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Gilead Races Against Competitors for an Oral Hepatitis-C Cure - Motley Fool

Gilead Races Against Competitors for an Oral Hepatitis-C Cure
Motley Fool
Vertex hopes to follow up its highly successful Incivek with another all-oral option.
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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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The Flavone Luteolin Suppresses SREBP-2 Expression and Post-Translational Activation in Hepatic Cells

The Flavone Luteolin Suppresses SREBP-2 Expression and Post-Translational Activation in Hepatic Cells | Hepatitis C New Drugs Review | Scoop.it

by Tsz Yan Wong, Shu-mei Lin, Lai K. Leung

Abstract

High blood cholesterol has been associated with cardiovascular diseases. The enzyme HMG CoA reductase (HMGCR) is responsible for cholesterol synthesis, and inhibitors of this enzyme (statins) have been used clinically to control blood cholesterol. Sterol regulatory element binding protein (SREBP) -2 is a key transcription factor in cholesterol metabolism, and HMGCRis a target gene of SREBP-2. Attenuating SREBP-2 activity could potentially minimize the expression of HMGCR. Luteolin is a flavone that is commonly detected in plant foods. In the present study, Luteolin suppressed the expression of SREBP-2 at concentrations as low as 1 μM in the hepatic cell lines WRL and HepG2. This flavone also prevented the nuclear translocation of SREBP-2. Post-translational processing of SREBP-2 protein was required for nuclear translocation. Luteolin partially blocked this activation route through increased AMP kinase (AMPK) activation. At the transcriptional level, the mRNA and protein expression of SREBP-2 were reduced through luteolin. A reporter gene assay also verified that the transcription of SREBF2 was weakened in response to this flavone. The reduced expression and protein processing of SREBP-2 resulted in decreased nuclear translocation. Thus, the transcription of HMGCR was also decreased after luteolin treatment. In summary, the results of the present study showed that luteolin modulates HMGCR transcription by decreasing the expression and nuclear translocation of SREBP-2.

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Citation: Wong TY, Lin S-m, Leung LK (2015) The Flavone Luteolin Suppresses SREBP-2 Expression and Post-Translational Activation in Hepatic Cells. PLoS ONE 10(8): e0135637. doi:10.1371/journal.pone.0135637

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Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent - Journal of Hepatology

Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
Grazoprevir+elbasvir+RBV for HCV gen1 after failure of combination therapy containing a DAA - Journal of Hepatology http://t.co/H63TAC4NBF

 

Abstract

 

Background & Aims

The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy.

Methods

C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment.

Results

Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related.

Conclusions

Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor.

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J. Hepatology

 

September 2015Volume 63, Issue 3, Pages 564–572Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agentXavier Forns, Stuart C. Gordon, Eli Zuckerman, Eric Lawitz, Jose L. Calleja, Harald Hofer, Christopher Gilbert,John Palcza, Anita Y.M. Howe, Mark J. DiNubile, Michael N. Robertson, Janice Wahl, Eliav Barr, Maria ButiReceived: March 6, 2015; Received in revised form: March 31, 2015; Accepted: April 16, 2015; Published Online: April 18, 2015DOI: http://dx.doi.org/10.1016/j.jhep.2015.04.009 | ;
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Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response | Hepatitis C New Drugs Review | Scoop.it
by Eliano Bonaccorsi-Riani, Richard Danger, Juan José Lozano, Marta Martinez-Picola, Elisavet Kodela, Roser Mas-Malavila, Miquel Bruguera, Helen L. Collins, Robert C.

 

Abstract

Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.

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Citation: Bonaccorsi-Riani E, Danger R, Lozano JJ, Martinez-Picola M, Kodela E, Mas-Malavila R, et al. (2015) Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response. PLoS ONE 10(8): e0136106. doi:10.1371/journal.pone.0136106

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The Hidden Truth Behind The High Cost of Hepatitis C Drugs - Center for Research on Globalization

The Hidden Truth Behind The High Cost of Hepatitis C Drugs - Center for Research on Globalization | Hepatitis C New Drugs Review | Scoop.it
Contrary to health executives’ views, treating this epidemic is a medical — not access or ethical — decision, and it is cost-effective.  Last week’s commentary “Who gets hepatitis C drugs? Who pays...
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Management of Direct Antiviral Agent Failures - Journal of Hepatology

Management of Direct Antiviral Agent Failures - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it
[In press] Management of Direct Antiviral Agent Failures
FREE review
http://t.co/bkboDvedrv
#HCV

 

Summary

Failure to respond to the approved combinations of multiple direct-acting antiviral agents is relatively low in hepatitis C virus treatment registration studies, with rates of 1% to 7%, depending on the patients’ baseline characteristics. In real life, failure is slightly higher, likely because of lower compliance. Treatment failures are usually related to relapse and less often to on-treatment viral breakthrough. Hepatitis C drug-resistant variants are detected in most patients who do not achieve viral eradication. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry resistance-associated variants may not obtain benefits from treatment and are at a risk of disease progression and transmission of the variants. Whether hepatitis C resistance-associated variants persist depends on their type: NS3-4A variants often disappear gradually after therapy is stopped, whereas NS5A variants tend to persist for more than 2 years.

The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent antivirals with genetic barriers to resistance. In patients failing first-generation protease inhibitors, combination therapies with sofosbuvir and NS5 inhibitors have proven effective. Some salvage regimens can be shortened to 12 weeks by addition of ribavirin. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.

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J. Hepatology

 

Management of Direct Antiviral Agent FailuresMaria Buti, Mar Riveiro-Barciela, Rafael EstebanReceived: June 1, 2015; Received in revised form: August 10, 2015; Accepted: August 11, 2015; Published Online: August 20, 2015Publication stage: In Press Accepted Manuscript DOI: http://dx.doi.org/10.1016/j.jhep.2015.08.010 ;
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Pharmacy Practice News - Incidence of HCV May Be Underestimated

Pharmacy Practice News - Incidence of HCV May Be Underestimated | Hepatitis C New Drugs Review | Scoop.it
With limited resources to track and ID #HepatitisC cases, the incidence of infection may be underestimated, http://t.co/g1m12nYT75 #HCV
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Expression of a single gene lets scientists easily grow hepatitis C virus. EurekAlert

Expression of a single gene lets scientists easily grow hepatitis C virus. EurekAlert | Hepatitis C New Drugs Review | Scoop.it
In devising a method to readily grow hepatitis C in the laboratory, scientists might have overcome a major hurdle for basic research into the virus and the disease it causes.
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Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy

Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy | Hepatitis C New Drugs Review | Scoop.it
AbstractBackground and Aims

Monitoring of chronic Hepatitis C (CHC) treatment relies on HCV RNA quantification by means of real-time PCR methods. Assay specific analytical sensitivities may impact therapy management.

Methods

Comparative analysis between three commercial assays (Roche COBAS AmpliPrep/COBAS TaqMan Version 1 (CAP/CTM Ver. 1), Version 2 (CAP/CTM Ver. 2) and the Abbott RealTime HCV (ART) assay) was performed on 247 available samples taken at key decision time points during antiviral therapy of 105 genotype 1 patients (triple therapy: n = 70; dual therapy: n = 35).

Results

Overall concordance of HCV RNA measurements was high between the two Roche systems (89%; n = 220/247) but lower between the Roche assays and the ART (CAP/CTM Ver. 1 vs ART: 77.3%; n = 191/247 and CAP/CTM v.2 vs ART: 80.1%; n = 198/247). Most discrepancies were noted in week 4/8 samples with residual viremia (<LLOQ) detected by ART (<LLOQ: n = 45, 44.1%) but undetectable HCV RNA by CAP/CTM Ver. 1 (<LLOQ: n = 18, 17.6%) or CAP/CTM Ver. 2 (<LLOQ: n = 26, 25.5%). Based on results by CAP/CTM Ver. 1, 13 eligible patients underwent an abbreviated course of therapy (24 weeks). Only 1 patient experienced virologic breakthrough. If tested by ART, only 6/13 patients (46.2%) would have been eligible for shortened treatment. Consequently, RGT guidelines were adapted and shortening of therapy was allowed if residual viremia was detected by ART at week 4/8.

Conclusion

An abbreviated course of treatment can safely be applied in patients with residual viremia (<LLOQ) detected by ART in samples collected at week 4/8 of treatment.

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Citation: Strassl R, Rutter K, Stättermayer AF, Beinhardt S, Kammer M, Hofer H, et al. (2015) Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy. PLoS ONE 10(8): e0135963. doi:10.1371/journal.pone.0135963

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Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5A - Journal of Hepatology

Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5A - Journal of Hepatology | Hepatitis C New Drugs Review | Scoop.it

Background & Aims

Single nucleotide polymorphisms within the interferon lambda 4 (IFNL4) locus are strongly associated with spontaneous clearance of hepatitis C virus (HCV) infection and early viral response to interferon therapy. Interaction between host genotype and amino acid substitutions might also influence the risk of antiviral resistance in interferon-free direct acting antiviral (DAA) therapies.

Methods

The relationship between IFNL4 genotype and HCV substitutions was analyzed in 929 patients with chronic HCV genotype 1b infection. Ultra-deep sequencing and quasispecies reconstruction was performed on the N-terminal region of NS5A in 57 patients.

Results

IFNL4 genotype was strongly associated with HCV NS5A Y93 and core protein substitutions, and the number and diversity of predicted quasispecies was marginally greater in IFNL4 TT/TT patients compared to TT/ΔG, ΔG/ΔG patients. RNA secondary structure prediction of the NS5A region suggests that variable sites are more likely to occupy unpaired, high entropy positions.

Conclusions

HCV infection is proposed to induce a more efficient antiviral response in individuals with the IFNL4 TT/TT genotype that results either in viral clearance or selection for viral adaptations. The association between IFNL4 TT/TT genotype and Y93 substitutions may impact the risk of antiviral resistance in NS5A inhibitors in DAA therapy.

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Journal of Hepatology

Volume 63, Issue 3, September 2015, Pages 554–563

Research Article Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5ASakura Akamatsu1, 2, †, C. Nelson Hayes1, 2, 3, †, Hidenori Ochi1, 2, 3, Takuro Uchida1, 2,Hiromi Kan1, 2, Eisuke Murakami1, 2, Hiromi Abe1, 2, 3, Masataka Tsuge2, 4, Daiki Miki1, 2,3, Rie Akiyama1, 2, 3, Nobuhiko Hiraga1, 2, 3, Michio Imamura1, 2, 3, Hiroshi Aikata1, 2,Tomokazu Kawaoka1, 2, 3, Yoshiiku Kawakami1, 2, 3, Kazuaki Chayama1, 2, 3, ,doi:10.1016/j.jhep.2015.03.033

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Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies - Deterding - 2015 - Alimentary Pharmacology & Therapeutics - Wiley Online Library

Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies - Deterding - 2015 - Alimentary Pharmacology & Therapeutics - Wiley Online Library | Hepatitis C New Drugs Review | Scoop.it
Improvement of liver function in advanced #HCV-associated #cirrhosis by #IFN-free antiviral therapies http://t.co/4tgLz2HtC3 #hepatology

 

SummaryBackground

Successful antiviral treatment of decompensated hepatitis B with HBV polymerase inhibitors is associated with improvement of liver function. To what extent liver function also improves in cirrhotic patients with chronic hepatitis C receiving novel interferon-free (IFN-free) therapies is unknown.

Aim

To study liver function in cirrhotic HCV patients receiving IFN-free therapies.

Methods

We here studied 80 consecutive patients with advanced HCV associated liver cirrhosis including 34 patients (43%) with Child B/C cirrhosis and 42 patients (53%) with platelet counts of <90.000/μL receiving different combinations of direct acting antivirals without interferon [sofosbuvir/ribavirin (n = 56), sofosbuvir/simeprevir ± ribavirin (n = 15) and sofosbuvir/daclatasvir ± ribavirin (n = 9)]. The majority of patients was infected with HCV genotype 1 (n = 50); HCV genotypes 2, 3 and 4 were present in 4, 24 and 2 patients, respectively.

Results

Liver function parameters including albumin, bilirubin, cholinesterase and prothrombin time all improved in the majority of patients during antiviral therapy irrespectively of the underlying HCV genotype, however, with different kinetics. MELD scores improved until post-treatment week 12 in 44% of the patients but worsened in 15%. A sustained virological response was achieved in 63% of the patients. HCV RNA relapse led to moderate ALT increases in 15/23 patients but was not associated with hepatic decompensations.

Conclusion

This real-world single centre study showed that interferon-free treatment of hepatitis C patients with advanced liver cirrhosis restores liver function, and may thereby reduce the need for liver transplantations.

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mprovement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapiesK. Deterding, C. Höner zu Siederdissen,K. Port, P. Solbach, L. Sollik, J. Kirschner,C. Mix, J. Cornberg, D. Worzala, H. Mix,M. P. Manns, M. Cornberg† andH. Wedemeyer†,*

Article first published online: 6 AUG 2015

DOI: 10.1111/apt.13343

© 2015 John Wiley & Sons Ltd

Issue

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

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New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A | Hepatitis C New Drugs Review | Scoop.it

ABSTRACT

In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatitis C virus (HCV) life cycle. We showed that monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Using the selective pressure of monensin, we selected a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces an N-glycosylation site within HVR1 and increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (anti-ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In summary, we identified a mutation in HVR1 that overcomes the vesicular pH dependence, modifies the biophysical properties of particles, and drastically reduces cell-to-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH dependence of cell-free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation.

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Accepted manuscript posted online 3 June 2015, doi:10.1128/JVI.00192-15                                                        J. Virol. August 2015 vol. 89no. 16 8346-8364
New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin ALucie Fénéanta, Julie Potela, Catherine Françoisb, Famara Sanéc, Florian Douamd,Sandrine Belouzarda, Noémie Callanda, Thibaut Vausselina, Yves Rouilléa,Véronique Descampsb, Thomas F. Baumerte, Gilles Duverlieb, Dimitri Lavilletted,Didier Hoberc, Jean Dubuissona, Czeslaw Wychowskia and Laurence CocquerelaaMolecular and Cellular Virology Laboratory, Center for Infection and Immunity of Lille, University Lille Nord de France, CNRS UMR8204, INSERM U1019, Pasteur Institute of Lille, Lille, FrancebVirology Department, EA4294 UPJV, Amiens University Hospital, Amiens, FrancecLaboratoire de Virologie EA3610, Université Lille 2, CHRU Lille, Lille, FrancedCNRS-UMR5557, Microbial Ecology, Université Claude Bernard Lyon 1, Villeurbanne, FranceeINSERM U1110, Université de Strasbourg, Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

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The Cure for Gilead - Huffington Post

The Cure for Gilead - Huffington Post | Hepatitis C New Drugs Review | Scoop.it
Gilead has the cure for Hepatitis C (HCV) known as Sofosbuvir, which is taken alone or in combination with other drugs. Now we need a cure for Gilead.
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Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells

Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells | Hepatitis C New Drugs Review | Scoop.it

by Masato Nagaoka, Motohiro Kobayashi, Chie Kawai, Sunil K. Mallanna, Stephen A. Duncan

Abstract

Maintenance and differentiation of human pluripotent stem cells (hPSCs) usually requires culture on a substrate for cell adhesion. A commonly used substratum is Matrigel purified from Engelbreth—Holm—Swarm sarcoma cells, and consists of a complex mixture of extracellular matrix proteins, proteoglycans, and growth factors. Several studies have successfully induced differentiation of hepatocyte-like cells from hPSCs. However, most of these studies have used Matrigel as a cell adhesion substrate, which is not a defined culture condition. In an attempt to generate a substratum that supports undifferentiated properties and differentiation into hepatic lineage cells, we designed novel substrates consisting of vitronectin fragments fused to the IgG Fc domain. hPSCs adhered to these substrates via interactions between integrins and the RGD (Arg-Gly-Asp) motif, and the cells maintained their undifferentiated phenotypes. Using a previously established differentiation protocol, hPSCs were efficiently differentiated into mesendodermal and hepatic lineage cells on a vitronectin fragment-containing substrate. We found that full-length vitronectin did not support stable cell adhesion during the specification stage. Furthermore, the vitronectin fragment with the minimal RGD-containing domain was sufficient for differentiation of human induced pluripotent stem cells into hepatic lineage cells under completely defined conditions that facilitate the clinical application of cells differentiated from hPSCs.

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Citation: Nagaoka M, Kobayashi M, Kawai C, Mallanna SK, Duncan SA (2015) Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells. PLoS ONE 10(8): e0136350. doi:10.1371/journal.pone.0136350

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Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1 — NEJM

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1 — NEJM | Hepatitis C New Drugs Review | Scoop.it
Original Article from The New England Journal of Medicine — Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

 

BACKGROUND

Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need.

 METHODS

We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.

 RESULTS

Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events.

 CONCLUSIONS

Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.)

  
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ORIGINAL ARTICLE

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

Susanna Naggie, M.D., M.H.S., Curtis Cooper, M.D., Michael Saag, M.D., Kimberly Workowski, M.D., Peter Ruane, M.D., William J. Towner, M.D., Kristen Marks, M.D., Anne Luetkemeyer, M.D., Rachel P. Baden, M.D., Paul E. Sax, M.D., Edward Gane, M.D., Jorge Santana-Bagur, M.D., Luisa M. Stamm, M.D., Ph.D., Jenny C. Yang, Pharm.D., Polina German, Pharm.D., Hadas Dvory-Sobol, Ph.D., Liyun Ni, M.A., Phillip S. Pang, M.D., Ph.D., John G. McHutchison, M.D., Catherine A.M. Stedman, M.B., Ch.B., Ph.D., Javier O. Morales-Ramirez, M.D., Norbert Bräu, M.D., Dushyantha Jayaweera, M.D., Amy E. Colson, M.D., Pablo Tebas, M.D., David K. Wong, M.D., Douglas Dieterich, M.D., and Mark Sulkowski, M.D. for the ION-4 Investigators

N Engl J Med 2015; 373:705-713August 20, 2015DOI: 10.1056/NEJMoa1501315

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Hepatitis C virus drug resistance–associated substitutions: State of the art summary - Lontok - 2015 - Hepatology - Wiley Online Library

Hepatitis C virus drug resistance–associated substitutions: State of the art summary - Lontok - 2015 - Hepatology - Wiley Online Library | Hepatitis C New Drugs Review | Scoop.it
RT @HEP_Journal: New summary on Hepatitis C virus (HCV) resistance http://t.co/eOuxXdaYkm http://t.co/eOuxXdaYkm #hcv

 

Abstract

Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon-free, all-oral combinations of direct-acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct-acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015)

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Hepatology

 

Review

Hepatitis C virus drug resistance–associated substitutions: State of the art summaryAuthorsErik Lontok, Patrick Harrington, Anita Howe, Tara Kieffer, Johan Lennerstrand, Oliver Lenz, Fiona McPhee, Hongmei Mo, Neil Parkin, Tami Pilot-Matias, Veronica Miller First published: 30 July 2015Full publication historyDOI: 10.1002/hep.27934View/save citation
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Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART)

Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART) | Hepatitis C New Drugs Review | Scoop.it
Background and aims HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART. Methods In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis. Results At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients. Conclusion Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.
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Citation: Dold L, Ahlenstiel G, Althausen E, Luda C, Schwarze-Zander C, Boesecke C, et al. (2015) Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART). PLoS ONE 10(8): e0134158. doi:10.1371/journal.pone.0134158

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Indian medicine, at 1/100th cost, saves Aussie's life - Times of India

Indian medicine, at 1/100th cost, saves Aussie's life - Times of India | Hepatitis C New Drugs Review | Scoop.it
Less than four months ago, Greg Jeffery was on the verge of getting liver cirrhosis.
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A Review Of Gilead's Pipeline (Part 2): Focus On Zydelig And Lymphoma/CLL ... - Seeking Alpha

A Review Of Gilead's Pipeline (Part 2): Focus On Zydelig And Lymphoma/CLL ... - Seeking Alpha | Hepatitis C New Drugs Review | Scoop.it
Gilead is making a large effort in oncology and related fields.Lymphoma and chronic lymphocytic leukemia represent the initial focus.An introduction to the potential of the company's efforts in these fields is presented herei...
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Gilead Sciences, Inc. Astonishing Performance In HCV Market

Gilead Sciences, Inc. Astonishing Performance In HCV Market | Hepatitis C New Drugs Review | Scoop.it
Bidness Etc looks at Gilead Sciences Inc.'s (NASDAQ:GILD) performance in the HCV market and its latest prescription data.

 

Gilead launched its first HCV drug, Sovaldi, in December 2013, which positioned the biotech firm as the leader of the HCV market. Later, in October 2014, Gilead launched another HCV drug, Harvoni, an advanced version of Sovaldi, which further strengthened its position as the leader in the market. Gilead’s leadership position was challenged by AbbVie’s launch of Viekira Pak in December 2014.

Viekira Pak was expected to cannibalize a large chunk of Harvoni’s sales, as AbbVie kept Viekira Pak’s price tag lower than Harvoni’s; Viekira Pak costs $83,320 for a 12-week standard treatment duration, while Harvoni costs $94,500 for the same duration.

 

Moreover, upon Viekira Pak’s launch, AbbVie struck a strategic deal with Express Scripts Holding Company (NASDAQ:ESRX), the nation’s largest pharmacy benefits manager (PBM). Under the deal, AbbVie offered the PBM a significant discount on the drug, and in exchange, Express Scripts agreed to remove Harvoni from its 2015 formulary.

Contrary to what analysts and investors had feared, Gilead continued to rule the HCV market by a significant margin.

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Gilead leads the HCV market by a wide margin leaving others in single digits.

 

According to Symphony Healthcare data compiled by Bloomberg, during the week ended August 8, new prescriptions for Gilead stood at 3,614 scripts, an 11% decline compared to the volumes for the prior week. In contrast, Viekira Pak’s new prescriptions for the same week stood at 534 scripts, a 25% decline compared to the scripts for the previous week. New prescription volume for Sovaldi for the week stood at 655 scripts, a 16% decline from the previous week.

Total HCV prescriptions for the week also declined slightly. The total prescription volume for Harvoni stood at 8,686 scripts, while the total prescription volume for AbbVie’s Viekira Pak stood at 994 scripts. Total prescriptions for Sovaldi stood at 1,930 scripts.

Total HCV prescriptions for last month saw an increase compared to the total prescriptions at the end of June. Total prescriptions for Harvoni, as of the end of July, stood at 41,530, a sequential 1.5% increase compared to its total prescriptions as of the end of June. During the month of July, Viekira Pak’s total prescriptions saw a 24% increase to 4,623, which clearly indicates that the drug’s prescriptions are still of no match to Gilead’s Harvoni. Sovaldi’s total prescriptions, as of June’s end, stood at 9,432.

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New Approach Disrupts HIV and Hepatitis C Infection Processes - MD Magazine

New Approach Disrupts HIV and Hepatitis C Infection Processes - MD Magazine | Hepatitis C New Drugs Review | Scoop.it
A new strategy may be able to effectively prevent transmission of the human immunodeficiency virus (HIV), other sexually transmitted viruses, and additional illnesses.
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Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway

Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway | Hepatitis C New Drugs Review | Scoop.it

by Yang You, Qiongdan Zheng, Yinying Dong, Yaohui Wang, Lan Zhang, Tongchun Xue, Xiaoying Xie, Chao Hu, Zhiming Wang, Rongxin Chen, Yanhong Wang, Jiefeng Cui, Zhenggang Ren 

 

Abstract

Increased stromal stiffness is associated with hepatocellular carcinoma (HCC) development and progression. However, the molecular mechanism by which matrix stiffness stimuli modulate HCC progress is largely unknown. In this study, we explored whether matrix stiffness-mediated effects on osteopontin (OPN) expression occur in HCC cells. We used a previously reported in vitro culture system with tunable matrix stiffness and found that OPN expression was remarkably upregulated in HCC cells with increasing matrix stiffness. Furthermore, the phosphorylation level of GSK3β and the expression of nuclear β-catenin were also elevated, indicating that GSK3β/β-catenin pathway might be involved in OPN regulation. Knock-down analysis of integrin β1 showed that OPN expression and p-GSK3β level were downregulated in HCC cells grown on high stiffness substrate compared with controls. Simultaneously, inhibition of GSK-3β led to accumulation of β-catenin in the cytoplasm and its enhanced nuclear translocation, further triggered the rescue of OPN expression, suggesting that the integrin β1/GSK-3β/β-catenin pathway is specifically activated for matrix stiffness-mediated OPN upregulation in HCC cells. Tissue microarray analysis confirmed that OPN expression was positively correlated with the expression of LOX and COL1. Taken together, high matrix stiffness upregulated OPN expression in HCC cells via the integrin β1/GSK-3β/β-catenin signaling pathway. It highlights a new insight into a pathway involving physical mechanical signal and biochemical signal molecules which contributes to OPN expression in HCC cells.

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Citation: You Y, Zheng Q, Dong Y, Wang Y, Zhang L, Xue T, et al. (2015) Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway. PLoS ONE 10(8): e0134243. doi:10.1371/journal.pone.0134243

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SEC14L2 enables pan-genotype HCV replication in cell culture

SEC14L2 enables pan-genotype HCV replication in cell culture | Hepatitis C New Drugs Review | Scoop.it

Since its discovery in 1989, efforts to grow clinical isolates of the hepatitis C virus (HCV) in cell culture have met with limited success. Only the JFH-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations1, 2, 3. We hypothesized that cultured cells lack one or more factors required for the replication of clinical isolates. To identify the missing factors, we transduced Huh-7.5 human hepatoma cells with a pooled lentivirus-based human complementary DNA (cDNA) library, transfected the cells with HCV subgenomic replicons lacking adaptive mutations, and selected for stable replicon colonies. This led to the identification of a single cDNA, SEC14L2, that enabled RNA replication of diverse HCV genotypes in several hepatoma cell lines. This effect was dose-dependent, and required the continuous presence ofSEC14L2. Full-length HCV genomes also replicated and produced low levels of infectious virus. Remarkably, SEC14L2-expressing Huh-7.5 cells also supported HCV replication following inoculation with patient sera. Mechanistic studies suggest that SEC14L2 promotes HCV infection by enhancing vitamin E-mediated protection against lipid peroxidation. This provides a foundation for development of in vitro replication systems for all HCV isolates, creating a useful platform to dissect the mechanisms by which cell culture-adaptive mutations act.

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NATURE | LETTER

PrintShare/bookmark SEC14L2 enables pan-genotype HCV replication in cell cultureMohsan Saeed,Ursula Andreo,Hyo-Young Chung,Christine Espiritu,Andrea D. Branch,Jose M. Silva& Charles M. RiceAffiliationsContributionsCorresponding authorNature (2015) doi:10.1038/nature14899Received 27 November 2014 Accepted 14 July 2015 Published online 12 August 2015Article tools
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NanoViricides Dramatic Effects of Topical Anti-Herpes Drug in Animal models

NanoViricides Dramatic Effects of Topical Anti-Herpes  Drug in Animal models | Hepatitis C New Drugs Review | Scoop.it

Each nanoviricide drug is designed as an antiviral agent specifically targeted for a particular type of virus or group of viruses. Most existing anti-viral agents are known to have non-specific effects against both host cells and viral machinery at the same time often leading to side effects. Most current anti-viral agents act inside human cells. It is believed that this intracellular mechanism leads to significant opportunities for unwanted side effects against host cells. Nanoviricides, on the other hand, are designed to work directly against virus particles in bodily fluids. The Company believes that this approach may make nanoviricides inherently safer than existing approaches.

 

A nanoviricide is designed to seek and attach to a specific virus particle, engulfing the virus particle in the process, thereby rendering it incapable of infecting new cells, and disabling it completely. This suggested mechanism of action encompasses much more than what the current entry and fusion inhibitors are expected to do. The fusion and entry inhibitors do not completely cover the virus particle, likely blocking only a few sites on the virus particle. This means the virus particle may still be capable of infecting cells using its unblocked attachment sites. In contrast, a nanoviricide, because of its larger size and flexible nature, is expected to engulf the virus particle completely, thus disabling the virus particle. The action of a nanoviricide, if it works as designed, may be expected to be superior to antibody agents that attack viruses. Antibodies, being large, are expected to block relatively greater portions of the virus particle surface compared to small molecule entry inhibitors. However, antibodies depend upon the human immune system responses for clearing the virus particle. In contrast, nanoviricides are thought to be capable of acting as completely programmed chemical robots that finish their task of destroying the virus particle on their own. 

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All of the nanoviricides® tested improved clinical scores dramatically, with clinical presentation being arrested at redness or simply raised local lesions, and a complete absence of zosteriform spreading. All of the nanoviricides treated animals survived the lethal HSV-1 infection challenge for the duration of the study while untreated animals died towards the end of the study. These nanoviricides are designed as topical treatment for the breakout of herpes sores.

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A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner - Fang - 2015 - Hepatology - Wiley Online Library

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner - Fang - 2015 - Hepatology - Wiley Online Library | Hepatitis C New Drugs Review | Scoop.it
Abstract

Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial–mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three-dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC+) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell–derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC– xenografts but did not affect that of VETC+ ones, although silencing of Snail or Slug substantially reduced the in vitromigration of both VETC+ and VETC– HCC cells. In contrast to human VETC– cases, EMT signatures were rarely observed in VETC+ cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. Conclusion: Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs. (Hepatology2015;62:452–465

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Hepatobiliary Malignancies

A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent mannerAuthorsJian-Hong Fang, Hui-Chao Zhou, Chong Zhang, Li-Ru Shang, Lei Zhang, Jing Xu, Limin Zheng, Yunfei Yuan, Rong-Ping Guo, Wei-Hua Jia, Jing-Ping Yun, Min-Shan Chen, Yaojun Zhang, Shi-Mei Zhuang First published: 22 April 2015Full publication historyDOI: 10.1002/hep.27760View/save citation
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New hepatitis C combination treatment effective in HIV coinfected patients - The Pharmaceutical Journal

New hepatitis C combination treatment effective in HIV coinfected patients - The Pharmaceutical Journal | Hepatitis C New Drugs Review | Scoop.it
Patients with both hepatitis C virus and HIV responded well to daclatasvir combined with sofosbuvir in a study.
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