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HCV cirrhosis at the edge of decompensation: Will paritaprevir with ritonavir, ombitasvir, dasabuvir, and ribavirin solve the need for treatment? - Journal of Hepatology

HCV cirrhosis at the edge of decompensation: Will paritaprevir with ritonavir, ombitasvir, dasabuvir, and ribavirin solve the need for treatment? - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
HCV cirrhosis at the edge of decompensation: Will paritaprevir/r, ombitasvir, dasabuvir and R solve the need for tx http://t.co/dVfDKqs8Ji

 

Abstract. BACKGROUND: The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.

METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B.

RESULTS: A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B.

CONCLUSIONS: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).

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Journal of Hepatology

 

HCV cirrhosis at the edge of decompensation: Will paritaprevir with ritonavir, ombitasvir, dasabuvir, and ribavirin solve the need for treatment?Tarik Asselah, Savino Bruno, Antonio CraxiReceived: June 13, 2014; Received in revised form: August 6, 2014; Accepted: August 9, 2014; Published Online: August 19, 2014 DOI: http://dx.doi.org/10.1016/j.jhep.2014.08.018
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Hepatitis C New Drugs Review
FDA approved Incivek(telaprevir, Vertex) on Monday 23 May by its PDUFA deadline.A paradigm shift in the treatment of Hepatitis C virus infection. http://knol.google.com/k/krishan-maggon/boceprevir-merck-telaprevir-vertex/3fy5eowy8suq3/151#
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Created public version #121 of the knol: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval"

Created public version #121 of the knol: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval" | Hepatitis C New Drugs Review | Scoop.it
Krishan Maggon published version 121 of a knol titled: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval"...
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Significance of pSmad2/3 and Smad4 in hepatitis C virus‐related liver fibrosis and hepatocellular carcinoma - Moussa - 2018 - APMIS - Wiley Online Library

Significance of pSmad2/3 and Smad4 in hepatitis C virus‐related liver fibrosis and hepatocellular carcinoma - Moussa - 2018 - APMIS - Wiley Online Library | Hepatitis C New Drugs Review | Scoop.it
This study aims to assess hepatic expression of pSmad2/3 and Smad4 in CHC with different stages of fibrosis and grades of necro‐inflammation as well as in HCC on top of CHC. This study was done on 33 core liver biopsies from patients with CHC (15 with early fibrosis and 18 with late fibrosis), 15 liver specimens from HCC cases on top of CHC, as well as five normal controls. pSmad2/3 and Smad4 show more immunopositivity, higher percentage of positive hepatocytes and stronger staining intensity in CHC with late fibrosis compared to early fibrosis. pSmad2/3 shows increase of the previous parameters in CHC with high grade activity than those with low activity. Smad4 shows increase of the previous parameters in HCC compared to CHC cases. pSmad2/3 and Smad4 can be used as diagnostic and/or prognostic markers for progression of HCV‐related fibrosis to cirrhosis and further progression to HCC.
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100% Sustained Virological Response and Fibrosis Improvement in Real-Life Use of Direct Acting Antivirals in Genotype-1b Recurrent Hepatitis C following Liver Transplantation. Journal of Gastrointe...

100% Sustained Virological Response and Fibrosis Improvement in Real-Life Use of Direct Acting Antivirals in Genotype-1b Recurrent Hepatitis C following Liver Transplantation. Journal of Gastrointe... | Hepatitis C New Drugs Review | Scoop.it

In HCV positive recipients, DAA regimens are highly effective and safe. A significant decrease of LS by transient elastography and fibrosis non-invasive scores can be observed after successful therapy.

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Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1α via Chaperone-Mediated Autophagy

Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1α via Chaperone-Mediated Autophagy | Hepatitis C New Drugs Review | Scoop.it
Many viruses use a protein degradation system, such as the ubiquitin-proteasome pathway or the autophagy pathway, for facilitating viral propagation and viral pathogenesis. We investigated the mechanistic details of the selective lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) induced by hepatitis C virus (HCV) NS5A protein. Using site-directed mutagenesis, we demonstrated that HNF-1α contains a pentapeptide chaperone-mediated autophagy (CMA)-targeting motif within the POU-specific domain of HNF-1α. The CMA-targeting motif is important for the association with HSC70. LAMP-2A is required for degradation of HNF-1α caused by NS5A. We propose that HCV NS5A interacts with HSC70, a key component of the CMA machinery, and recruits HSC70 to HNF-1α to target HNF-1α for CMA-mediated lysosomal degradation, thereby facilitating HCV pathogenesis. We discovered a role of HCV NS5A in CMA-dependent degradation of HNF-1α. Our results may lead to a better understanding of the role of CMA in the pathogenesis of HCV.
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Immunotherapy with oral administration of humanized anti‐CD3 monoclonal antibody: A novel gut‐immune system‐based therapy for metaflammation and NASH - Ilan - - Clinical & Experimental Immunolo...

Oral administration of anti CD3 may provide an effective therapy for patients with NASH.
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Effect of Hepatocellular Carcinoma on Mortality among Individuals with Hepatitis B or Hepatitis C Infection in New York City, 2001–2012 | Open Forum Infectious Diseases | Oxford Academic

Effect of Hepatocellular Carcinoma on Mortality among Individuals with Hepatitis B or Hepatitis C Infection in New York City, 2001–2012 | Open Forum Infectious Diseases | Oxford Academic | Hepatitis C New Drugs Review | Scoop.it
AbstractBackground. Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B and C virus (HBV and HCV) infection.New York City (NYC) has a high...
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Clinical and Economic Burden of Hepatic and Extrahepatic Complications from Chronic Hepatitis C: A Retrospective Analysis of German Sickness Fund Data

Clinical and Economic Burden of Hepatic and Extrahepatic Complications from Chronic Hepatitis C: A Retrospective Analysis of German Sickness Fund Data | Hepatitis C New Drugs Review | Scoop.it
Introduction German data regarding the burden of complications from chronic hepatitis C (CHC) virus infection are limited. To address this issue, this study evaluates the clinical and economic burden...
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Change in hepatic profile in hepatitis C virus genotype 4 patients with compensated cirrhosis receiving ombitasvir, paritaprevir, and ritonavir plus ribavirin: a subanalysis of the AGATE‐II study -...

Change in hepatic profile in hepatitis C virus genotype 4 patients with compensated cirrhosis receiving ombitasvir, paritaprevir, and ritonavir plus ribavirin: a subanalysis of the AGATE‐II study -... | Hepatitis C New Drugs Review | Scoop.it
Sixty patients with compensated cirrhosis were randomized to treatment for 12 weeks (n=31) or 24 weeks (n=29). In the 12‐week arm, significant improvements were observed in biomarkers of liver injury (alanine aminotransferase: –53.7 U/L, p<0.001; aspartate aminotransferase: –35.9 U/L, p<0.001) and liver fibrosis (aspartate aminotransferase to platelet ratio index: –0.987, p<0.001; fibrosis‐4 index: –1.165, p<0.001). Similar results were reported in the 24‐week arm. Conclusion: Treatment with ombitasvir/paritaprevir/ritonavir plus RBV in HCV GT4‐infected Egyptians with compensated cirrhosis resulted in improvements in certain biomarkers of liver synthetic function, injury, and fibrosis, independent of treatment duration.
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El Ciclo de Vida del virus de la Hepatitis C | aidsinfonet.org | The AIDS InfoNet

El Ciclo de Vida del virus de la Hepatitis C | aidsinfonet.org | The AIDS InfoNet | Hepatitis C New Drugs Review | Scoop.it
A collection of patient education fact sheets on HIV/AIDS treatments and conditions, in English and Spanish. Also, an extensive listing of AIDS-related internet web site addresses.
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Frontiers | Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine | Immunology

Frontiers | Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine | Immunology | Hepatitis C New Drugs Review | Scoop.it
Hepatitis C virus (HCV) continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved i
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Utilization and efficacy of elbasvir/grazoprevir for treating hepatitis C virus infection after liver transplantation - Miuma - - Hepatology Research - Wiley Online Library

Utilization and efficacy of elbasvir/grazoprevir for treating hepatitis C virus infection after liver transplantation - Miuma - - Hepatology Research - Wiley Online Library | Hepatitis C New Drugs Review | Scoop.it
All patients treated with EBR/GZR therapy obtained rapid virological response and sustained at 12 weeks post‐treatment. There was no evidence of worsening estimated glomerular filtration rates (eGFR). Three patients were administrated tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n=8) and sofosbuvir/ledipasvir combination therapy (n=11). EBR/GZR therapy was not inferior to other therapies in its early phase and late‐phase antiviral effects.

Conclusions
Although further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post‐LT genotype 1 HCV re‐infections.
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Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses | BMC Medical Research Methodology | Full Text

Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses | BMC Medical Research Methodology | Full Text | Hepatitis C New Drugs Review | Scoop.it
Decisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs.
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Persistence of hepatitis A virus antibodies after primary immunization and response to revaccination in children and adolescents with perinatal HIV exposure

Persistence of hepatitis A virus antibodies after primary immunization and response to revaccination in children and adolescents with perinatal HIV exposure | Hepatitis C New Drugs Review | Scoop.it

 In recent years, advances in the diagnosis, treatment, and clinical and laboratory monitoring of the infection by the human immunodeficiency virus (HIV) in children have allowed longer survival and better quality of life for this population.1 , 2 In this sense, it is important to vaccinate HIV-infected children who will reach adulthood and monitor the maintenance of antibodies after vaccination. To monitor and revaccinate HIV-infected patients when necessary can prevent vaccine-preventable disease outbreaks in this population.3 To protect adolescents infected with HIV against infection by the hepatitis A virus (HAV) is need, considering that the HIV/HAV coinfection can influence the clinical course of hepatitis A4 and be associated with an increase in HIV replication.5 , 6

 

To maintain protection against hepatitis B, there are national24 and international25 recommendations on the revaccination of immunosuppressed individuals who lost their antibodies. There is no such recommendation regarding hepatitis A, but the data shown here suggest that, for children and adolescents infected with HIV, antibody titer monitoring is necessary, and revaccination is advisable to maintain protective levels of antibodies. It is known that HIV-infected patients should be vaccinated as early as possible, at a time when immunological impairment has not occurred yet. It can be concluded, based on the multivariate analysis shown here, that the level of hepatitis A antibodies in the first vaccination is the only factor independently associated with the maintenance of these antibodies after a period of seven years. This association was also observed by Sharapov et al.26 A less intense response at the primary vaccination suggests an immunological impairment at this moment. Nevertheless, 83.3% of patients seronegative for hepatitis A responded to revaccination, although the duration of these antibodies is something to be studied in the future.

 

 

 

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Evaluation of the Xpert HCV Viral Load Finger-Stick Point-of-Care Assay | The Journal of Infectious Diseases | Oxford Academic

Evaluation of the Xpert HCV Viral Load Finger-Stick Point-of-Care Assay | The Journal of Infectious Diseases | Oxford Academic | Hepatitis C New Drugs Review | Scoop.it
Point-of-care hepatitis C virus (HCV) RNA testing is advantageous, enabling diagnosis of active infection in a single visit. This study evaluated the sensitivity and specificity of the Xpert HCV Viral Load Finger-Stick assay (Xpert HCV VL FS) for HCV RNA detection (finger-stick) and the Xpert HCV Viral Load assay (plasma) compared with the Abbott RealTime HCV Viral Load assay by venepuncture. Plasma and finger-stick capillary whole-blood samples were collected from participants in an observational cohort in Australia. Of 223 participants enrolled, HCV RNA was detected in 40% of participants (85 of 210) with available Xpert HCV Viral Load testing. Participants receiving HCV therapy were excluded from subsequent analyses (n = 16). Sensitivity of the Xpert HCV Viral Load assay for HCV RNA quantification in plasma collected by venepuncture was 100.0% (95% confidence interval [CI] 96.9%–100.0%) and specificity was 100.0% (95% CI, 94.4%–100.0%). Sensitivity of the Xpert HCV VL FS assay for HCV RNA quantification in samples collected by finger-stick was 100.0% (95% CI, 93.9%–100.0%) and specificity was 100.0% (95% CI, 96.6%–100.0%). The Xpert HCV VL FS test can accurately detect active infection from a finger-stick sample in 1 hour allowing single-visit HCV diagnosis.

testing, diagnostics, rapid, PWID, HCV
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GP205, a new hepatitis C virus NS3/4A protease inhibitor, displays higher metabolic stability in vitro and drug exposure in vivo

GP205, a new hepatitis C virus NS3/4A protease inhibitor, displays higher metabolic stability in vitro and drug exposure in vivo | Hepatitis C New Drugs Review | Scoop.it
Abstract
NS3/4A serine protease is a prime target for direct-acting antiviral therapies against hepatitis C virus (HCV) infection. Several NS3/4A inhibitors have been widely used in clinic, while new inhibitors with better characteristics are still urgently needed. GP205 is a new macrocyclic inhibitor of NS3/4A with low nanomolar activities against HCV replicons of genotypes 1b, 2a, 4a, and 5a, with EC50 values ranging from 1.5 to 12.8 nmol/L. In resistance selection study in vitro, we found resistance-associated substitutions on D168: The activity of GP205 was significantly attenuated against 1b replicon with D168V or D168A mutation, similar as simeprevir. No cross resistance of GP205 with NS5B or NS5A inhibitor was observed. Combination of GP205 with sofosbuvir or daclatasvir displayed additive or synergistic efficacy. The pharmacokinetic profile of GP205 was characterized in rats and dogs after oral administration, which revealed good drug exposure both in plasma and in liver and long plasma half-life. The in vitro stability test showed ideal microsomal and hepatic cells stability of GP205. The preclinical profiles of GP205 support further research on this NS3/4A inhibitor to expand the existing HCV infection therapies.

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Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma

Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma | Hepatitis C New Drugs Review | Scoop.it

Our study provided a novel methodology to evaluate PD-L1 expression in the tumour microenvironment, which might help to select patients who would benefit from anti-PD-1/PD-L1 immunotherapies.

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Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients

Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients | Hepatitis C New Drugs Review | Scoop.it
Abstract
Background/Purpose
The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations.

Methods
Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations.

Results
The exposures [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (< 20% difference) in healthy Chinese subjects residing in China or the United States. In addition, the trough plasma concentrations (C trough ) in HCV GT1b-infected Asian patients were either similar to (ombitasvir) or within 75% of (paritaprevir and dasabuvir) those in Western patients without cirrhosis, or similar to (ombitasvir and paritaprevir) or within 100% of (dasabuvir) those in Western patients with cirrhosis, with widely overlapping ranges of individual values. Generally comparable drug exposures were observed among Chinese, South Korean, and Taiwanese ethnicities for noncirrhotic and cirrhotic patients.

Conclusion
Collectively, the results of these pharmacokinetic analyses support the use of the same dose of the 3D regimen for Asian and Western patients.

Clinicaltrials.gov
NCT02534870, NCT02517515, NCT02517528.
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Frontiers | The Complement System and C1q in Chronic Hepatitis C Virus Infection and Mixed Cryoglobulinemia | Immunology

Frontiers | The Complement System and C1q in Chronic Hepatitis C Virus Infection and Mixed Cryoglobulinemia | Immunology | Hepatitis C New Drugs Review | Scoop.it
The complement system bridges innate and adaptive immunity against microbial infections, with viral infection being a major trigger. Activation of the classical, alternative, and lectin pathways have been reported in chronic hepatitis C Virus (HCV) infection and/or cryoglobulinemia. HCV infection leads to dysregulation of complement-mediated immune responses. Clinical and experimental evidence support involvement of complement in intra- and extrahepatic manifestations of HCV infection such as liver fibrosis and type II cryoglobulinemia. In this review, we summarize studies that have investigated the interplay between HCV and the complement system to establish chronic infection and autoimmunity, as well as the association between HCV pathogenesis and abnormal complement profiles. Several unanswered questions are highlighted which suggest additional informative lines of investigation.
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Improvement of Hepatic and Extrahepatic Complications from Chronic Hepatitis C After Antiviral Treatment: A Retrospective Analysis of German Sickness Fund Data

Improvement of Hepatic and Extrahepatic Complications from Chronic Hepatitis C After Antiviral Treatment: A Retrospective Analysis of German Sickness Fund Data | Hepatitis C New Drugs Review | Scoop.it
Introduction German data regarding the economic burden of chronic hepatitis C (CHC) and potential benefits of CHC treatment are limited. To address this issue, we evaluated the role of treatment in...
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Frontiers | Computational Modeling of Hepatitis C Virus Envelope Glycoprotein Structure and Recognition | Immunology

Frontiers | Computational Modeling of Hepatitis C Virus Envelope Glycoprotein Structure and Recognition | Immunology | Hepatitis C New Drugs Review | Scoop.it
Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies. Due to the challenges in determining experimental structures, structural information on E1 and E2 and their interaction is relatively limited, providing opportunities to model the structures, interactions, and dynamics of these proteins. This review highlights efforts to model the E2 glycoprotein structure, the assembly of the functional E1E2 heterodimer, the structure and binding of human coreceptors, and recognition by key neutralizing antibodies. We also discuss a comparison of recently described models of full E1E2 heterodimer structures, a simulation of the dynamics of key epitope sites, and modeling glycosylation. These modeling efforts provide useful mechanistic hypotheses for further experimental studies of HCV envelope assembly, recognition, and viral fitness, and underscore the benefit of combining experimental and computational modeling approaches to reveal ne
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Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1–4 in Italy

Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1–4 in Italy | Hepatitis C New Drugs Review | Scoop.it
Abstract
Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2–45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4–19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1–4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.
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Effects of Resistance-Associated NS5A Mutations in Hepatitis C Virus on Viral Production and Susceptibility to Antiviral Reagents

Effects of Resistance-Associated NS5A Mutations in Hepatitis C Virus on Viral Production and Susceptibility to Antiviral Reagents | Hepatitis C New Drugs Review | Scoop.it
Abstract
Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have potent anti-HCV effects but may provoke resistance-associated variants (RAVs). In this study, we assessed the characteristics of these RAVs and explored efficacious anti-HCV reagents using recombinant HCV with NS5A from a genotype 1b strain. We replaced the NS5A of JFH1 with that of Con1 (JFH1/5ACon1) and introduced known NS5A inhibitor resistance mutations (L31M, L31V, L31I and Y93H) individually or in combination. Susceptibilities against anti-HCV reagents were also investigated. RAVs with Y93H exhibited high extracellular core antigen levels and infectivity titers. Variants with any single mutation showed mild to moderate resistance against NS5A inhibitors, whereas variants with double mutations at both L31 and Y93 showed severe resistance. The variants with mutations exhibited similar levels of susceptibility to interferon (IFN)-α, IFN-λ1, IFN-λ3 and Ribavirin. Variants with the Y93H mutation were more sensitive to protease inhibitors compared with JFH1/5ACon1. In conclusion, the in vitro analysis indicated that the Y93H mutation enhanced infectious virus production, suggesting advantages in the propagation of RAVs with this mutation. However, these RAVs were susceptible to protease inhibitors. Thus, a therapeutic regimen that includes these reagents is a promising means to eradicate these RAVs.
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Successful treatment of chronic hepatitis C infection with crushed elbasvir/grazoprevir administered via a percutaneous endoscopic gastrostomy tube - Yap - - Journal of Clinical Pharmacy and Therap...

Successful treatment of chronic hepatitis C infection with crushed elbasvir/grazoprevir administered via a percutaneous endoscopic gastrostomy tube - Yap - - Journal of Clinical Pharmacy and Therap... | Hepatitis C New Drugs Review | Scoop.it
We present the first known clinical case of a non‐cirrhotic patient with HCV genotype 1A with HCV‐related MPGN treated successfully with crushed Elbasvir/Grazoprevir administered through a PEG tube. With the prevalence of PEG tube insertion and HCV on a rise, we expect these 2 population cohorts to intersect in the future. Our report may serve as a guidance in such clinical scenario.
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Now Is the Time to Quickly Eliminate Barriers Along the Hepatitis C Cascade of Care | The Journal of Infectious Diseases | Oxford Academic

Now Is the Time to Quickly Eliminate Barriers Along the Hepatitis C Cascade of Care | The Journal of Infectious Diseases | Oxford Academic | Hepatitis C New Drugs Review | Scoop.it
(See the Major Article by Lamoury et al, on pages 1889–96.)...
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Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity

Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity | Hepatitis C New Drugs Review | Scoop.it
chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
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Immune system does not recover despite cured hepatitis C infection - Karolinska Institutet

Immune system does not recover despite cured hepatitis C infection - Karolinska Institutet | Hepatitis C New Drugs Review | Scoop.it
[PRESS RELEASE 2018-06-11] Changes to the immune system remain many years after a hepatitis C...
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