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Susan Uprichard

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https://www.readbyqxmd.com/read/27458506/hepatitis-c-virus-cures-after-direct-acting-antiviral-related-drug-induced-liver-injury-case-report
#1
Yaakov Hasin, Shimon Shteingart, Harel Dahari, Inna Gafanovich, Sharon Floru, Marius Braun, Amir Shlomai, Anthony Verstandig, Ilana Dery, Susan L Uprichard, Scott J Cotler, Yoav Lurie
The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R...
July 18, 2016: World Journal of Hepatology
https://www.readbyqxmd.com/read/26907973/hcv-kinetic-and-modeling-analyses-indicate-similar-time-to-cure-among-sofosbuvir-combination-regimens-with-daclatasvir-simeprevir-or-ledipasvir
#2
Harel Dahari, Laetitia Canini, Frederik Graw, Susan L Uprichard, Evaldo S A Araújo, Guillaume Penaranda, Emilie Coquet, Laurent Chiche, Aurelie Riso, Christophe Renou, Marc Bourliere, Scott J Cotler, Philippe Halfon
BACKGROUND & AIMS: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. METHODS: 58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers...
June 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/26787620/antioxidant-and-anti-hepatitis-c-viral-activities-of-commercial-milk-thistle-food-supplements
#3
Kevin Anthony, Gitanjali Subramanya, Susan Uprichard, Faiza Hammouda, Mahmoud Saleh
Milk thistle dietary supplements that contain silymarin are widely marketed and used in the USA and other countries for liver enhancement and recovery. More recently, silymarin has also been identified as a possible antiviral for the treatment of hepatitis C virus (HCV) infection. To assess different brands of commercially sold silymarin, 45 products were collected from local stores and analyzed for their silymarin content, antioxidant activities, and antiviral activity against HCV. Antioxidant activity was measured as radical scavenging activity using DPPH and by estimating their antioxidant capacity as trolox equivalent...
2013: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/26189433/oral-prenylation-inhibition-with-lonafarnib-in-chronic-hepatitis-d-infection-a-proof-of-concept-randomised-double-blind-placebo-controlled-phase-2a-trial
#4
RANDOMIZED CONTROLLED TRIAL
Christopher Koh, Laetitia Canini, Harel Dahari, Xiongce Zhao, Susan L Uprichard, Vanessa Haynes-Williams, Mark A Winters, Gitanjali Subramanya, Stewart L Cooper, Peter Pinto, Erin F Wolff, Rachel Bishop, Ma Ai Thanda Han, Scott J Cotler, David E Kleiner, Onur Keskin, Ramazan Idilman, Cihan Yurdaydin, Jeffrey S Glenn, Theo Heller
BACKGROUND: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. METHODS: In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up...
October 2015: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/25833046/quantification-of-hepatitis-c-virus-cell-to-cell-spread-using-a-stochastic-modeling-approach
#5
Frederik Graw, Danyelle N Martin, Alan S Perelson, Susan L Uprichard, Harel Dahari
UNLABELLED: It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors...
July 2015: Journal of Virology
https://www.readbyqxmd.com/read/24991010/unexpected-structural-features-of-the-hepatitis-c-virus-envelope-protein-2-ectodomain
#6
REVIEW
Ali Sabahi, Susan L Uprichard, William C Wimley, Srikanta Dash, Robert F Garry
Hepatitis C virus (HCV), a member of the family Flaviviridae, is a leading cause of chronic liver disease and cancer. Recent advances in HCV therapeutics have resulted in improved cure rates, but an HCV vaccine is not available and is urgently needed to control the global pandemic. Vaccine development has been hampered by the lack of high-resolution structural information for the two HCV envelope glycoproteins, E1 and E2. Recently, Kong and coworkers (Science 342:1090-1094, 2013, doi:10.1126/science.1243876) and Khan and coworkers (Nature 509[7500]:381-384, 2014, doi:10...
September 2014: Journal of Virology
https://www.readbyqxmd.com/read/24554660/determining-the-involvement-and-therapeutic-implications-of-host-cellular-factors-in-hepatitis-c-virus-cell-to-cell-spread
#7
Naina Barretto, Bruno Sainz, Snawar Hussain, Susan L Uprichard
UNLABELLED: Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, "cell-free" entry of infectious extracellular virions that have been released by infected cells and direct "cell-to-cell" transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread...
May 2014: Journal of Virology
https://www.readbyqxmd.com/read/24277664/establishment-of-mice-with-inheritable-susceptibility-to-productive-hepatitis-c-virus-infection
#8
COMMENT
Susan L Uprichard
No abstract text is available yet for this article.
May 2014: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/24130685/high-throughput-screening-hts-and-hit-validation-to-identify-small-molecule-inhibitors-with-activity-against-ns3-4a-proteases-from-multiple-hepatitis-c-virus-genotypes
#9
Hyun Lee, Tian Zhu, Kavankumar Patel, Yan-Yan Zhang, Lena Truong, Kirk E Hevener, Joseph L Gatuz, Gitanjali Subramanya, Hyun-Young Jeong, Susan L Uprichard, Michael E Johnson
Development of drug-resistant mutations has been a major problem with all currently developed Hepatitis C Virus (HCV) NS3/4A inhibitors, including the two FDA approved drugs, significantly reducing the efficacy of these inhibitors. The high incidence of drug-resistance mutations and the limited utility of these inhibitors against only genotype 1 highlight the need for novel, broad-spectrum HCV therapies. Here we used high-throughput screening (HTS) to identify low molecular weight inhibitors against NS3/4A from multiple genotypes...
2013: PloS One
https://www.readbyqxmd.com/read/23899277/the-hepatitis-c-virus-ns5a-inhibitor-daclatasvir-has-a-dual-mode-of-action-and-leads-to-a-new-virus-half-life-estimate
#10
EDITORIAL
Jeremie Guedj, Harel Dahari, Susan L Uprichard, Alan S Perelson
No abstract text is available yet for this article.
July 2013: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/23754414/identification-of-transferrin-receptor-1-as-a-hepatitis-c-virus-entry-factor
#11
Danyelle N Martin, Susan L Uprichard
Hepatitis C virus (HCV) is a liver tropic pathogen that affects ∼170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection...
June 25, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/23431163/modeling-shows-that-the-ns5a-inhibitor-daclatasvir-has-two-modes-of-action-and-yields-a-shorter-estimate-of-the-hepatitis-c-virus-half-life
#12
Jeremie Guedj, Harel Dahari, Libin Rong, Natasha D Sansone, Richard E Nettles, Scott J Cotler, Thomas J Layden, Susan L Uprichard, Alan S Perelson
The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents...
March 5, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/22948883/identification-of-hepatitis-c-virus-inhibitors-targeting-different-aspects-of-infection-using-a-cell-based-assay
#13
Xuemei Yu, Bruno Sainz, Pavel A Petukhov, Susan L Uprichard
With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle...
December 2012: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/22861052/new-hepatitis-c-virus-drug-discovery-strategies-and-model-systems
#14
REVIEW
Snawar Hussain, Naina Barretto, Susan L Uprichard
INTRODUCTION: Hepatitis C virus (HCV) is a major cause of liver disease worldwide and the leading indication for liver transplantation in the United States. Current treatment options are expensive, not effective in all patients and are associated with serious side effects. Although preclinical, anti-HCV drug screening is still hampered by the lack of readily infectable small animal models, the development of cell culture HCV experimental model systems has driven a promising new wave of HCV antiviral drug discovery...
September 2012: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/22273112/permissiveness-of-human-hepatoma-cell-lines-for-hcv-infection
#15
Bruno Sainz, Naina Barretto, Xuemei Yu, Peter Corcoran, Susan L Uprichard
BACKGROUND: Although primary and established human hepatoma cell lines have been evaluated for hepatitis C virus (HCV) infection in vitro, thus far only Huh7 cells have been found to be highly permissive for infectious HCV. Since our understanding of the HCV lifecycle would benefit from the identification of additional permissive cell lines, we assembled a panel of hepatic and non-hepatic cell lines and assessed their ability to support HCV infection. Here we show infection of the human hepatoma cell lines PLC/PRF/5 and Hep3B with cell culture-derived HCV (HCVcc), albeit to lower levels than that achieved in Huh7 cells...
2012: Virology Journal
https://www.readbyqxmd.com/read/22231557/identification-of-the-niemann-pick-c1-like-1-cholesterol-absorption-receptor-as-a-new-hepatitis-c-virus-entry-factor
#16
Bruno Sainz, Naina Barretto, Danyelle N Martin, Nobuhiko Hiraga, Michio Imamura, Snawar Hussain, Katherine A Marsh, Xuemei Yu, Kazuaki Chayama, Waddah A Alrefai, Susan L Uprichard
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable...
February 2012: Nature Medicine
https://www.readbyqxmd.com/read/21331152/potential-treatment-options-and-future-research-to-increase-hepatitis-c-virus-treatment-response-rate
#17
Veronica Tencate, Bruno Sainz, Scott J Cotler, Susan L Uprichard
Hepatitis C virus (HCV) is a liver-tropic blood-borne pathogen that affects more than 170 million people worldwide. Although acute infections are usually asymptomatic, up to 90% of HCV infections persist with the possibility of long-term consequences such as liver fibrosis, cirrhosis, steatosis, insulin resistance, or hepatocellular carcinoma. As such, HCV-associated liver disease is a major public health concern. Although the currently available standard of care therapy of pegylated interferon α plus ribavirin successfully treats infection in a subset of patients, the development of more effective, less toxic HCV antivirals is a health care imperative...
October 2010: Hepatic Medicine: Evidence and Research
https://www.readbyqxmd.com/read/20960298/hepatitis-c-virus-experimental-model-systems-and-antiviral-drug-research
#18
REVIEW
Susan L Uprichard
An estimated 130 million people worldwide are chronically infected with hepatitis C virus (HCV) making it a leading cause of liver disease worldwide. Because the currently available therapy of pegylated interferon-alpha and ribavirin is only effective in a subset of patients, the development of new HCV antivirals is a healthcare imperative. This review discusses the experimental models available for HCV antiviral drug research, recent advances in HCV antiviral drug development, as well as active research being pursued to facilitate development of new HCV-specific therapeutics...
August 2010: Virologica Sinica
https://www.readbyqxmd.com/read/20812217/cell-based-hepatitis-c-virus-infection-fluorescence-resonance-energy-transfer-fret-assay-for-antiviral-compound-screening
#19
Xuemei Yu, Susan L Uprichard
Hepatitis C virus (HCV) affects an estimated 3% of the population and is a leading cause of chronic liver disease worldwide. Since HCV therapeutic and preventative options are limited, the development of new HCV antivirals has become a global health care concern. This has spurred the development of cell-based infectious HCV high-throughput screening assays to test the ability of compounds to inhibit HCV infection. This unit describes methods that may be used to assess the in vitro efficacy of HCV antivirals using a cell-based high-throughput fluorescence resonance energy transfer (FRET) HCV infection screening assay, which allows for the identification of inhibitors that target HCV at any step in the viral life cycle...
August 2010: Current Protocols in Microbiology
https://www.readbyqxmd.com/read/20800257/the-rate-of-hepatitis-c-virus-infection-initiation-in-vitro-is-directly-related-to-particle-density
#20
Ali Sabahi, Katherine A Marsh, Harel Dahari, Peter Corcoran, Jennifer M Lamora, Xuemei Yu, Robert F Garry, Susan L Uprichard
To gain a more complete understanding of hepatitis C virus (HCV) entry, we initially assessed the rate at which HCV initiates productive attachment/infection in vitro and discovered it to be slower than most viruses. Since HCV, including cell culture-derived HCV (HCVcc), exhibits a broad-density profile (1.01-1.16 g/ml), we hypothesized that the varying densities of the HCVcc particles present in the inoculum may be responsible for this prolonged entry phenotype. To test this hypothesis, we show that during infection, particles of high density disappeared from the viral inoculum sooner and initiated productive infection faster than virions of low density...
November 10, 2010: Virology
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