Hepatitis: Zoulim F

Zoulim F. · No affiliation provided · Hepatology. · Pubmed #17133478 No free full text.

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Durantel D, Zoulim F. · No affiliation provided · J Hepatol. · Pubmed #17112625 No free full text.

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Zoulim F. · No affiliation provided · Hepatology. · Pubmed #14647043 No free full text.

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Zoulim F. · No affiliation provided · J Hepatol. · Pubmed #12763381 No free full text.

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Zoulim F. · No affiliation provided · Gastroenterol Clin Biol. · Pubmed #12658124 No free full text.

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Zoulim F. · INSERM Unité 271, et Service d'Hépatologie et de Gastroentérologie, Hôtel-Dieu, 151, cours Albert-Thomas, 69003 Lyon, France. · Gastroenterol Clin Biol. · Pubmed #11173726 No free full text.

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Zoulim F, Trépo C. · No affiliation provided · Hepatology. · Pubmed #11050072 No free full text.

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Si Ahmed SN, Zoulim F. · INSERM, U871, 69003 Lyon, France. · Expert Rev Anti Infect Ther. · Pubmed #19344244 No free full text.

Abstract: HBV is the leading cause of liver cancer and frequently leads to cirrhosis and liver failure. The goals of nucleos(t)ide analog treatments are to suppress viral replication to as low as possible, to halt disease progression and to prevent the onset of complications. Due to the mechanism of viral genome persistence, chronic hepatitis B requires long-term therapy that exposes patients to the risk of selection of resistant mutants and treatment failure. Genotypic resistance is defined as the detection of resistant mutations that are known to confer resistance to antiviral drugs. Virologic rebound is defined as an increase in viral load of at least 1 log(10) copies/ml compared with the lowest value during therapy. Clinical breakthrough is defined as a rise in alanine aminotransferase levels and liver disease progression following the emergence of resistant mutants and the rise in viral load. Currently, the management of antiviral therapy should be based on precise virologic monitoring to enable an early diagnosis of partial response and treatment failure. An early treatment adaptation is recommended at least at the time of virologic breakthrough or in the case of insufficient viral suppression. The choice of drug for second-line therapy should be based on cross-resistance data to tailor therapy to the virologic situation of the patient. The addition of a complementary drug is the preferred strategy. Clinical experience shows that an optimal management of antiviral therapy allows the control of viral replication in the majority of patients in whom liver disease progression is halted.

Zoulim F, Durantel D, Deny P. · INSERM, U871, Lyon, France. · Liver Int. · Pubmed #19207973 No free full text.

Abstract: The management of hepatitis B virus resistance to antivirals has evolved rapidly in recent years. The definition of resistance is now well established, with the importance of partial response and the improvement of assays to detect genotypic resistance and virological breakthrough. Data on phenotypic resistance have allowed to define the cross-resistance profile for the main resistant mutants, providing a rationale for treatment adaptation. Clinical studies have shown that an early treatment intervention in case of a virological breakthrough or a partial response with the addition of a second drug having a complementary cross-resistance profile allows one to maintain the majority of patients in clinical remission. The prevention of resistance should rely on the use of the most potent antivirals with a high genetic barrier to resistance as a first-line therapy. The future perspectives are to design strategies to hasten the HBsAg clearance, which should become a new treatment endpoint, to prevent drug resistance and to decrease the incidence of complications of chronic hepatitis B.

Zoulim F, Radenne S, Ducerf C. · INSERM, [corrected] U871 Lyon, France. · Liver Transpl. · Pubmed #18825719 No free full text.

Abstract: 1. Hepatitis B virus replication is associated with a severe outcome in patients with decompensated cirrhosis. 2. Viral suppression induced by antivirals results in a clinical improvement that allows liver transplantation to be delayed or avoided. 3. Early treatment intervention is mandatory in patients with decompensated cirrhosis because of the delay in the restoration of liver functions. 4. Lamivudine is no longer the drug of choice because the initial enthusiasm has been tempered by the high rate of resistance development. 5. Early add-on therapy with adefovir allows us to rescue lamivudine resistance, but its use may be limited by nephrotoxicity. 6. Studies are ongoing with the newer generation of antivirals (telbivudine, tenofovir, entecavir, and emtricitabine) in monotherapy or in combination to determine the best strategy for achieving rapid and prolonged suppression of viral replication. These improved strategies should enhance treatment success enough to obtain clinical stabilization, to delay or prevent the need for transplantation, and to reduce the risk of hepatitis B virus recurrence on the graft.AASLD.

Fournier C, Zoulim F. · INSERM, U871, 151, cours Albert Thomas, 69003 Lyon, France. · Gastroenterol Clin Biol. · Pubmed #18662609 No free full text.

Abstract: The HBV genome variability is responsible for the complexitiy of the viral quasi-species and its evolution during the course of the infection. During antiviral therapy, the persistence of infected cells is another important determinant involved in the selection of drug resistant strains. The development of nucleoside analogs with complementary resistance profiles has provided the rationale for add-on strategies in case of virologic breakthrough. The current trend is to add antivirals earlier, before the rebound of viral load, especially in case of partial virologic response. Clinical trials are required to determine if a de novo combination of nucleoside analogs provides an added benefit compared to an early add-on strategy. However, de novo combination is recommended in patients whose liver functions cannot tolerate treatment failure, and in patients with a high risk of developing viral resistance because of a complex viral quasi-species prior to therapy.

Soriano V, Puoti M, Peters M, Benhamou Y, Sulkowski M, Zoulim F, Mauss S, Rockstroh J. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · AIDS. · Pubmed #18614862 No free full text.

Abstract: Nearly 10% of the estimated 36 million people having HIV worldwide suffer from chronic hepatitis B virus (HBV) infection. The advent of new antiviral agents against HBV and the recent availability of improved molecular diagnostic tools have revolutioned the management of HIV/HBV coinfected patients. The present study represents an update of the current knowledge about HBV/HIV coinfection and an intent to provide practical advise about how to give the best care to HIV-infected persons with chronic hepatitis B.

Soriano V, Perelson AS, Zoulim F. · Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029 Madrid, Spain. · J Antimicrob Chemother. · Pubmed #18441341 links to  free full text

Abstract: The arrival of new antiviral drugs to treat chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections has given rise to great expectations along with concerns regarding the selection of drug-resistant variants. Many lessons learnt from HIV therapeutics can be helpful for designing adequate treatment strategies against viral hepatitis, the avoidance of sequential weak monotherapies being one of them. Although HIV, HBV and HCV share many biological features, including very rapid viral dynamics, distinctive characteristics explain why the speed of selection of drug resistance differs substantially between these viruses, being faster for HCV than for HIV and slower for HBV.

Durantel D, Zoulim F. · Molecular Physiopathology and New Treatments for Hepatitis Viruses, INSERM, U871, Lyon, France. · J HIV Ther. · Pubmed #18391894 No free full text.

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Zoulim F, Perrillo R. · INSERM, U871, 69003 Lyon, France; Université Lyon 1, IFR62 Lyon-Est, 69008 Lyon, France. · J Hepatol. · Pubmed #18304680 No free full text.

Abstract: This article summarizes the current state of antiviral therapy of hepatitis B with special attention given to areas that remain controversial or poorly defined. Strict adherence to liver association practice guidelines may result in missed opportunities to treat patients with significant underlying liver disease. In particular, recommended ALT thresholds may not appropriately reflect disease activity or degree of fibrosis. There is growing evidence that an alternative treatment paradigm for preventing late-stage disease complications may be indicated in highly viremic patients with early life exposure to hepatitis B. Pegylated interferon therapy is often a better choice for young to middle-aged patients with genotype A and B because of the higher rate of HBeAg seroconversion and a greater chance for HBsAg seroconversion in both HBeAg-positive and -negative patients as compared to nucleoside analogs. Nucleoside analog monotherapy is the current standard of care for many patients. However, long-term monotherapy results in resistance to a variable degree and sequential monotherapy may result in multi-drug resistant virus. Which patients would specifically benefit from early combination therapy also remains poorly defined. The rapidity and robustness of the suppression of HBV DNA while on a nucleoside analog should be monitored relatively early during treatment because it affects treatment outcome and the rate of resistance. While great progress has been made in treating hepatitis B, many important issues require further study.

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.

Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany. · Nat Rev Drug Discov. · Pubmed #18049473 links to  free full text

Abstract: Infection with the hepatitis C virus (HCV) represents an important health-care problem worldwide. The prevalence of HCV-related disease is increasing, and no vaccine is yet available. Since the identification of HCV as the causative agent of non-A, non-B hepatitis, treatment has progressed rapidly, but morbidity and mortality rates are still predicted to rise. Novel, more efficacious and tolerable therapies are urgently needed, and a greater understanding of the viral life cycle has led to an increase in the number of possible targets for antiviral intervention. Here we review the specific challenges posed by HCV, and recent developments in the design of vaccines and novel antiviral agents.

Zoulim F. · Service d'hépatogastroentérologie, Hôtel-Dieu, F-69002 Lyon, France. · Presse Med. · Pubmed #18042341 No free full text.

Abstract: Despite the development of new therapeutic options, treatment of chronic hepatitis B remains a clinical challenge because of the need for long-term treatment in most patients. Treatment with pegylated interferon is the only option that allows a defined duration of treatment. Nonetheless, approximately 70% of the patients treated do not have a prolonged treatment response. A variety of nucleoside analog viral polymerase (reverse transcriptase) inhibitors have been developed (lamivudine, adefovir dipivoxil, entecavir, telbivudine); they can be administered orally and are well tolerated. These antiviral agents effectively induce viral suppression, which is accompanied by an improvement in transaminases and hepatic histology. Nonetheless, the rates of HBe and HBs seroconversion remain low with nucleoside analogs, and the absence of these immunologic events necessitates prolonged antiretroviral treatment. Treatment with nucleoside analogs leads to selection of resistant mutant viruses. They therefore require close clinical and virologic follow-up to enable early screening for resistance and adaptation of treatment before the liver disease worsens. The development of these different treatment options has made possible very significant improvements in the management of patients with chronic hepatitis B, by preventing aggravation of liver disease in most of them.

Fournier C, Zoulim F. · Hospices Civils de Lyon, Hôtel Dieu, Service d'hépato-gastroentérologie, 69002 Lyon, France. · Clin Liver Dis. · Pubmed #17981233 No free full text.

Abstract: The emergence of viral resistance during treatment is becoming an important clinical issue for hepatitis B virus (HBV) antiviral therapy. Considerable progress has been achieved in the efficacy of treatment, with the development of new drugs that allow a sustained suppression of HBV replication, or at least maintain the viral load below a clinically relevant threshold. Although most drugs currently registered for the treatment of chronic hepatitis B are effective in suppressing viral load, long-term therapy is required to avoid viral reactivation and progression of liver disease. Because of the variability of the HBV genome, such long-term treatments are associated with the emergence of resistant viral strains, which may compromise the initial clinical benefit of the treatment.

Zoulim F, Buti M, Lok AS. · INSERM, U871, 69003 Lyon, France. · J Viral Hepat. · Pubmed #17958640 No free full text.

Abstract: Despite the recent progress in antiviral therapy of chronic hepatitis B, clinical experience has shown that antiviral drug resistance is inevitable with the administration of nucleoside analog monotherapy. The long-term persistence of the viral genome in infected cells and the high rate of spontaneous mutation is the basis for the selection of HBV mutants that are resistant to polymerase inhibitors. Selection of antiviral-resistant mutations leads to a rise in viral load and progression of liver disease. The incidence of antiviral resistance depends on the potency and genetic barrier to resistance of the antiviral drug, highlighting the importance of the choice if first line therapy. The determination of cross-resistance profile of each drug has allowed the design of rescue therapy for patients with virologic breakthrough. Early diagnosis and treatment intervention allow the majority of patients to maintain in clinical remission despite the occurrence of drug resistance. Clinical studies are ongoing to determine the best strategy to prevent or delay antiviral drug resistance and of its impact on liver disease.

Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane EJ, Jacobson IM, Lim SG, Naoumov N, Marcellin P, Piratvisuth T, Zoulim F. · Stanford University School of Medicine, Stanford, California 94304-1509, USA. · Clin Gastroenterol Hepatol. · Pubmed #17632041 No free full text.

Abstract: An international group of experienced hepatologists and virologists conducted a single-day workshop to review the management of patients with chronic hepatitis B receiving treatment with oral nucleosides or nucleotides. Guidelines regarding on-treatment management and available published data on the importance of serum hepatitis B virus (HBV) DNA as a marker of outcomes were reviewed. On-treatment monitoring strategies to define early virologic responses that might be predictive of better outcomes and a reduced risk of viral resistance were proposed for further study. This treatment plan, labeled the roadmap concept, recommends monitoring of serum HBV DNA levels to identify outcomes of therapy. Primary treatment failure was defined as a reduction of serum HBV DNA levels by less than 1 log10 IU/mL from baseline at week 12. Measurement of the HBV DNA level at week 24 was considered essential to characterize virologic responses as complete, partial, or inadequate. Complete virologic response was defined as negative HBV DNA by a sensitive assay (<60 IU/mL or <300 copies/mL); partial virologic response was defined as HBV DNA levels less than 2000 IU/mL (4 log10 copies/mL), and inadequate virologic response was defined as HBV DNA levels of 2000 IU/mL or greater (4 log10 copies/mL). Strategies are proposed for managing patients in each of these categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug. Future studies of the use of the roadmap concept in improving outcomes of chronic hepatitis B are warranted.

Zoulim F. · INSERM, U871, 151 cours Albert Thomas, 69424 Lyon cedex 03, France. · Expert Opin Emerg Drugs. · Pubmed #17604497 No free full text.

Abstract: Chronic hepatitis B remains a treatment challenge despite the availability of new nucleoside analogs. This is due to the persistence of viral infection during therapy, which exposes the patient to the risk of developing antiviral drug resistance. Therefore, new polymerase inhibitors are needed to manage resistance to existing drugs and new trials of combination therapy are required to delay drug resistance. In the future, antiviral agents targeting other steps of the viral life cycle will be needed to achieve antiviral synergy and prevent antiviral drug resistance. Immune modulators are also expected to enhance antiviral response and to achieve sustained response. Discovery of new antiviral drugs and design of new treatment strategies are, therefore, needed to manage this disease, which is still the main cause of cirrhosis and hepatocellular carcinoma worldwide.

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.

Kay A, Zoulim F. · INSERM, U871, Physiopathologie moléculaire et nouveaux traitements des hépatites virales, 151 cours A. Thomas, Lyon F-69424, France. · Virus Res. · Pubmed #17383765 No free full text.

Abstract: Hepatitis B virus has been evolving gradually over a long period of time, resulting in a large amount of genetic diversity, despite the constraints imposed by the complex genetic organization of the viral genome. This diversity is partly due to virus/host interactions and partly due to parallel evolution in geographically distinct areas. Recombination also appears to be an important element in HBV evolution. Also, human intervention in the form of mass vaccination and antiviral treatment will reduce the burden of HBV-related liver disease but may also be accelerating evolution of the virus.

Durantel D, Alotte C, Zoulim F. · INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, Lyon F-69424, France. · Curr Opin Investig Drugs. · Pubmed #17328228 No free full text.

Abstract: HBV and HCV infections are a major public health concern. New antiviral drugs are urgently needed with improved efficacy. Compounds that specifically target viral enzymes are the most attractive in terms of drug development and are therefore the most studied. However, antiviral strategies based entirely on this class of compounds encounter problems caused by the emergence of viral escape mutants, as already widely described for HIV. One way to prevent or delay viral resistance is to combine antiviral agents that target different steps of the virus life cycle. Future therapy may also combine such virus-specific antivirals with compounds targeting host proteins or functions. In this respect, viral morphogenesis and infectivity represent interesting, and still unexploited, novel molecular targets. Endoplasmic reticulum glucosidase inhibitors have demonstrated anti-HBV and anti-HCV properties by inhibiting viral morphogenesis and infectivity. One such compound, celgosivir, is currently being evaluated in clinical trials against HCV infection, and encouraging phase IIa data have been disclosed. This review will discuss HBV and HCV morphogenesis, with a particular focus on the role of N-glycosylation for viral protein folding and assembly, and will present the antiviral properties of glucosidase inhibitors.