Semin Liver Dis 2005; 25(1): 72-83
DOI: 10.1055/s-2005-864783
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Current and Future Concepts in Hepatitis C Therapy

Jean-Michel Pawlotsky1
  • 1Professor, Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris XII, Créteil, France
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
25. Februar 2005 (online)

ABSTRACT

The goal of hepatitis C virus (HCV) therapy is permanent viral eradication. This requires the use of drug combinations with multiple modes of action. Steady-state HCV replication kinetics can be disrupted by drugs that inhibit virus production (antiviral molecules), inhibit de novo cell infection, and/or accelerate the clearance of infected cells. Pegylated interferon-α and ribavirin combine all of these mechanisms of action when used together, yet fail to clear HCV from a significant number of patients. New therapeutic approaches are needed. The next generation of anti-HCV therapeutic agents will fall into four main categories: new interferons and interferon inducers, alternatives to ribavirin, specific HCV inhibitors, and immune therapies. Ideally, these new treatments will increase the rate of sustained viral eradication and improve tolerability and acceptability. Drug combinations will be tailored to the individual patient, based on baseline parameters and viral kinetics during therapy.

REFERENCES

  • 1 Consensus Panel . National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: 2002.  Hepatology. 2002;  36 S3-S20
  • 2 McHutchison J, Davis G L, Esteban-Mur R et al.. Durability of sustained virologic response in patients with chronic hepatitis C after treatment with interferon alfa-2b alone or in combination with ribavirin.  Hepatology. 2001;  34 244A
  • 3 Neumann A U, Lam N P, Dahari H et al.. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.  Science. 1998;  282 103-107
  • 4 Fried M W, Shiffman M L, Reddy K R et al.. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 975-982
  • 5 Hadziyannis S J, Sette Jr H, Morgan T R et al.. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;  140 346-355
  • 6 Manns M P, McHutchison J G, Gordon S C et al.. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 958-965
  • 7 Pawlotsky J M. Mechanisms of antiviral treatment efficacy and failure in chronic hepatitis C.  Antiviral Res. 2003;  59 1-11
  • 8 Lerat H, Rumin S, Habersetzer F et al.. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype.  Blood. 1998;  91 3841-3849
  • 9 Negro F, Levrero M. Does the hepatitis C virus replicate in cells of the hematopoietic lineage?.  Hepatology. 1998;  28 261-264
  • 10 Shimizu Y K, Iwamoto A, Hijikata M, Purcell R H, Yoshikura H. Evidence for in vitro replication of hepatitis C virus genome in a human T-cell line.  Proc Natl Acad Sci USA. 1992;  89 5477-5481
  • 11 Shimizu Y K, Yoshikura H. Multicycle infection of hepatitis C virus in cell culture and inhibition by alpha and beta interferons.  J Virol. 1994;  68 8406-8408
  • 12 Goutagny N, Fatmi A, De Ledinghen V et al.. Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection.  J Infect Dis. 2003;  187 1951-1958
  • 13 Katze M G, He Y, Gale Jr M. Viruses and interferon: a fight for supremacy.  Nat Rev Immunol. 2002;  2 675-687
  • 14 Sen G C, Ransohoff R M. Interferon-induced antiviral actions and their regulation.  Adv Virus Res. 1993;  42 57-102
  • 15 Frese M, Pietschmann T, Moradpour D, Haller O, Bartenschlager R. Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway.  J Gen Virol. 2001;  82 723-733
  • 16 Guo J T, Bichko V V, Seeger C. Effect of alpha interferon on the hepatitis C virus replicon.  J Virol. 2001;  75 8516-8523
  • 17 Lanford R E, Guerra B, Lee H et al.. Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(i)-poly(c), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons.  J Virol. 2003;  77 1092-1104
  • 18 Castet V, Fournier C, Soulier A et al.. Alpha interferon inhibits hepatitis C virus replication in primary human hepatocytes infected in vitro.  J Virol. 2002;  76 8189-8199
  • 19 Peters M. Actions of cytokines on the immune response and viral interactions: an overview.  Hepatology. 1996;  23 909-916
  • 20 Tilg H. New insights into the mechanisms of interferon alfa: an immunoregulatory and anti-inflammatory cytokine.  Gastroenterology. 1997;  112 1017-1021
  • 21 Pawlotsky J M, Dahari H, Neumann A U et al.. Antiviral action of ribavirin in chronic hepatitis C.  Gastroenterology. 2004;  126 703-714
  • 22 Lau J Y, Tam R C, Liang T J, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection.  Hepatology. 2002;  35 1002-1009
  • 23 Dixit N M, Layden-Almer J E, Layden T J, Perelson A S. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection.  Nature. 2004;;  432 922-924
  • 24 Crotty S, Maag D, Arnold J J et al.. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen.  Nat Med. 2000;  6 1375-1379
  • 25 Crotty S, Cameron C E, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin.  Proc Natl Acad Sci USA. 2001;  98 6895-6900
  • 26 Contreras A M, Hiasa Y, He W, Terella A, Schmidt E V, Chung R T. Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system.  J Virol. 2002;  76 8505-8517
  • 27 Lutchman G A, Danehower S, Park Y et al.. Mutation rate of hepatitis C virus in patients during ribavirin monotherapy.  Hepatology. 2004;  40(suppl 1) 385A
  • 28 Pawlotsky J M, Brillet R, Hezode C, Dhumeaux D. Mechanisms of ribavirin early antiviral effect in chronic hepatitis C: is it related to ribavirin mutagenic properties inducing “error catastrophe”?.  Hepatology. 2003;  38(suppl 1) 730A
  • 29 Fang S H, Hwang L H, Chen D S, Chiang B L. Ribavirin enhancement of hepatitis C virus core antigen-specific type 1 T helper cell response correlates with the increased IL-12 level.  J Hepatol. 2000;  33 791-798
  • 30 Hultgren C, Milich D R, Weiland O, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses.  J Gen Virol. 1998;  79 2381-2391
  • 31 McHutchison J G, Gordon S C, Schiff E R et al.. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.  N Engl J Med. 1998;  339 1485-1492
  • 32 Poynard T, Marcellin P, Lee S S et al.. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.  Lancet. 1998;  352 1426-1432
  • 33 Dore J G, Thomas D L. Management and treatment of injection drug users with hepatitis C virus monoinfection and HCV/human immunodeficiency virus coinfection.  Semin Liver Dis. 2005;  25 8-32
  • 34 Torriani F J, Rodriguez-Torres M, Rockstroh J K et al.. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.  N Engl J Med. 2004;  351 438-450
  • 35 Chung R T, Andersen J, Volberding P et al.. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.  N Engl J Med. 2004;  351 451-459
  • 36 Pawlotsky J M. Treating hepatitis C in “difficult-to-treat” patients.  N Engl J Med. 2004;  351 422-423
  • 37 Bräu N. Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin.  Semin Liver Dis. 2005;  25 33-51
  • 38 Neumann A U, Zeuzem S, Ferrari C et al.. Ditto-HCV early viral kinetics report: novel decline patterns in genotype 1 but not genotypes 2 and 3 patients treated with peg-interferon alfa-2a and ribavirin.  J Hepatol. 2002;  36(suppl 1) 121
  • 39 Pawlotsky J M, Hezode C, Pellegrin B et al.. Early HCV genotype 4 replication kinetics during treatment with peginterferon alpha-2a (Pegasys)-ribavirin combination: a comparison with HCV genotypes 1 and 3 kinetics.  Hepatology. 2002;  36(suppl 1) 291A
  • 40 Pawlotsky J M, Germanidis G, Frainais P O et al.. Evolution of the hepatitis C virus second envelope protein hypervariable region in chronically infected patients receiving alpha interferon therapy.  J Virol. 1999;  73 6490-6499
  • 41 Pawlotsky J M, Germanidis G, Neumann A U, Pellerin M, Frainais P O, Dhumeaux D. Interferon resistance of hepatitis C virus genotype 1b: relationship to nonstructural 5A gene quasispecies mutations.  J Virol. 1998;  72 2795-2805
  • 42 Young K C, Lindsay K L, Lee K J et al.. Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy.  Hepatology. 2003;  38 869-878
  • 43 Pawlotsky J M, McHutchison J G. Hepatitis C. Development of new drugs and clinical trials: promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003.  Hepatology. 2004;  39 554-567
  • 44 Pawlotsky J M. Hepatitis C virus genetic variability: pathogenic and clinical implications.  Clin Liver Dis. 2003;  7 45-66
  • 45 Buckwold V E, Beer B E, Donis R O. Bovine viral diarrhea virus as a surrogate model of hepatitis C virus for the evaluation of antiviral agents.  Antiviral Res. 2003;  60 1-15
  • 46 Wakita T, Kato T, Date T, Miyamoto M. Paper presented at: 11th International Symposium on Hepatitis C Virus and Related Viruses; October 3-7 2004 Heidelberg, Germany;
  • 47 Pietschmann T, Koutsoudakis G, Kallis S et al.. Paper presented at: 11th International Symposium on Hepatitis C Virus and Related Viruses; October 3-7 2004 Heidelberg, Germany;
  • 48 Bukh J. A critical role for the chimpanzee model in the study of hepatitis C.  Hepatology. 2004;  39 1469-1475
  • 49 Ilan E, Arazi J, Nussbaum O et al.. The hepatitis C virus (HCV)-Trimera mouse: a model for evaluation of agents against HCV.  J Infect Dis. 2002;  185 153-161
  • 50 Mercer D F, Schiller D E, Elliott J F et al.. Hepatitis C virus replication in mice with chimeric human livers.  Nat Med. 2001;  7 927-933
  • 51 Thibeault D, Bousquet C, Gingras R et al.. Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061.  J Virol. 2004;  78 7352-7359
  • 52 Lamarre D, Anderson P C, Bailey M et al.. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.  Nature. 2003;  426 186-189
  • 53 Hinrichsen H, Benhamou Y, Wedemeyer H et al.. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.  Gastroenterology. 2004;  127 1347-1355
  • 54 Pawlotsky J M. Hepatitis C: it's a long way to new therapy, it's a long way to go.  Gastroenterology. 2004;  127 1629-1632
  • 55 Richman D D. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B.  Hepatology. 2000;  32 866-867
  • 56 Locarnini S, Hatzakis A, Heathcote J et al.. Management of antiviral resistance in patients with chronic hepatitis B.  Antivir Ther. 2004;  9 679-693
  • 57 Buckheit Jr R W. Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy.  Expert Opin Investig Drugs. 2004;  13 933-958
  • 58 Pai S B, Pai R B, Schinazi R F. Treatment modalities for hepatitis B viral infection and resistance to antiviral therapy.  Panminerva Med. 2003;  45 165-173
  • 59 Martell M, Esteban J I, Quer J et al.. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution.  J Virol. 1992;  66 3225-3229
  • 60 Weiner A J, Brauer M J, Rosenblatt J et al.. Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins.  Virology. 1991;  180 842-848
  • 61 Soler M, Penin F, Ray S, Dhumeaux D, Pawlotsky J M. Hepatitis C virus NS3 serine protease variability and evolution are strongly constrained by the need for structural and functional conservation.  J Hepatol. 2002;  36(suppl 1) 5
  • 62 Migliaccio G, Tomassini J E, Carroll S S et al.. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro.  J Biol Chem. 2003;  278 49164-49170
  • 63 Lin C, Lin K, Luong Y P et al.. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms.  J Biol Chem. 2004;  279 17508-17514
  • 64 Trozzi C, Bartholomew L, Ceccacci A et al.. In vitro selection and characterization of hepatitis C virus serine protease variants resistant to an active-site peptide inhibitor.  J Virol. 2003;  77 3669-3679
  • 65 Nguyen T T, Gates A T, Gutshall L L et al.. Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor.  Antimicrob Agents Chemother. 2003;  47 3525-3530
  • 66 Melian E B, Plosker G L. Interferon alfacon-1: a review of its pharmacology and therapeutic efficacy in the treatment of chronic hepatitis C.  Drugs. 2001;  61 1661-1691
  • 67 Moskovitz D N, Manoharan P, Heathcote E J. High dose consensus interferon in nonresponders to interferon alpha-2b and ribavirin with chronic hepatitis C.  Can J Gastroenterol. 2003;  17 479-482
  • 68 Sjogren M H, Sjogren R, Lyons M F et al.. Antiviral response of HCV genotype 1 to consensus interferon and ribavirin compared with pegylated interferon and ribavirin. A preliminary report.  Hepatology. 2004;  40(suppl 1) 396A
  • 69 Masci P, Bukowski R M, Patten P A, Osborn B L, Borden E C. New and modified interferon alfas: preclinical and clinical data.  Curr Oncol Rep. 2003;  5 108-113
  • 70 Arduini R M, Li Z, Rapoza A et al.. Expression, purification, and characterization of rat interferon-beta, and preparation of an N-terminally pegylated form with improved pharmacokinetic parameters.  Protein Expr Purif. 2004;  34 229-242
  • 71 Osborn B L, Olsen H S, Nardelli B et al.. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys.  J Pharmacol Exp Ther. 2002;  303 540-548
  • 72 Balan V, Sulkowski M S, Nelson D et al.. Albuferon, a novel therapeutic agent for hepatitis C: results of a phase 1/2 study in treatment-experienced subjects with chronic hepatitis C.  Hepatology. 2004;  40(suppl 1) 280A
  • 73 Leevy C, Blatt L M, Chalmers C. Interim results of a pilot study of the combination of type 1 (IFN alfacon 1) and type 2 (IFN gamma 1b) interferons in chronic hepatitis C patients who have failed to respond to peginterferon alfa-2a plus ribavirin.  Hepatology. 2004;  40(suppl 1) 394A
  • 74 Martinand-Mari C, Lebleu B, Robbins I. Oligonucleotide-based strategies to inhibit human hepatitis C virus.  Oligonucleotides. 2003;  13 539-548
  • 75 Ryu K J, Lee S W. Identification of the most accessible sites to ribozymes on the hepatitis C virus internal ribosome entry site.  J Biochem Mol Biol. 2003;  36 538-544
  • 76 Soler M, McHutchison J G, Kwoh T J, Dorr F A, Pawlotsky J M. Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination into the potential role of primary and secondary HCV resistance in the outcome of treatment.  Antivir Ther. 2004;  9 953-968
  • 77 Gordon S C, Bacon B R, Jacobson I M et al.. Treatment of chronic hepatitis c with ISIS 14803, an antisense inhibitor of HCV, given for 12 weeks.  Hepatology. 2003;  38(suppl 1) 306A-307A
  • 78 Wu J, Nandamuri K M. Inhibition of hepatitis viral replication by siRNA.  Expert Opin Biol Ther. 2004;  4 1649-1659
  • 79 Zhang J, Yamada O, Sakamoto T et al.. Down-regulation of viral replication by adenoviral-mediated expression of siRNA against cellular cofactors for hepatitis C virus.  Virology. 2004;  320 135-143
  • 80 Randall G, Grakoui A, Rice C M. Clearance of replicating hepatitis C virus replicon RNAs in cell culture by small interfering RNAs.  Proc Natl Acad Sci USA. 2003;  100 235-240
  • 81 Kim J L, Morgenstern K A, Lin C et al.. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.  Cell. 1996;  87 343-355
  • 82 Love R A, Parge H E, Wickersham J A et al.. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site.  Cell. 1996;  87 331-342
  • 83 Yan Y, Li Y, Munshi S et al.. Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 A resolution structure in a hexagonal crystal form.  Protein Sci. 1998;  7 837-847
  • 84 Reiser M, Hinrichsen H, Benhamou Y et al.. Antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C, non-genotype 1.  Hepatology. 2003;  38(suppl 1) 221A
  • 85 Standring D N, Lanford R, Wright T et al.. NM 283 has potent antiviral activity against genotype 1 chronic hepatitis C virus (HCV-1) infection in the chimpanzee.  J Hepatol. 2003;  38(suppl 2) 3
  • 86 McKercher G, Beaulieu P L, Lamarre D et al.. Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/primer substrate.  Nucleic Acids Res. 2004;  32 422-431
  • 87 Tomei L, Altamura S, Bartholomew L et al.. Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.  J Virol. 2003;  77 13225-13231
  • 88 Beaulieu P L, Bos M, Bousquet Y et al.. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives.  Bioorg Med Chem Lett. 2004;  14 119-124
  • 89 Chan L, Pereira O, Reddy T J et al.. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides.  Bioorg Med Chem Lett. 2004;  14 797-800
  • 90 Sarisky R T. Non-nucleoside inhibitors of the HCV polymerase.  J Antimicrob Chemother. 2004;  54 14-16
  • 91 Tomei L, Altamura S, Bartholomew L et al.. Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides.  J Virol. 2004;  78 938-946
  • 92 Pockros P, Pessoa M G, Diago M et al.. Combination of levovirin (LVV) and peginterferon alfa-2a (40 KD) (Pegasys) fails to generate a virological response comparable to ribavirin (RBV, Copegus) and peginterferon alfa-2a (40 KD) in patients with chronic hepatitis C.  Hepatology. 2004;  40(suppl 1) 391A
  • 93 Gish R G, Arora S, Nelson D et al.. End-of-treatment (EOT) response in therapy-naive patients treated for chronic hepatitis C with viramidine in combination with pegylated interferon alfa-2a.  Hepatology. 2004;  40(suppl 1) 388A
  • 94 Dagan S, Eren R. Therapeutic antibodies against viral hepatitis.  Curr Opin Mol Ther. 2003;  5 148-155
  • 95 Bartosch B, Dubuisson J, Cosset F L. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes.  J Exp Med. 2003;  197 633-642
  • 96 Lavillette D, Morice Y, Germanidis G et al.. Human serum facilitates HCV infection and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C.  J Virol. 2005;  , In press
  • 97 Krawczynski K, Fattom A, Culver D et al.. Passive transfer of anti-HCV in chronic and acute HCV infection in chimpanzees: trials of experimental immune treatment.  Hepatology. 1999;  30(suppl 1) 423A
  • 98 Krawczynski K, Fattom A, Spelbring J et al.. Early termination of HCV infection by passive anti-HCV transfer in experimentally infected chimpanzees.  Hepatology. 1998;  28(suppl 1) 398A
  • 99 Martin P, Parroche P, Chatel L et al.. Genetic immunization and comprehensive screening approaches in HLA-A2 transgenic mice lead to the identification of three novel epitopes in hepatitis C virus NS3 antigen.  J Med Virol. 2004;  74 397-405
  • 100 Bain C, Parroche P, Lavergne J P et al.. Memory T-cell-mediated immune responses specific to an alternative core protein in hepatitis C virus infection.  J Virol. 2004;  78 10460-10469
  • 101 Puig M, Major M E, Mihalik K, Feinstone S M. Immunization of chimpanzees with an envelope protein-based vaccine enhances specific humoral and cellular immune responses that delay hepatitis C virus infection.  Vaccine. 2004;  22 991-1000
  • 102 Nascimbeni M, Mizukoshi E, Bosmann M et al.. Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.  J Virol. 2003;  77 4781-4793
  • 103 Shoukry N H, Grakoui A, Houghton M et al.. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.  J Exp Med. 2003;  197 1645-1655
  • 104 Bassett S E, Guerra B, Brasky K et al.. Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.  Hepatology. 2001;  33 1479-1487
  • 105 Nevens F, Roskams T, Van Vlierberghe H et al.. A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C.  Hepatology. 2003;  38 1289-1296
  • 106 Horsmans Y, Berg T, Desager J P et al.. Isatoribine, a toll-like receptor 7 agonist, significantly reduced plasma viral load in a clinical proof-of-concept study in patients with chronic hepatitis C virus infection.  Hepatology. 2004;  40(suppl 1) 282A-283A

 Professor
Jean-Michel Pawlotsky

Service de Virologie, Hôpital Henri Mondor

51 avenue du Maréchal de Lattre de Tassigny

94010 Créteil, France

eMail: jean-michel.pawlotsky@hmn.aphp.fr

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