Hepatitis: Pawlotsky JM

de Araújo ES, Mendonça JS, Barone AA, Gonçales FL, Ferreira MS, Focaccia R, Pawlotsky JM. · No affiliation provided · Braz J Infect Dis. · Pubmed #17962867 links to  free full text

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Pawlotsky JM. · No affiliation provided · Gastroenterology. · Pubmed #17418174 No free full text.

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Pawlotsky JM. · No affiliation provided · Gastroenterol Clin Biol. · Pubmed #17075451 No free full text.

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Pawlotsky JM. · No affiliation provided · Gastroenterology. · Pubmed #15521029 No free full text.

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Chevaliez S, Pawlotsky JM. · Department of Virology, Hopital Henri Mondor, Universite Paris 12, Creteil, France. · Ann Hepatol. · Pubmed #19221527 No free full text.

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Chevaliez S, Pawlotsky JM. · Department of Virology & INSERM U841, French National Reference Center for Viral Hepatitis B, C and delta, Hôpital Henri Mondor, Université Paris 12, Créteil, France. · Liver Int. · Pubmed #19207960 No free full text.

Abstract: Chronic hepatitis C is a global health problem that may cause cirrhosis and progression to hepatocellular carcinoma. Currently available antiviral treatments are moderately effective. Several virological assays are available to help diagnose and manage patients infected with the hepatitis C virus (HCV). These include the anti-HCV antibody assays, measurement of HCV RNA viral load and HCV genotyping. HCV RNA can be assayed by two types of molecular biology-based techniques: target amplification as in polymerase chain reaction methods and signal amplification such as the branched DNA assay. Monitoring of viral kinetics during the early phases of antiviral treatment is crucial in making treatment decisions such as early stopping rules and also in optimizing the length of treatment. The HCV genotype can be determined by several methods. Whatever the method, pretreatment determination allows treatment length and ribavirin dose to be optimized and also offers prognostic information on treatment outcomes as certain genotypes respond more favourably to treatment. Thus, virological assays are indispensable in the diagnosis and management of individuals infected with the HCV.

Chevaliez S, Pawlotsky JM. · Department of Virology & INSERM U955, French National Reference Centre for Viral Hepatitis B, C and delta, Hôpital Henri Mondor, Université Paris, Créteil, France. · Best Pract Res Clin Gastroenterol. · Pubmed #19187865 No free full text.

Abstract: Virological tools, including serological and molecular tools, are needed to diagnose chronic hepatitis B and C infections. They may also be useful to establish their prognosis, but they have found their principal application in guiding treatment decisions and assessing the virological responses to therapy. The goal of chronic hepatitis B therapy is to prevent progression of liver disease. This is achieved if HBV replication is durably abolished or significantly reduced. In HBeAg-positive patients, HBeAg clearance followed by the HBe seroconversion phase can be achieved. In HBeAg-negative patients, long-term antiviral suppression of viral replication is needed. The loss of HBsAg, eventually associated with an HBs seroconversion, is the most desirable endpoint of therapy but is rarely achieved. The efficacy endpoint of chronic hepatitis C treatment is the sustained virological response, defined by an undetectable HCV RNA in serum with a sensitive assay 24 weeks after the end of treatment. The HCV genotype and on-treatment viral kinetics can be used to tailor treatment dosages and duration.

Chevaliez S, Pawlotsky JM. · French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. · Handb Exp Pharmacol. · Pubmed #19048202 No free full text.

Abstract: In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN) by Isaacs and Lindenmann. Subsequently, the IFN-alpha gene was cloned, fully sequenced and IFN-alpha was produced in recombinant form. Recombinant IFN-alpha is now used as the basis for treatment of chronic hepatitis C virus infection and can also be used to treat certain forms of chronic hepatitis B virus infections. IFNs have also been used in other viral infections, although with less success. The antiviral mechanisms of IFNs are reviewed in this chapter as well as the utility of IFNs in the treatment of persistent viral infections.

Pawlotsky JM. · Centre National de Référence des Hépatites B, C et delta, Laboratoire de Virologie, INSERM U841, Hôpital Henri Mondor, Université Paris 12, 51, avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. · Gastroenterol Clin Biol. · Pubmed #18662611 No free full text.

Abstract: Both serologic and molecular tools are useful for the diagnosis, monitoring and therapeutic management of viral hepatitis associated with hepatitis B virus (HBV). Compared with the standard tests to detect viral antigens and the antibodies directed against them, real-time PCR techniques today make it possible to quantify viral DNA more sensitively and more precisely. They thus replace the techniques previously used in most virology laboratories. New markers, such as the HBV genotype or the amino-acid substitution profile associated with HBV resistance to nucleoside and nucleotide analogs (NRTIs), can also be characterized by techniques based on sequencing or reverse hybridization. There is not currently any consensus about the first-line treatment for chronic HBV infection. Patients with a wild-type virus (HBe antigen-positive), a moderate viral load, and elevated serum alanine aminotransferase (from 2 to 5 times the upper limit of normal) are good candidates for treatment with pegylated interferon-alpha. Patients who are HBe antigen-positive and do not respond to this first-line treatment, as well as patients with chronic e-antigen-negative hepatitis B, are candidates for prolonged treatment, probably lifelong, by nucleoside or nucleotide analogs. Whatever the HBe serologic status and treatment, the efficacy of antiviral treatment is assessed by repeated measurements of viral load and serum alanine aminotransferase levels, in principle, every 12-24 months. In patients who are HBe antigen-positive, the efficacy of antiviral treatment is shown by the loss of HBe antigen, followed by the appearance of anti-HBe antibodies (HBe seroconversion), a reduction in viral load below 2x10(4)IU/mL and normalization of serum aminotransferase. In patients who are HBe antigen-negative or HBe antigen-positive but do not seroconvert after short-term treatment and who receive nucleoside or nucleotide analogs, the treatment objective is for HBV DNA to become undetectable by real-time PCR. Nonetheless, this objective is not always met, and it is recommended that viral replication be maintained at the lowest possible level for the longest possible time (ideally, lifelong). In all cases, when a virologic response to treatment is observed (significant reduction in viral load) and is followed by a relapse characterized by a viral load augmentation of at least 1 Log(10)IU/mL relative to the nadir, viral resistance to treatment must be suspected, after treatment adherence has been verified.

Keeffe EB, Dieterich DT, Pawlotsky JM, Benhamou Y. · Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #18328434 No free full text.

Abstract: Licensed oral agents for antiviral therapy in patients with chronic hepatitis B virus (HBV) infection include lamivudine, adefovir, entecavir, and telbivudine. Emtricitabine, tenofovir, and the combination of tenofovir plus emtricitabine in 1 tablet, which are licensed for the treatment of human immunodeficiency virus infection, are additional off-label options for treating HBV infection. Preventing HBV antiviral drug resistance to nucleoside/nucleotide analogues and appropriate management when resistance occurs has become a major focus in the management of chronic hepatitis B. HBV antiviral drug resistance may be best prevented by using an agent or combination of agents with a high genetic barrier to resistance, and 2 potent nucleoside and nucleotide drugs with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B. Frequent assessment of quantitative serum HBV DNA remains the best approach to early detection of resistance, and antiviral therapy should be modified as soon as resistance is detected. Results from several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalize alanine aminotransferase levels, and reverse histologic progression in patients with resistance to lamivudine, but little information exists regarding the long-term benefits of second-line treatment regimens. Despite the substantial advances in treatment made to date, new agents with novel viral targets will be needed for patients who ultimately may fail second- or third-line therapy.

Pawlotsky JM, Dusheiko G, Hatzakis A, Lau D, Lau G, Liang TJ, Locarnini S, Martin P, Richman DD, Zoulim F. · French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology, Henri Mondor Hospital, University of Paris XII, Créteil, France. · Gastroenterology. · Pubmed #18242209 links to  free full text

Abstract: Treatment of chronic hepatitis B virus (HBV) infection is aimed at suppressing viral replication to the lowest possible level, and thereby to halt the progression of liver disease and prevent the onset of complications. Two categories of drugs are used in HBV therapy: the interferons, including standard interferon alfa or pegylated interferon alfa, and specific nucleoside or nucleotide HBV inhibitors that target the reverse-transcriptase function of HBV-DNA polymerase. The reported results of clinical trials have used varying definitions of efficacy, failure, and resistance based on different measures of virologic responses. This article discusses HBV virologic markers and tests, and their optimal use both for planning and reporting clinical trials and in clinical practice.

Marcellin P, Bourlière M, Pawlotsky JM, Ouzan D. · Service d'Hépatologie, INSERM U773 CRB3, Université Paris VII, Hôpital Beaujon, Clichy, France. · Gastroenterol Clin Biol. · Pubmed #17965630 No free full text.

Abstract: About half of patients with chronic hepatitis C do not respond to the current treatment combining pegylated interferon and ribavirin. One must distinguish the "false" non responders who did not receive an optimal treatment and the "true" non responders who received an optimal treatment. In "false" non responders, the management of the factors of non response (alcohol consumption, body overweight...) or the improvement of tolerability to therapy (anti-depressive therapy, erythropoietin...) may allow an optimized retreatment with a chance of viral eradication. On the opposite, in "true" non responders, the probability to obtain with retreatment a viral eradication is very low and one must envisage, in case of severe liver disease (fibrosis stage F3 or F4), maintenance therapy. The objective of maintenance therapy is to decrease the activity of the chronic hepatitis and stabilize fibrosis in order to decrease the risk of complications and hepatocellular carcinoma. The ongoing trials will determine the optimal schedule of maintenance therapy. The new antivirals, mainly protease inhibitors and polymerase inhibitors, will probably be used in triple therapy with pegylated interferon and ribavirin. The drugs, currently in phase 1 and 2, which will demonstrate their efficacy and safety, should not be available before several years.

Chevaliez S, Pawlotsky JM. · Department of Virology, Henri Mondor Hospital, University of Paris XII, Paris, France. · J Viral Hepat. · Pubmed #17958647 No free full text.

Abstract: Prevention of hepatitis C virus (HCV) infection complications can be achieved by antiviral therapy based on the use of a combination of pegylated interferon (IFN)-alpha and ribavirin. The steady-state kinetics of HCV infection represents the treatment target. The goal is cure, which is achieved when all infected cells have been cleared from the body. Because of their intrinsic properties, real-time polymerase chain reaction (PCR) methods are rapidly replacing other technologies for routine quantification of HCV-RNA during antiviral therapy. The virological response at week 12 of therapy is currently used to tailor treatment duration in HCV genotype 1 infection only. Recent reports suggest that the virological response at week 4 could be used to tailor treatment duration, whatever the HCV genotype.

Chevaliez S, Pawlotsky JM. · French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil, France. · Adv Drug Deliv Rev. · Pubmed #17869375 No free full text.

Abstract: In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN). The first clinical trial of recombinant IFN-alpha in patients with chronic hepatitis C was published in 1986. This article reviews the classification of IFNs, IFN production during viral infections, IFN signaling pathways and the mechanisms of their antiviral and immunomodulatory properties. Hepatitis C virus infection treatment is currently based on the combination of pegylated IFN-alpha and ribavirin. The pegylated IFN-alpha molecules are described, as well as the putative mechanisms of action of ribavirin. Current treatment guidelines are discussed and new results suggesting that the treatment schedule should be tailored to the early virological response during therapy are presented. Finally, insights into new hepatitis C drug developments are given.

Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C, Anonymous00198. · Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0362, USA. · Hepatology. · Pubmed #17596850 No free full text.

Abstract: Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Approved treatments for chronic hepatitis B include 2 formulations of interferon and 4 nucleos(t)ide analogues (NAs). Sustained viral suppression is rarely achieved after withdrawal of a 48-week course of NA therapy, necessitating long, and in many cases, indefinite treatment with increasing risk of development of drug resistance. Antiviral resistance and poor adherence are the most important factors in treatment failure of hepatitis B. Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy.

Chevaliez S, Pawlotsky JM. · French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology & INSERM U 841, Hopital Henri Mondor, 94010 Creteil, France. · World J Gastroenterol. · Pubmed #17552030 links to  free full text

Abstract: Hepatitis C virus (HCV) infects approximately 170 million individuals worldwide. Prevention of HCV infection complications is based on antiviral therapy with the combination of pegylated interferon alfa and ribavirin. The use of serological and virological tests has become essential in the management of HCV infection in order to diagnose infection, guide treatment decisions and assess the virological response to antiviral therapy. Anti-HCV antibody testing and HCV RNA testing are used to diagnose acute and chronic hepatitis C. The HCV genotype should be systematically determined before treatment, as it determines the indication, the duration of treatment, the dose of ribavirin and the virological monitoring procedure. HCV RNA monitoring during therapy is used to tailor treatment duration in HCV genotype 1 infection, and molecular assays are used to assess the end-of-treatment and, most importantly the sustained virological response, i.e. the endpoint of therapy.

Pawlotsky JM, Chevaliez S, McHutchison JG. · French National Reference Center for Viral Hepatitis B, C, and delta, Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil, France. · Gastroenterology. · Pubmed #17484890 No free full text.

Abstract: The burden of disease consequent to hepatitis C virus (HCV) infection has been well described and is expected to increase dramatically over the next decade. Current approved antiviral therapies are effective in eradicating the virus in approximately 50% of infected patients. However, pegylated interferon and ribavirin-based therapy is costly, prolonged, associated with significant adverse effects, and not deemed suitable for many HCV-infected patients. As such, there is a clear and pressing need for the development of additional agents that act through alternate or different mechanisms, in the hope that such regimens could lead to enhanced response rates more broadly applicable to patients with hepatitis C infection. Recent basic science enhancements in HCV cell culture systems and replication assays have led to a broadening of our understanding of many of the mechanisms of HCV replication and, therefore, potential novel antiviral targets. In this article, we have attempted to highlight important new information as it relates to our understanding of the HCV life cycle. These steps broadly encompass viral attachment, entry, and fusion; viral RNA translation; posttranslational processing; HCV replication; and viral assembly and release. In each of these areas, we present up-to-date knowledge of the relevant aspects of that component of the viral life cycle and then describe the preclinical and clinical development targets and pathways being explored in the translational and clinical settings.

Pawlotsky JM, Gish RG. · Department of Virology, INSERM U635, Henri Mondor Hospital, University of Paris, Créteil, France. · Antivir Ther. · Pubmed #16856613 No free full text.

Abstract: Although pegylated interferon-alpha plus ribavirin has become the standard for treating chronic hepatitis C virus infection, a substantial number of patients do not tolerate therapy and require dose reduction or discontinuation, or do not respond to this combination therapy. Thus, new therapeutic options are needed. An increased knowledge of the hepatitis C virus and an understanding of its replication cycle, as well as advances in biotechnology, have stimulated the development of numerous new antiviral treatments for patients with hepatitis C virus infection. This review focuses on four classes of new agents: new interferons, ribavirin-like molecules, specific small-molecule hepatitis C virus inhibitors and new immune therapies, with particular emphasis on medications in the later stages of development.

Castera L, Pawlotsky JM. · Department of Hepatology and Gastroenterology, C.H.U. Bordeaux, Hôpital Haut Lévêque, Pessac, France. · MedGenMed. · Pubmed #16614661 links to  free full text

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Pawlotsky JM. · Service de Virologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. · Curr Top Microbiol Immunol. · Pubmed #16568902 No free full text.

Abstract: Hepatitis C virus (HCV) behaves as an evolving viral quasispecies in its continuously changing environment. The study of HCV quasispecies population dynamics in experimental models and infected patients can provide useful information on factors involved in the HCV life cycle and pathogenicity. HCV quasispecies variability also has therapeutic implications, as the continuous generation and selection of fitter or truly resistant variants can allow the virus to escape control by antiviral drugs.

Pawlotsky JM. · Department of Virology, INSERM U635, Hôpital Henri Mondor, Unioersité Paris 12, Créteil, France. jean-michel.pawlotskyhmn.aphp.fr · J Clin Virol. · Pubmed #16461211 No free full text.

Abstract: Hepatitis B virus (HBV) reverse transcriptase is an error-prone enzyme, and this results in a large number of nucleotide substitutions during replication. As a result, HBV has a "quasispecies" distribution in infected individuals, meaning that HBV circulates as a complex mixture of genetically distinct but closely related variants that are in equilibrium at a given time point of infection in a given replicative environment. The quasispecies distribution of HBV implies that any newly generated mutation conferring a selective advantage to the virus in a given replicative environment will allow the corresponding viral population to overtake the other variants. Such selection processes occur at any step of infection to allow the emergence of variant viruses, such as precore and core promoter mutants during the natural course of infection, HBs antigen mutants under the pressure of active or passive anti-HBs immunization, or HBV mutants that are resistant to the antiviral action of specific HBV inhibitors.

Pawlotsky JM. · Hôpital Henri Mondor, Créteil, France. · Hepatology. · Pubmed #16447262 No free full text.

Abstract: The complications of chronic hepatitis C virus infection can be prevented by antiviral therapy. The initial choice of interferon alfa and, subsequently, ribavirin as potential treatments for chronic hepatitis C was empirical. Nevertheless, the combination of pegylated interferon alfa and ribavirin has become the standard treatment of chronic hepatitis C. Since the advent of interferon-based therapy, enormous progress has been made in understanding the mechanisms of treatment efficacy and failure, and in everyday patient management. The principal advances are: a better understanding of hepatitis C virus steady-state kinetics and the antiviral mechanisms of interferon and ribavirin; easier treatment decisions thanks to novel assays to assess liver disease severity and the virological characteristics of infection; a better use of virological tests to tailor therapy; a better management of adverse effects; a better understanding of virological treatment failure; and a better management of "special" populations, including patients with decompensated cirrhosis and end-stage liver disease, liver transplant recipients, hemodialysis patients and renal transplant recipients, human immunodeficiency virus-coinfected patients, intravenous drug users and patients on opiate replacement therapy, or virological non responders to previous therapies. Steady-state HCV kinetics offers several potential targets for new drugs. These targets should ideally be hit simultaneously in order to achieve viral eradication within a reasonable time frame. Future drugs for HCV infection will belong to four main categories, including new interferons, alternatives to ribavirin, specific HCV inhibitors, and immune modulators. New treatments and vaccines might make it possible to eradicate HCV in the future.

McHutchison JG, Bartenschlager R, Patel K, Pawlotsky JM. · Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Centre, 2400 Pratt Street, Room 0311, Terrace Level, Durham, NC 27707, USA. · J Hepatol. · Pubmed #16364491 No free full text.

This publication has no abstract.

Pawlotsky JM. · Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris 12, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. · J Hepatol. · Pubmed #16338022 No free full text.

Abstract: Hepatitis B and C viruses belong to two distinct virus families, the Hepadnaviridae and the Flaviviridae, respectively, and have different virological characteristics. Better knowledge of their lifecycles and variability offers the opportunity to develop novel therapeutic approaches and classes of drugs. The issue of cccDNA clearance, however, remains in hepatitis B treatment, whereas HCV infection is curable.

Adler M, Goubau P, Leroux-Roels G, Sprengers D, Pawlotsky JM. · Department of Gastroenterology and Hepatopancreatology, Hôpital Erasme, ULB, Brussels, Belgium. · Acta Gastroenterol Belg. · Pubmed #16268416 No free full text.

Abstract: This article discusses the use of virologic assays in the diagnosis and management of hepatitis C virus (HCV) and hepatitis B (HBV) infection. The use of virologic tests has become essential in the management of HCV and HBV infection to diagnose viral infection, guide treatment decisions, and assess the virologic response to antiviral therapy. The continuing development of test systems accompanied by new antiviral drugs and novel therapeutic approaches should lead to an optimization of the treatment of HCV infection. Molecular methods for viral testing have become an integral part of the diagnostic and therapeutic management of infections with hepatitis C virus (HCV) and hepatitis B virus (HBV).