a patient with chronic hepatitis C after telaprevir-based treatment

Background: Telaprevir is a selective inhibitor of the hepatitis C virus NS3 center dot 4A serine protease. Treatment with telaprevir resulted in a rapid HCV-RNA decline in chronic hepatitis C genotype 1 patients. Objectives: To report the clinical and viral course of a patient treated with telaprevir in combination with pegylated interferon-alpha-2a and ribavirin in a Phase 2 clinical trial (PROVE3). Study design: This previous non-responder to interferon based therapy was treated for 40 weeks with a telaprevir, pegylated interferon alpha-2a, and ribavirin regimen. Viral sequencing and phylogenetic analysis were performed before, during and after therapy. Results: The patient, a 54 years old male patient, experienced a viral relapse 4 weeks post-treatment and HCV-RNA levels continued to increase 14 weeks post-treatment (150,000 IU/mL). The viral population, which was wild type at baseline, consisted of only V36A variants at both of these post-treatment time-points. Subsequently, this patient had a transient disappearance of HCV-RNA for more than 1 year in the absence of antiviral therapy. Thereafter, HCV-RNA reappeared again with a viral population consisting of only wild type virus. Phylogenetic analysis of NS3 center dot 4A corresponded with a viral population bottleneck resulting in changes in viral quasispecies. Conclusion: In this case report, significant viral load reductions resulted in a genetic bottleneck leading to a reduction of variability in the hepatitis C viral population. We hypothesize that the reduction in viral heterogeneity potentially led to a reduced viral capacity to adapt to a host immune response leading to a transient loss of detectable HCV-RNA. (C) 2011 Elsevier B.V. All rights reserve

The Impact of Hepatitis C Virus Direct-Acting Antivirals on Patient-Reported Outcomes: A Dutch Prospective Cohort Study

Contains fulltext : 194900.pdf (publisher's version ) (Open Access

Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log(10)IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24weeks in three patients. However, the R155K mutation was still observed 3.1years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients

Emergence of Hepatitis C Virus Genotype 4: Phylogenetic Analysis Reveals Three Distinct Epidemiological Profiles ▿

Hepatitis C virus (HCV) genotype 4 (HCV-4) infection is considered to be difficult to treat and has become increasingly prevalent in European countries, including The Netherlands. Using a molecular epidemiological approach, the present study investigates the genetic diversity and evolutionary origin of HCV-4 in Amsterdam, The Netherlands. Phylogenetic analysis of the NS5B sequences (668 bp) obtained from 133 patients newly diagnosed with HCV-4 infection over the period from 1999 to 2008 revealed eight distinct HCV-4 subtypes; the majority of HCV-4 isolates were of subtypes 4d (57%) and 4a (37%). Three distinct monophyletic clusters were identified, with each one having a specific epidemiological profile: (i) Egyptian immigrants infected with HCV-4a (n = 46), (ii) Dutch patients with a history of injecting drug use infected with HCV-4d (n = 44), and (iii) Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) infected with HCV-4d (n = 26). Subsequent molecular clock analyses confirmed that the emergence of HCV-4 within these three risk groups coincided with (i) the parenteral antischistosomal therapy campaigns in Egypt (1920 to 1960), (ii) the popularity of injecting drug use in The Netherlands (1960 to 1990), and (iii) the rise in high-risk sexual behavior among MSM after the introduction of highly active antiretroviral therapy (1996 onwards). Our data show that in addition to the influx of HCV-4 strains from countries where HCV-4 is endemic, the local spread of HCV-4d affecting injecting drug users and, in recent years, especially HIV-positive MSM will further increase the relative proportion of HCV-4-infected patients in The Netherlands. HCV-4-specific agents are drastically needed to improve treatment response rates and decrease the future burden of HCV-4-related disease

Adherence to ursodeoxycholic acid therapy in patients with cholestatic and autoimmune liver disease.

BACKGROUND: Ursodeoxycholic acid (UDCA) is used for treatment of cholestatic liver diseases and may improve long-term outcome. Although treatment with this hydrophilic bile acid is virtually without side effects, medication adherence might be suboptimal due to patient misconceptions, compromising clinical outcome. Our aim was to evaluate adherence to UDCA in relation to patient beliefs about medicine and to identify potential predictors of poor adherence. METHODS: Prospective open-label study recruiting patients in treatment with UDCA from April 2016 to March 2017. Adherence was assessed both by the Sensemedic dispenser and by patient-reported adherence, during 12 weeks. Good adherence was defined as ≥ 80% intake. Quality of life (by SF-36) and beliefs about medicine (by BMQ) were also assessed. RESULTS: A total of 75 patients were enrolled (32% primary biliary cholangitis, 31% autoimmune hepatitis, 29% primary sclerosing cholangitis and 8% other conditions). Average adherence according to the medication dispenser was 92 ± 16% (range: 17-100). Eighty-nine percent of the patients exhibited good adherence and 11% poor adherence. According to the BMQ, 42% of all patients were accepting, 50% ambivalent, 8% indifferent and 0% skeptical to UDCA treatment. Poor adherence was associated with young age (P = 0.029) and male gender (P = 0.021). CONCLUSIONS: Despite the excellent safety profile of UDCA, still a significant number of patients are poorly adherent. Young age and male sex are associated with poor adherence. Efforts should be made to identify patients with poor adherence and to improve their compliance to therapy