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Locarnini S.,Victorian Infectious Diseases Reference Laboratory | Hatzakis A.,National and Kapodistrian University of Athens | Chen D.-S.,National Taiwan University Hospital | Lok A.,University of Michigan
Journal of Hepatology | Year: 2015

The last 50 years of hepatitis B research has resulted in the development of effective screening assays for surveillance, vaccines for prevention and antiviral drugs that significantly improve patient clinical outcomes. Not surprisingly then, the global epidemiology of hepatitis B virus (HBV) is set to change dramatically over the next decade. For example, the success and the high coverage of universal HBV vaccination and the ageing cohorts of patients with chronic hepatitis B (CHB) will result in reductions of incidence and prevalence of chronic hepatitis, cirrhosis and probably hepatocellular carcinoma. This will be further accelerated by the impressive progress in the treatment outcomes for patients with CHB. In spite of this success, challenges remain, such as planning for the impact of migration from countries with high prevalence rates to those countries with low rates of HBV infection. The recent establishment of the World Health Organisation Global Hepatitis Program with the provision of a framework for global action has become the cornerstone for all countries to now frame their own particular national responses to control hepatitis B. An effective policy framework can prevent new infections, ensure people can access clinical care, and in doing so reduce the burden of infection at an individual, country and regional level. These developments present a real opportunity to reduce the significant, social and economic burden of global hepatitis B, ultimately the critical next steps to render the world hepatitis B free. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Halfon P.,Virological Departement Laboratoire Alphabio | Locarnini S.,Victorian Infectious Diseases Reference Laboratory
Journal of Hepatology | Year: 2011

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase, and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to generations of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of those mutations that give rise to amino-acid substitutions within the targeted protein, and that affect the viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. In vitro or in vivo, six major position mutations in the NS3 HCV protease (36, 54, 155, 156, 168, and 170) have now been reported associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take into consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


News Article | March 31, 2016
Site: www.nanotech-now.com

Abstract: Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that the company will make presentations at the following upcoming events. The International Liver Congress™ 2016 (ILC 2016) - The Annual Meeting of the European Association for the Study of the Liver - Barcelona, Spain, April 13-17, 2016 April 14, 8:00 a.m. CEST - Zhao Xu, Ph.D., Arrowhead senior scientist, and coauthors, will deliver a poster presentation titled, "Treatment of chronically HBV-infected chimpanzees with RNA interference therapeutic ARC-520 led to potent reduction of viral mRNA, DNA and proteins without observed drug resistance" (abstract THU-213) April 14, 8:00 a.m. CEST - Man-Fung Yuen, M.D., Ph.D., chair of gastroenterology and hepatology, The University of Hong Kong, and deputy chief of service, Queen Mary Hospital department of medicine, Hong Kong, and coauthors, will deliver a poster presentation titled, "Differential reductions in viral antigens expressed from cccDNA vs integrated DNA in treatment naïve HBeAg positive and negative patients with chronic HBV after RNA interference therapy with ARC-520" (abstract THU-193) April 15, 8:00 a.m. CEST - Renae Walsh, Ph.D., senior scientist, Victorian Infectious Diseases Reference Laboratory, and coauthors, will deliver a poster presentation titled, "Predicting HBsAg clearance responses during ARC-520 RNA interference (RNAi) therapy based on HBsAg epitope profile analysis" (abstract FRI-144) American Association for Cancer Research Annual Meeting 2016 (AACR16) - New Orleans, April 16-20, 2016 April 18, 1:00 p.m. CDT - So Wong, Ph.D., Arrowhead director of oncology, and coauthors, will deliver a poster presentation titled, "Novel HIF-2α targeted RNAi therapeutic for renal cell carcinoma" (abstract 2064) Copies of presentation materials can be accessed by visiting the Events section of the company's website after each presentation is delivered. About ARC-520 Arrowhead's RNAi-based candidate ARC-520 is being investigated in the treatment of chronic HBV infection. The small interfering RNAs (siRNAs) in ARC-520 intervene at the mRNA level, upstream of the reverse transcription process where current standard of care nucleotide and nucleoside analogues act. Arrowhead is investigating ARC-520 specifically to determine if it can be used to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without seroconversion. Approximately 350-400 million people worldwide are chronically infected with the hepatitis B virus, which can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally. Arrowhead is currently conducting Phase 2b multiple dose and combination studies in chronic HBV patients. In clinical studies to date, the most common reported adverse events in all subjects completing treatment were upper respiratory infection and headache. About Arrowhead Research Corporation Arrowhead Research Corporation is a biopharmaceutical company developing targeted RNAi therapeutics. The company is leveraging its proprietary Dynamic Polyconjugate™ delivery platform to develop targeted drugs based on the RNA interference mechanism that efficiently silences disease-causing genes. Arrowhead's pipeline includes ARC-520 and ARC-521 for chronic hepatitis B virus, ARC-AAT for liver disease associated with alpha-1 antitrypsin deficiency, ARC-F12 for hereditary angioedema and thromboembolic diseases, ARC-LPA for cardiovascular disease, and ARC-HIF2 for renal cell carcinoma. For more information please visit www.arrowheadresearch.com, or follow us on Twitter @ArrowRes. To be added to the Company's email list and receive news directly, please visit ir.arrowheadresearch.com/alerts.cfm. Safe Harbor Statement under the Private Securities Litigation Reform Act: This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties, including our ability to finance our operations, the future success of our scientific studies, our ability to successfully develop drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, and the enforcement of our intellectual property rights. Arrowhead Research Corporation's most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q discuss some of the important risk factors that may affect our business, results of operations and financial condition. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. DYNAMIC POLYCONJUGATES is a trademark of Arrowhead Research Corporation. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Dandri M.,University of Hamburg | Locarnini S.,Victorian Infectious Diseases Reference Laboratory
Gut | Year: 2012

Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus-host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.


Revill P.,Victorian Infectious Diseases Reference Laboratory | Yuan Z.,Fudan University
Antiviral Therapy | Year: 2013

The mechanisms by which HBV establishes and maintains chronic infection are poorly understood. Although adult acquired HBV is generally cleared by a robust immune response, most individuals infected at childbirth or in very early childhood develop lifelong chronic infection. In addition, acute infections are unresolved in approximately 5% of individuals infected in adulthood. The host cell mechanisms that ensure establishment and resolution of acute infection and persistent infection remain unclear. Currently, two schools of thought suggest that either HBV is a 'stealth' virus, which initially establishes infection by avoiding host innate immune responses, or that HBV facilitates initial infection and progression to persistence by actively manipulating the host innate immune response to its advantage. There is increasing evidence that activation of innate host cell signalling pathways plays a major role in limiting adult acquired HBV infection and that, in turn, HBV has evolved numerous strategies to counteract these defence mechanisms. In this review, we summarize current knowledge regarding innate immune responses to HBV infection and discuss how HBV regulates cell signalling pathways to its advantage, particularly in the setting of chronic HBV infection. In turn, we show how an intimate knowledge of innate immune responses is driving development of novel therapeutic agents to treat chronic HBV infection. © 2013 International Medical Press.


Gish R.,University of California at San Diego | Jia J.-D.,Capital Medical University | Locarnini S.,Victorian Infectious Diseases Reference Laboratory | Zoulim F.,French Institute of Health and Medical Research | Zoulim F.,Institut Universitaire de France
The Lancet Infectious Diseases | Year: 2012

Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies. © 2012 Elsevier Ltd.


Zoulim F.,University of Lyon | Locarnini S.,Victorian Infectious Diseases Reference Laboratory
Liver International | Year: 2013

The management of treatment failure in patients with chronic hepatitis B, remains a clinical concern. Incomplete viral suppression and the emergence of drug resistance are key determinants of treatment failure. The correct choice of a potent first-line therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance have significantly lower rates of resistance compared with those with a low barrier to resistance. Management of treatment failure requires precise clinical and virological monitoring as well as early treatment intervention with appropriate noncross-resistant antivirals. Long-term surveillance of treatment efficacy and possible emergence of drug resistance is necessary in patients who have been sequentially treated with multiple antivirals. The identification of novel treatment targets remains a major research goal to improve the efficacy of current antiviral therapy through combination therapy regimens. © 2012 John Wiley & Sons A/S.


Locarnini S.A.,Victorian Infectious Diseases Reference Laboratory | Yuen L.,Victorian Infectious Diseases Reference Laboratory
Antiviral Therapy | Year: 2010

A high rate of viral turnover, combined with an error-prone polymerase, results in a very high frequency of mutational events during HBV replication. Not surprisingly, particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select out new 'escape' mutants. The introduction of nucleoside/nucleotide analogue (NA) therapy for chronic hepatitis B has witnessed the emergence of antiviral drug resistance as the major factor limiting drug efficacy. Furthermore, because of the overlap of the viral polymerase and envelope reading frames in the HBV DNA genome, NA resistance-associated mutations selected in the catalytic domains of the polymerase frequently result in important changes to the neutralizing antibody-binding domains of the hepatitis B surface antigen, including the emergence of antiviral drug-associated potential vaccine escape mutants (ADAPVEMs). The public health significance of ADAPVEMs is considerable in terms of the global programme for control of hepatitis B via universal infant immunization. Thus, prevention of resistance requires the adoption of strategies that not only effectively control HBV replication, but also prevent the emergence of ADAPVEMs. ©2010 International Medical Press.


Lookera C.,Victorian Infectious Diseases Reference Laboratory | Kellya H.,Victorian Infectious Diseases Reference Laboratory
Bulletin of the World Health Organization | Year: 2011

Programmes that provide no-fault compensation for an adverse event following vaccination have been implemented in 19 countries worldwide, the first in Germany in 1961 and the most recent in Hungary in 2005. We performed a review of these programmes and determined elements that were common to all of them: administration and funding, eligibility, process and decision-making, standard of proof, elements of compensation and litigation rights. Most programmes were administered by state or national governments except in Finland and Sweden where they are coordinated by pharmaceutical manufacturers. Although funding is usually from Treasury, Taiwan (China) and the United States of America impose a tax on vaccine doses distributed. Decisions on compensation are made using established criteria or assessed on a case-by-case basis, while the standard of proof required is usually less than that required for court cases. Benefits provided by programmes include medical costs, disability pensions and benefits for noneconomic loss and death. Most countries allow claimants to seek legal damages through the courts or a compensation scheme payout but not both. We conclude that a variety of programmes, based on ethical principles, have been successful and financially viable in developed countries throughout the world. We believe there is a strong argument for widespread implementation of these programmes in other developed countries.


Marshall J.A.,Victorian Infectious Diseases Reference Laboratory
International journal of environmental research and public health | Year: 2011

Noroviruses are a major cause of gastroenteritis outbreaks worldwide. Norovirus outbreaks frequently occur as epidemics which appear to be related to both genetic and environmental factors. This review considers recent progress in understanding these factors. The norovirus genome undergoes continuous change and this appears to be important in the persistence of the virus in the community. Studies on the common GII.4 genotype have shown that some norovirus outbreak epidemics involving this genotype are correlated with specific changes in the genome. In contrast to the growing understanding of the role of genetic factors in norovirus outbreak epidemics, the role of environmental factors is less well understood. Topics reviewed here include long term excretion of norovirus in some individuals, long term survivability of norovirus in the environment, the role of meteorological factors in the control of norovirus outbreaks and the possible zoonotic transmission of the virus.

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