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US FDA puts hold on Vertex hepatitis study; shares fall - Reuters

US FDA puts hold on Vertex hepatitis study; shares fall
Reuters
Vertex said the U.S.
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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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A network meta-analysis to compare simeprevir with boceprevir and telaprevir in combination with peginterferon-α and ribavirin in patients infected with genotype 1 Hepatitis C virus, Journal of Med...

A network meta-analysis to compare simeprevir with boceprevir and telaprevir in combination with peginterferon-α and ribavirin in patients infected with genotype 1 Hepatitis C virus, Journal of Med... | Hepatitis C New Drugs Review | Scoop.it
Just Accepted! Meta-analysis of simeprevir + boceprevir and telaprevir w/ peginterferon-α & ribavirin in gen 1 #HCV http://t.co/qyOiEWLblZ

 

Results: A total of 15 publications were considered for the base case of the meta-analysis. Simeprevir was associated with higher SVR rates than PR alone. Compared to telaprevir and boceprevir, SVR rates tended to be higher for simeprevir with odds ratios ranging from 1.27 [0.81-2.00] to 2.61 [1.44-4.74] in treatment-naïve and from 1.04 [0.78-1.38] to 1.74 [0.84-3.61] in treatment-experienced patients, respectively. In terms of safety, the risks of anemia and discontinuations due to AEs were lower for simeprevir compared to PR alone, telaprevir and boceprevir. The risk of rash was lower for simeprevir compared to telaprevir, and similar compared to PR alone and boceprevir.

Conclusion: This NMA in genotype 1 HCV patients suggests a similar or better efficacy and tolerability profile for simeprevir compared to telaprevir and boceprevir.




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A network meta-analysis to compare simeprevir with boceprevir and telaprevir in combination with peginterferon-α and ribavirin in patients infected with genotype 1 Hepatitis C virus

 

Posted online on May 1, 2015. (doi:10.3111/13696998.2015.1046880)Vanessa Taieb, Maud Pacou, Sophia Ho, Ségolène Pettré, Suzy Van Sanden, Marta Pisini, Andrew Ustianowski, and Angelika Mehnert1Amaris, London, United Kingdom2Amaris, Paris, France3Janssen EMEA, Beerse, Belgium4North Manchester General Hospital, Manchester, United Kingdom5Janssen-Cilag GmbH, Neuss, GermanyCorresponding author: Vanessa Taieb, The Fitzpatrick Building, 188 York Way, London N7 9AS, United Kingdom, Telephone: +44 20 3372 9455 Fax: +44 20 3372 9454 E mail: Vanessa.taieb@amaris.com, Maud Pacou, 24 rue de Mogador , 75009 Paris France, Telephone : +33 1 76 71 63 72, E mail: mpacou@amaris.com


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Bristol-Myers Squibb Outpaces AbbVie in Hepatitis C (ABBV, BMY)

Bristol-Myers Squibb Outpaces AbbVie in Hepatitis C (ABBV, BMY) | Hepatitis C New Drugs Review | Scoop.it
Bristol-Myers Squibb's hepatitis C sales topped AbbVie's in the first quarter. Is this trend set to continue? - Todd Campbell - Health Care
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Gilead with blockbusters Harvoni and Sovaldi is the current and future maket leader.

 

BMS takes a second spot due to first oral interferon free ribavarine and interferon free cocktail in Japan and EU market.

 

 

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Gilead (GILD), Achillion (ACHN) In Race Against Time To Lower HCV Treatment ... - Bidness ETC

Gilead (GILD), Achillion (ACHN) In Race Against Time To Lower HCV Treatment ... - Bidness ETC | Hepatitis C New Drugs Review | Scoop.it
As competition intensifies in the US HCV space, Gilead Sciences, Inc. (NASDAQ:GILD) and Achillion Pharmaceuticals, Inc. (NASDAQ:ACHN) are in a race to develop a single drug that can lower treatment time to six weeks or less for all HCV patients.
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Gilead 1st-qtr profit doubles on strong hepatitis C drug sales

Gilead 1st-qtr profit doubles on strong hepatitis C drug sales | Hepatitis C New Drugs Review | Scoop.it
April 30 (Reuters) - Gilead Sciences Inc said onThursday its quarterly net profit nearly doubled, driven bysales of its novel hepatitis C drugs, as it topped Wall Streetestimates.Gilead posted first-quarter...
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A Human Monoclonal Antibody against Hepatitis B Surface Antigen with Potent Neutralizing Activity

A Human Monoclonal Antibody against Hepatitis B Surface Antigen with Potent Neutralizing Activity | Hepatitis C New Drugs Review | Scoop.it

by Antonella Cerino, Corinna M. Bremer, Dieter Glebe, Mario U. Mondelli

Abstract

We describe the production and characterization of human monoclonal antibodies (mAb) specific for the major hepatitis B virus (HBV) S protein. The mAbs, two IgG1κ and one IgG1λ, were secreted by B-cell clones obtained from peripheral blood mononuclear cells (PBMC) of one person convalescent from acute hepatitis B and one vaccinated individual. The former recognized a denaturation-insensitive epitope within the p24 protein whereas the latter recognized a denaturation-sensitive, conformational epitope located within the HBsAg common “a” determinant. This mAb, denominated ADRI-2F3, displayed a very high protective titer of over 43,000 IU/mg mAb and showed an extremely potent neutralizing activity in the in vitro model of HBV infection using primary hepatocytes from Tupaia belangeri as target. Recombinant variable heavy and light domain sequences derived from mAb ADRI-2F3 were cloned into eukaryotic expression vectors and showed identical fine specificity and 1 log10higher titer than the original IgG1λ. It is envisaged that such mAb will be able to efficiently prevent HBV reinfection after liver transplantation for end-stage chronic HBV infection or infection after needle-stick exposure, providing an unlimited source of valuable protective anti-HBs antibody.

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Citation: Cerino A, Bremer CM, Glebe D, Mondelli MU (2015) A Human Monoclonal Antibody against Hepatitis B Surface Antigen with Potent Neutralizing Activity. PLoS ONE 10(4): e0125704. doi:10.1371/journal.pone.0125704

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Achillion Pharmaceuticals Could Hang With The HCV Big Boys (ACHN) - Seeking Alpha

Achillion Pharmaceuticals Could Hang With The HCV Big Boys (ACHN) - Seeking Alpha | Hepatitis C New Drugs Review | Scoop.it
Achillion Pharmaceuticals, Inc. (NASDAQ:ACHN) is a medium-cap company with a pipeline focused on infectious disease. It has a market value of $1.2 billion and almost $300 million in cash and equivalents.
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Human platelets and their capacity of binding viruses: meaning and challenges? - BMC Blogs Network

Human platelets and their capacity of binding viruses: meaning and challenges? - BMC Blogs Network | Hepatitis C New Drugs Review | Scoop.it
Abstract

Blood platelets are first aimed at ensuring primary hemostasis. Beyond this role, they have been acknowledged as having functions in the maintenance of the vascular arborescence and, more recently, as being also innate immune cells, devoted notably to the detection of danger signals, of which infectious ones. Platelets express pathogen recognition receptors that can sense bacterial and viral moieties. Besides, several molecules that bind epithelial or sub-endothelial molecules and, so forth, are involved in hemostasis, happen to be able to ligate viral determinants, making platelets capable of either binding viruses or even to be infected by some of them. Further, as platelets express both Fc-receptors for Ig and complement receptors, they also bind occasionally virus-Ig or virus-Ig-complement immune complexes. Interplays of viruses with platelets are very complex and viral infections often interfere with platelet number and functions. Through a few instances of viral infections, the present review aims at presenting some of the most important interactions from pathophysiological and clinical points of view, which are observed between human viruses and platelets.

Krishan Maggon 's insight:
Human platelets and their capacity of binding viruses: meaning and challenges?

Adrien Chabert1, Hind Hamzeh-Cognasse1, Bruno Pozzetto12, Fabrice Cognasse13, Mirta Schattner4, Ricardo M Gomez5 and Olivier Garraud167*

*Corresponding author: Olivier Garraud ogarraud@ints.fr

Author Affiliations

1EA3064—GIMAP, Université de Lyon, Saint-Etienne, 42023, France

2Service des Agents infectieux et d’Hygiène, CHU de Saint-Etienne, Saint-Etienne, 42055, France

3EFS Auvergne-Loire, Saint-Etienne, 42023, France

4Laboratorio de Trombosis Experimental, Instituto de Medicina Experimental, ANM-CONICET, Buenos Aires, Argentina

5Laboratorio de Virus Animales, Instituto de Biotecnología y Biología Molecular, UNLP-CONICET, La Plata, Argentina

6Institut National de la Transfusion Sanguine, Paris, 75015, France

7INTS, 6 rue Alexandre-Cabanel, Paris, 75015, France

For all author emails, please log on.

BMC Immunology 2015, 16:26  doi:10.1186/s12865-015-0092-1

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Simplification of antiviral hepatitis C virus therapy to support expanded access in resource-limited settings - Journal of Hepatology

Simplification of antiviral hepatitis C virus therapy to support expanded access in resource-limited settings - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

Currently, access to treatment for HCV is limited, with treatment rates lowest in the more resource-limited countries, including those countries with the highest prevalence. The use of oral DAAs has the potential to provide treatment at scale by offering opportunities to simplify drug regimens, laboratory requirements, and service delivery models. Key desirable characteristics of future HCV treatment regimens include high efficacy, tolerability, pan-genotype activity, short treatment duration, oral therapy, affordability, and availability as fixed-dose combination. Using such a regimen, HCV treatment delivery could be greatly simplified. Treatment could be initiated following confirmation of the presence of viraemia, with an initial assessment of the stage of liver disease. A combination DAA therapy that is safe and effective across genotypes could remove the need for genotyping and intermediary viral load assessments for response-guided therapy and reduce the need for adverse event monitoring. Simpler, safer, shorter therapy will also facilitate simplified service delivery, including task shifting, decentralization, and integration of treatment and care. The opportunity to scale up HCV treatment using such delivery approaches will depend on efforts needed to guarantee that the new DAAs are affordable in low-income settings. This will require the engagement of all stakeholders, ranging from the companies developing these new treatments, WHO and other international organizations, including procurement and funding mechanisms, governments and civil society.

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J. Hepatology

 

November 2014Volume 61, Issue 1, Supplement, Pages S132–S138Simplification of antiviral hepatitis C virus therapy to support expanded access in resource-limited settingsNathan Ford, Tracy Swan, Peter Beyer, Gottfried Hirnschall, Philippa Easterbrook, Stefan WiktorOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.09.019
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Management of acute and chronic HCV infection in persons with HIV coinfection - Journal of Hepatology

Management of acute and chronic HCV infection in persons with HIV coinfection - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.

Krishan Maggon 's insight:

J. Hepatology

 

November 2014Volume 61, Issue 1, Supplement, Pages S108–S119Management of acute and chronic HCV infection in persons with HIV coinfectionMark S. SulkowskiJohns Hopkins University, School of Medicine, Baltimore, MD, United StatesOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.08.006
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HCV animal models and liver disease - Journal of Hepatology

HCV animal models and liver disease - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

The development and evaluation of effective therapies and vaccines for the hepatitis C virus (HCV) and the study of its interactions with the mammalian host have been hindered for a long time by the absence of suitable small animal models. Due to the narrow host tropism of HCV, the development of mice that can be robustly engrafted with human hepatocytes was a major breakthrough since they recapitulate the complete HCV life cycle. This model has been useful to investigate many aspects of the HCV life cycle, including antiviral interventions. However, studies of cellular immunity, immunopathogenesis and resulting liver diseases have been hampered by the lack of a small animal model with a functional immune system. In this review, we summarize the evolution of in vivo models for the study of HCV.

Krishan Maggon 's insight:

J. Hepatology

 

November 2014Volume 61, Issue 1, Supplement, Pages S26–S33

HCV animal models and liver diseaseKoen Vercauteren, Ype P. de Jong, Philip MeulemanOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.07.013
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Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases - Journal of Hepatology

Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.

Krishan Maggon 's insight:

J. Hepatology                                                                          November 2014Volume 61, Issue 1, Supplement, Pages S69–S78

 

 

Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseasesFrancesco NegroDivisions of Gastroenterology and Hepatology, University Hospitals, Geneva, SwitzerlandDivision of Clinical Pathology, University Hospitals, Geneva, SwitzerlandOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.08.003
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Regulus Therapeutics RG-101 Potent, Durable and Pan-Genotypic Effects in Diverse HCV Population. Late-Breaking ILC 2015

Regulus Therapeutics RG-101 Potent, Durable and Pan-Genotypic Effects in Diverse HCV Population. Late-Breaking ILC 2015 | Hepatitis C New Drugs Review | Scoop.it
Late-Breaking Oral Presentation at The International Liver Congressb" (ILC ...

 

LA JOLLA, Calif., April 25, 2015 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today presented new data strengthening the profile of RG-101, a wholly-owned, GalNAc-conjugated anti-miR targeting microRNA-122 ("miR-122") for the treatment of HCV, during an oral late-breaking session at ILC 2015 in Vienna, Austria. Extended follow-up results evaluating a single subcutaneous administration of either 2 mg/kg or 4 mg/kg of RG-101 as monotherapy in HCV patients with varied genotypes, liver fibrosis status and treatment history showed that 10/22 patients had HCV RNA levels below the limit of quantification ("BLOQ") at 12 weeks and 70 percent of those patients remained BLOQ at 20 weeks (7/10).  In addition, the positive results that were previously reported from the completed clinical study of RG-101 were reviewed during the oral late-breaker.

Krishan Maggon 's insight:

Targeting microRNAs with anti-miRs, chemically modified, single-stranded oligonucleotides, offers a unique approach to treating disease by modulating entire biological pathways and may become a new and major class of drugs with broad therapeutic application.


RG-101 is a  GalNAc-conjugated anti-miR targeting microRNA-122 ("miR-122") for the treatment of HCV. 

 

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CRISPR as antiviral tool: Cas9 for Hepatitis C - Biotechin.Asia

CRISPR as antiviral tool: Cas9 for Hepatitis C - Biotechin.Asia | Hepatitis C New Drugs Review | Scoop.it
Clustered, regularly interspaced, short palindromic repeats–CRISPR associated systems (CRISPR-Cas) are prokaryotic RNA-directed endonuclease machineries that act as an adaptive immune system agains...
Krishan Maggon 's insight:
Aryn A. Price, doi: 10.1073/pnas.1422340112Cas9-mediated targeting of viral RNA in eukaryotic cellsAryn A. Pricea,b,c,1, Timothy R. Sampsona,b,c,1,2, Hannah K. Ratnera,b,c, Arash Grakouib,c,d,3, andDavid S. Weissb,c,d,e,3

Author Affiliations

Edited by Scott J. Hultgren, Washington University School of Medicine, St. Louis, MO, and approved April 8, 2015 (received for review November 24, 2014)

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The Role of New HCV Agents in Managing HIV/HCV Coinfection.2014

The Role of New HCV Agents in Managing HIV/HCV Coinfection.2014

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Ledipasvir/Sofosbuvir: A Review of Its Use in Chronic Hepatitis C - Springer

Ledipasvir/Sofosbuvir: A Review of Its Use in Chronic Hepatitis C - Springer | Hepatitis C New Drugs Review | Scoop.it
RT @RevistaMFSamfyc: Ledipasvir/sofosbuvir: revisión de su uso en la hepatitis C crónica http://t.co/Al7uri1rgr PMID 25837989

 

Abstract

The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni®) was recently approved in the US and the EU. The phase III ION trials included treatment-naive (ION-1 and -3) or treatment-experienced (ION-2) patients with chronic HCV genotype 1 infection (≈20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 had cirrhosis). A sustained virological response 12 weeks’ post-treatment (SVR12) was seen in 99 % of treatment-naive patients receiving ledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. Moreover, in ION-3, an 8-week regimen achieved an SVR12 rate of 94 % overall and 97 % in the subgroup of patients with a baseline HCV RNA level of <6 million IU/mL. SVR12 rates of 94 and 99 % were seen in treatment-experienced patients who received ledipasvir/sofosbuvir for 12 and 24 weeks in ION-2. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated. In conclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that represents a significant advance in the treatment of chronic hepatitis C.

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Citation

 

DrugsApril 2015, Volume 75, Issue 6, pp 675-685Date: 03 Apr 2015Ledipasvir/Sofosbuvir: A Review of Its Use in Chronic Hepatitis CGillian M. Keating
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Gilead CEO: “We are taking suggestions” on companies to buy

Gilead CEO: “We are taking suggestions” on companies to buy | Hepatitis C New Drugs Review | Scoop.it
After reporting unexpectedly high earnings, biotech Gilead indicated it was shopping for ways to spend that cash.
Krishan Maggon 's insight:

Vertex is not worth buying, Gilead should look for companies with strong pipeline in immuno-oncology, stem cells, vaccines and therapeutic human monoclonal antibodies

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Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy

Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy | Hepatitis C New Drugs Review | Scoop.it
by Karin Neukam, Daniela I. Munteanu, Antonio Rivero-Juárez, Thomas Lutz, Jan Fehr, Mattias Mandorfer, Sanjay Bhagani, Luis F.

 

AbstractBackground and Aims

 

Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions.

Methods

 

In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated.

Results

 

Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%.

Conclusion

 

The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.

Krishan Maggon 's insight:

Citation: Neukam K, Munteanu DI, Rivero-Juárez A, Lutz T, Fehr J, et al. (2015) Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy. PLoS ONE 10(4): e0125080. doi:10.1371/journal.pone.0125080

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Preventing HBV Reactivation Due to Immunosuppressive Treatments

Preventing HBV Reactivation Due to Immunosuppressive Treatments | Hepatitis C New Drugs Review | Scoop.it
This Viewpoint discusses important questions about how to efficiently screen for hepatitis B virus (HBV) for those at risk of HBV reactivation.
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Hepatitis C Competitive Landscape: The Holy Grail - Seeking Alpha

Hepatitis C Competitive Landscape: The Holy Grail - Seeking Alpha | Hepatitis C New Drugs Review | Scoop.it
Over the last few days, I had been inundated with various news articles discussing the Hepatitis C market developments, partly because of the recent International Liver Congress 2015.
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Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase ... - Journal of Virology

Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase ... - Journal of Virology | Hepatitis C New Drugs Review | Scoop.it

Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase ...
Journal of Virology

 

ABSTRACT

Hepatitis C virus (HCV) NS3 is a multifunctional protein composed of a protease domain and a helicase domain linked by a flexible linker. Protease activity is required to generate viral nonstructural (NS) proteins involved in RNA replication. Helicase activity is required for RNA replication, and genetic evidence implicates the helicase domain in virus assembly. Binding of protease inhibitors (PIs) to the protease active site blocks NS3-dependent polyprotein processing but might impact other steps of the virus life cycle. Kinetic analyses of antiviral suppression of cell culture-infectious genotype 1a strain H77S.3 were performed using assays that measure different readouts of the viral life cycle. In addition to the active-site PI telaprevir, we examined an allosteric protease-helicase inhibitor (APHI) that binds a site in the interdomain interface. By measuring nucleotide incorporation into HCV genomes, we found that telaprevir inhibits RNA synthesis as early as 12 h at high but clinically relevant concentrations. Immunoblot analyses showed that NS5B abundance was not reduced until after 12 h, suggesting that telaprevir exerts a direct effect on RNA synthesis. In contrast, the APHI could partially inhibit RNA synthesis, suggesting that the allosteric site is not always available during RNA synthesis. The APHI and active-site PI were both able to block virus assembly soon (<12 h) after drug treatment, suggesting that they rapidly engage with and block a pool of NS3 involved in assembly. In conclusion, PIs and APHIs can block NS3 functions in RNA synthesis and virus assembly, in addition to inhibiting polyprotein processing.

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Accepted manuscript posted online 4 March 2015, doi:10.1128/JVI.03188-14J. Virol. May 2015 vol. 89 no. 105362-5370
Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase during the Hepatitis C Virus Life CycleDavid R. McGiverna,b, Takahiro Masakia,b*, William Lovella,b, Chris Hamlettc,Susanne Saalau-Bethellc and Brent Grahamc
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Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation - Journal of Hepatology

Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon-free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon-free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multi-drug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT.

Krishan Maggon 's insight:

J. Hepatology

 

November 2014Volume 61, Issue 1, Supplement, Pages S120–S131Treatment options in patients with decompensated cirrhosis, pre- and post-transplantationMartina Gambato, Sabela Lens, Miquel Navasa, Xavier FornsLiver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, SpainOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.07.020
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Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors - Journal of Hepatology

Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Summary

The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.

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J. Hepatology

November 2014Volume 61, Issue 1, Supplement, Pages S98–S107Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitorsTania Mara Welzel, Georg Dultz, Stefan ZeuzemDepartment of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, GermanyOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.08.014
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Global epidemiology and genotype distribution of the hepatitis C virus infection - Journal of Hepatology

Global epidemiology and genotype distribution of the hepatitis C virus infection - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it

Summary

The treatment of chronic hepatitis C virus (HCV) infection has the potential to change significantly over the next few years as therapeutic regimens are rapidly evolving. However, the burden of chronic infection has not been quantified at the global level using the most recent data. Updated estimates of HCV prevalence, viremia and genotypes are critical for developing strategies to manage or eliminate HCV infection. To achieve this, a comprehensive literature search was conducted for anti-HCV prevalence, viraemic prevalence and genotypes for all countries. Studies were included based on how well they could be extrapolated to the general population, sample size and the age of the study. Available country estimates were used to develop regional and global estimates. Eighty-seven countries reported anti-HCV prevalence, while HCV viraemic rates were available for fifty-four countries. Total global viraemic HCV infections were estimated at 80 (64–103) million infections. Genotype distribution was available for ninety-eight countries. Globally, genotype 1 (G1) was the most common (46%), followed by G3 (22%), G2 (13%), and G4 (13%). In conclusion, the total number of HCV infections reported here are lower than previous estimates. The exclusion of data from earlier studies conducted at the peak of the HCV epidemic, along with adjustments for reduced prevalence among children, are likely contributors. The results highlight the need for more robust surveillance studies to quantify the HCV disease burden more accurately.

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J. Hepatology

 

November 2014Volume 61, Issue 1, Supplement, Pages S45–S57

Global epidemiology and genotype distribution of the hepatitis C virus infectionErin Gower, Chris Estes, Sarah Blach, Kathryn Razavi-Shearer, Homie RazaviCenter for Disease Analysis, Louisville, CO, USAOpen AccessDOI: http://dx.doi.org/10.1016/j.jhep.2014.07.027

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FDA Priority Review AbbVie Oral, Interferon-Free HCV Genotype 4 Therapy

FDA Priority Review AbbVie Oral, Interferon-Free HCV Genotype 4 Therapy | Hepatitis C New Drugs Review | Scoop.it

NORTH CHICAGO, Ill., April 24, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) has announced that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) and granted priority review for the company's, all-oral, interferon-free, two direct-acting antiviral treatment of ombitasvir, paritaprevir, ritonavir (OBV/PTV/r), with ribavirin (RBV). The NDA is for the treatment of adults with chronic genotype 4 (GT4) hepatitis C virus (HCV) infection.

AbbVie's regimen is the first all-oral, interferon-free therapy being evaluated by the FDA for patients in the United Stateswith chronic GT4 HCV infection. This submission affirms the company's commitment to seeking access to curative* therapy for patients living with chronic HCV infection (*curative is defined as when the virus is no longer detectable in the patient's blood 12 weeks after treatment ends; sustained virologic response [SVR12]).

The FDA granted priority review to AbbVie for the regimen based in part on data from the PEARL-I study, which was recently published online in The Lancet. The FDA grants priority review designation to investigational therapies that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. This designation shortens the regulatory review period for non-new chemical entity NDAs from the normal 10 months to six months. AbbVie's regimen was also granted a Breakthrough Therapy designation by the FDA on June 30, 2014, a status given to investigational treatments for serious or life-threatening conditions with preliminary clinical evidence that may demonstrate substantial improvement on at least one clinically significant endpoint compared to available therapy.1

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THE NEW DRUG APPLICATION (NDA) WAS ACCEPTED BY THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) AND IS BASED ON RESULTS FROM THE PEARL-I STUDY, WHICH DEMONSTRATED UP TO 100 PERCENT SUSTAINED VIROLOGIC RESPONSE RATES AT 12 WEEKS POST-TREATMENT WITH NO DISCONTINUATIONS DUE TO ADVERSE EVENTS- FIRST ALL-ORAL, INTERFERON-FREE THERAPY BEING EVALUATED BY THE FDA FOR PATIENTS WITH CHRONIC GENOTYPE 4 (GT4) HEPATITIS C VIRUS (HCV) INFECTION- ABBVIE'S INVESTIGATIONAL REGIMEN HAS BEEN PREVIOUSLY DESIGNATED AS A BREAKTHROUGH THERAPY AND RECEIVED PRIORITY REVIEW BY THE FDA

 

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

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Gilead Sofosbuvir-Based Regimens Results in Chronic Hepatitis C Patients With Genotypes 2-5. ILC 2015

Gilead Sofosbuvir-Based Regimens Results in Chronic Hepatitis C Patients With Genotypes 2-5. ILC 2015 | Hepatitis C New Drugs Review | Scoop.it

VIENNA, Austria--(BUSINESS WIRE)--Apr. 25, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from two studies evaluating the safety and efficacy of investigational uses of sofosbuvir-based regimens in chronic hepatitis C virus (HCV)-infected patients with genotypes 2, 3, 4 and 5. Results from the BOSON study of Sovaldi® (sofosbuvir 400 mg) in combination with ribavirin (RBV) or with pegylated interferon (PEG)/RBV demonstrated high cure rates across all patients with genotypes 2 and 3. Separately, results from a Phase 2 study demonstrate the safety and efficacy of Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) in patients with genotypes 4 or 5 infection. Data from both studies will be presented in oral sessions at the 50th Annual Meeting of the European Association for the Study of the Liver(The International Liver Congress™ 2015) in Vienna, Austria.


BOSON (Study GS-US-334-0153, #LB05), a randomized Phase 3 study of 592 patients, evaluated the safety and efficacy of Sovaldi plus RBV for 16 or 24 weeks compared with Sovaldi plus PEG/RBV for 12 weeks among treatment-naïve or treatment-experienced genotype 3 patients with and without cirrhosis and treatment-experienced genotype 2 patients with cirrhosis. Thirty-seven percent of study participants had cirrhosis.

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