PDF icon Download PDF
Semin Liver Dis 2011; 31(4): 410-419
DOI: 10.1055/s-0031-1297929
© Thieme Medical Publishers

The Conundrum of Relapse in STAT-C Therapy: Does HCV Play the Red Queen or Rip Van Winkle?

Robert Ralston1 , 3 , Ira Jacobson2 , Margaret Scull1
  • 1Laboratory of Virology and Infectious Disease and Center for the Study of Hepatitis C, The Rockefeller University, New York, New York
  • 2Department of Medicine, Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Medical College, New York, New York
  • 3Current address: Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri
Further Information

Publication History

Publication Date:
21 December 2011 (online)

   Permissions and Reprints
Preview

ABSTRACT

New treatments for chronic hepatitis C combining direct-acting antivirals (DAAs) with pegylated interferon and ribavirin (PEG-IFN/RBV) have dramatically increased the number of patients whose viral load declines to undetectable levels early in treatment. Most go on to achieve a sustained virologic response, but some patients who maintain undetectable levels of virus throughout treatment later relapse during follow-up. These data suggest that hepatitis C virus (HCV) genomes may persist in form(s) that are refractory to eradication by DAAs and PEG-IFN/RBV. Here we examine the molecular biology of HCV replication and review the clinical virology of relapse for clues as to how the virus might survive months of antiviral therapy to later reappear when treatment is withdrawn.

KEYWORDS

Hepatitis C virus - direct-acting antivirals - relapse - resistance

REFERENCES

  • 1 Poordad F, McCone Jr J, Bacon B R SPRINT-2 Investigators et al. Boceprevir for untreated chronic HCV genotype 1 infection.  N Engl J Med. 2011;  364 (13) 1195-1206
    Search in Google Scholar
  • 2 Bacon B R, Gordon S C, Lawitz E HCV RESPOND-2 Investigators et al. Boceprevir for previously treated chronic HCV genotype 1 infection.  N Engl J Med. 2011;  364 (13) 1207-1217
    Search in Google Scholar
  • 3 Jacobson I M, McHutchison J G, Dusheiko G ADVANCE Study Team et al. Telaprevir for previously untreated chronic hepatitis C virus infection.  N Engl J Med. 2011;  364 (25) 2405-2416
    Search in Google Scholar
  • 4 Zeuzem S, Andreone P, Pol S REALIZE Study Team et al. Telaprevir for retreatment of HCV infection.  N Engl J Med. 2011;  364 (25) 2417-2428
    Search in Google Scholar
  • 5 Pawlotsky J M, Cocquerel L, Durantel D et al.. HCV research 20 years after discovery: a summary of the 16th international symposium on hepatitis C virus and related viruses.  Gastroenterology. 2010;  138 (1) 6-12, e1–e2
    Search in Google Scholar
  • 6 Lange C M, Sarrazin C, Zeuzem S. Review article: specifically targeted anti-viral therapy for hepatitis C - a new era in therapy.  Aliment Pharmacol Ther. 2010;  32 (1) 14-28
    Search in Google Scholar
  • 7 Forestier N, Larrey D, Guyader D et al.. Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study.  J Hepatol. 2011;  54 (6) 1130-1136
    Search in Google Scholar
  • 8 Reesink H W, Fanning G C, Farha K A et al.. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients.  Gastroenterology. 2010;  138 (3) 913-921
    Search in Google Scholar
  • 9 McHutchison J G, Lawitz E J, Shiffman M L IDEAL Study Team et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.  N Engl J Med. 2009;  361 (6) 580-593
    Search in Google Scholar
  • 10 U.S. Food and Drug Administration. US FDA Antiviral Drugs Advisory Committee Briefing Document: Background Material for Boceprevir. Silver Spring, MD: U.S. Food and Drug Administration; 2011: 31
    Search in Google Scholar
  • 11 U.S. Food and Drug Administration. US FDA Antiviral Drugs Advisory Committee Briefing Document for NDA 201–917 Telaprevir 375 mg Tablets. Silver Spring, MD: U.S. Food and Drug Administration; 2011: 22
    Search in Google Scholar
  • 12 U.S. Food and Drug Administration. US FDA Antiviral Drugs Advisory Committee Briefing Document: Boceprevir Capsules (NDA 202–258) Briefing Document. Whitehouse Station, NJ: Merck and Co; 2011: 90
    Search in Google Scholar
  • 13 U.S. Food and Drug Administration. US FDA Antiviral Drugs Advisory Committee Briefing Document: Telaprevir 375-mg Film-Coated Tablet for the Treatment of Genotype 1 Chronic Hepatitis C. Cambridge, MA: Vertex Pharmaceuticals; 2011: 147
    Search in Google Scholar
  • 14 Ludmerer S W, Graham D J, Boots E et al.. Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay.  Antimicrob Agents Chemother. 2005;  49 (5) 2059-2069
    Search in Google Scholar
  • 15 Le Pogam S, Seshaadri A, Kosaka A et al.. Existence of hepatitis C virus NS5B variants naturally resistant to non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients.  J Antimicrob Chemother. 2008;  61 (6) 1205-1216
    Search in Google Scholar
  • 16 Pockros P, Jensen D, Tsai N et al.. First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial. Paper presented at: European Association for the Study of the Liver 46th Annual Meeting March 30–April 3, 2011. Berlin, Germany;
    Search in Google Scholar
  • 17 van Valen L. A new evolutionary law.  Evol Theory. 1973;  1 1-30
    Search in Google Scholar
  • 18 Domingo E, Escarmís C, Sevilla N et al.. Basic concepts in RNA virus evolution.  FASEB J. 1996;  10 (8) 859-864
    Search in Google Scholar
  • 19 Pham T N, Michalak T I. Occult persistence and lymphotropism of hepatitis C viral infection.  World J Gastroenterol. 2008;  14 (18) 2789-2793
    Search in Google Scholar
  • 20 Sumpter Jr R, Loo Y M, Foy E et al.. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I.  J Virol. 2005;  79 (5) 2689-2699
    Search in Google Scholar
  • 21 Shoukry N H, Cawthon A G, Walker C M. Cell-mediated immunity and the outcome of hepatitis C virus infection.  Annu Rev Microbiol. 2004;  58 391-424
    Search in Google Scholar
  • 22 Tillmann H L, Thompson A J, Patel K German Anti-D Study Group et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice.  Gastroenterology. 2010;  139 (5) 1586-1592, 1592, e1
    Search in Google Scholar
  • 23 Walters K A, Katze M G. Using high-throughput genomics to study hepatitis C: what determines the outcome of infection?.  Antiviral Res. 2009;  81 (3) 198-208
    Search in Google Scholar
  • 24 Sugano M, Hayashi Y, Yoon S et al.. Quantitation of hepatitis C viral RNA in liver and serum samples using competitive polymerase chain reaction.  J Clin Pathol. 1995;  48 (9) 820-825
    Search in Google Scholar
  • 25 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 (5386) 103-107
    Search in Google Scholar
  • 26 Guedj J, Dahari H, Rong L et al.. New insights into the mechanism of action of interferon-alpha and BMS-790052: a multi-scale mathematical modeling approach. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 27 Gowans EJ. Distribution of markers of hepatitis C virus infection throughout the body.  Semin Liver Dis. 2001;  20 (1) 85-102
    Search in Google Scholar
  • 28 Idrees M, Lal A, Malik F A et al.. Occult hepatitis C virus infection and associated predictive factors: the Pakistan experience.  Infect Genet Evol. 2011;  11 (2) 442-445
    Search in Google Scholar
  • 29 Carreño V, Pardo M, López-Alcorocho J M, Rodríguez-Iñigo E, Bartolomé J, Castillo I. Detection of hepatitis C virus (HCV) RNA in the liver of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients with normal alanine aminotransferase levels.  J Infect Dis. 2006;  194 (1) 53-60
    Search in Google Scholar
  • 30 Castillo I, Rodríguez-Iñigo E, López-Alcorocho J M, Pardo M, Bartolomé J, Carreño V. Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment.  Clin Infect Dis. 2006;  43 (10) 1277-1283
    Search in Google Scholar
  • 31 Carreño V. Occult hepatitis C virus infection: a new form of hepatitis C.  World J Gastroenterol. 2006;  12 (43) 6922-6925
    Search in Google Scholar
  • 32 Chang M, Williams O, Mittler J et al.. Dynamics of hepatitis C virus replication in human liver.  Am J Pathol. 2003;  163 (2) 433-444
    Search in Google Scholar
  • 33 Egger D, Wölk B, Gosert R et al.. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.  J Virol. 2002;  76 (12) 5974-5984
    Search in Google Scholar
  • 34 Moradpour D, Penin F, Rice C M. Replication of hepatitis C virus.  Nat Rev Microbiol. 2007;  5 (6) 453-463
    Search in Google Scholar
  • 35 Gosert R, Egger D, Lohmann V et al.. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons.  J Virol. 2003;  77 (9) 5487-5492
    Search in Google Scholar
  • 36 Rouillé Y, Helle F, Delgrange D et al.. Subcellular localization of hepatitis C virus structural proteins in a cell culture system that efficiently replicates the virus.  J Virol. 2006;  80 (6) 2832-2841
    Search in Google Scholar
  • 37 Pfeifer U, Thomssen R, Legler K et al.. Experimental non-A, non-B hepatitis: four types of cytoplasmic alteration in hepatocytes of infected chimpanzees.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1980;  33 (3) 233-243
    Search in Google Scholar
  • 38 Schaff Z, Tabor E, Jackson D R, Gerety R J. Ultrastructural alterations in serial liver biopsy specimens from chimpanzees experimentally infected with a human non-A, non-B hepatitis agent.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;  45 (3) 301-312
    Search in Google Scholar
  • 39 De Vos R, Verslype C, Depla E et al.. Ultrastructural visualization of hepatitis C virus components in human and primate liver biopsies.  J Hepatol. 2002;  37 (3) 370-379
    Search in Google Scholar
  • 40 Kasprzak A, Seidel J, Biczysko W, Wysocki J, Spachacz R, Zabel M. Intracellular localization of NS3 and C proteins in chronic hepatitis C.  Liver Int. 2005;  25 (4) 896-903
    Search in Google Scholar
  • 41 Falcón V, Acosta-Rivero N, Chinea G et al.. Ultrastructural evidences of HCV infection in hepatocytes of chronically HCV-infected patients.  Biochem Biophys Res Commun. 2003;  305 (4) 1085-1090
    Search in Google Scholar
  • 42 Asselah T, Bièche I, Mansouri A et al.. In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C.  J Pathol. 2010;  221 (3) 264-274
    Search in Google Scholar
  • 43 Ferraris P, Blanchard E, Roingeard P. Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes.  J Gen Virol. 2010;  91 (Pt 9) 2230-2237
    Search in Google Scholar
  • 44 Reiss S, Rebhan I, Backes P et al.. Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment.  Cell Host Microbe. 2011;  9 (1) 32-45
    Search in Google Scholar
  • 45 Knoops K, Kikkert M, Worm S H et al.. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum.  PLoS Biol. 2008;  6 (9) e226
    Search in Google Scholar
  • 46 Uchil P D, Satchidanandam V. Architecture of the flaviviral replication complex. Protease, nuclease, and detergents reveal encasement within double-layered membrane compartments.  J Biol Chem. 2003;  278 (27) 24388-24398
    Search in Google Scholar
  • 47 Mackenzie J M, Jones M K, Young P R. Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication.  Virology. 1996;  220 (1) 232-240
    Search in Google Scholar
  • 48 Westaway E G, Mackenzie J M, Kenney M T, Jones M K, Khromykh A A. Ultrastructure of Kunjin virus-infected cells: colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures.  J Virol. 1997;  71 (9) 6650-6661
    Search in Google Scholar
  • 49 Quinkert D, Bartenschlager R, Lohmann V. Quantitative analysis of the hepatitis C virus replication complex.  J Virol. 2005;  79 (21) 13594-13605
    Search in Google Scholar
  • 50 Syed G H, Amako Y, Siddiqui A. Hepatitis C virus hijacks host lipid metabolism.  Trends Endocrinol Metab. 2010;  21 (1) 33-40
    Search in Google Scholar
  • 51 Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari F V. Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion.  J Virol. 2008;  82 (5) 2120-2129
    Search in Google Scholar
  • 52 Russell R S, Meunier J C, Takikawa S et al.. Advantages of a single-cycle production assay to study cell culture-adaptive mutations of hepatitis C virus.  Proc Natl Acad Sci U S A. 2008;  105 (11) 4370-4375
    Search in Google Scholar
  • 53 Brimacombe C L, Grove J, Meredith L W et al.. Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission.  J Virol. 2011;  85 (1) 596-605
    Search in Google Scholar
  • 54 Valli M B, Serafino A, Crema A et al.. Transmission in vitro of hepatitis C virus from persistently infected human B-cells to hepatoma cells by cell-to-cell contact.  J Med Virol. 2006;  78 (2) 192-201
    Search in Google Scholar
  • 55 Timpe J M, Stamataki Z, Jennings A et al.. Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies.  Hepatology. 2008;  47 (1) 17-24
    Search in Google Scholar
  • 56 Witteveldt J, Evans M J, Bitzegeio J et al.. CD81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells.  J Gen Virol. 2009;  90 (Pt 1) 48-58
    Search in Google Scholar
  • 57 Catanese M T, Loureiro J, Jones C T et al.. Viral and cellular determinants of HCV cell-to-cell spread. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 58 Sigal A, Kim J T, Balazs A B et al.. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy.  Nature. 2011;  477 (7362) 95-98
    Search in Google Scholar
  • 59 Hu Y, Shahidi A, Park S, Guilfoyle D, Hirshfield I. Detection of extrahepatic hepatitis C virus replication by a novel, highly sensitive, single-tube nested polymerase chain reaction.  Am J Clin Pathol. 2003;  119 (1) 95-100
    Search in Google Scholar
  • 60 Sung V M, Shimodaira S, Doughty A L et al.. Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection.  J Virol. 2003;  77 (3) 2134-2146
    Search in Google Scholar
  • 61 Steffan A, Marianneau P, Caussin-Schwemling C et al.. Ultrastructural observations in hepatitis C virus-infected lymphoid cells.  Microbes Infect. 2001;  3 (3) 193-202
    Search in Google Scholar
  • 62 Pham T N, Michalak T I. Occult persistence and lymphotropism of hepatitis C virus infection.  World J Gastroenterol. 2008;  14 (18) 2789-2793
    Search in Google Scholar
  • 63 Zehender G, Meroni L, De Maddalena C, Varchetta S, Monti G, Galli M. Detection of hepatitis C virus RNA in CD19 peripheral blood mononuclear cells of chronically infected patients.  J Infect Dis. 1997;  176 (5) 1209-1214
    Search in Google Scholar
  • 64 Boisvert J, He X S, Cheung R, Keeffe E B, Wright T, Greenberg H B. Quantitative analysis of hepatitis C virus in peripheral blood and liver: replication detected only in liver.  J Infect Dis. 2001;  184 (7) 827-835
    Search in Google Scholar
  • 65 Laporte J, Bain C, Maurel P, Inchauspe G, Agut H, Cahour A. Differential distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells.  Blood. 2003;  101 (1) 52-57
    Search in Google Scholar
  • 66 Sansonno D, Tucci F A, Lauletta G et al.. Hepatitis C virus productive infection in mononuclear cells from patients with cryoglobulinaemia.  Clin Exp Immunol. 2007;  147 (2) 241-248
    Search in Google Scholar
  • 67 Laskus T, Radkowski M, Jablonska J et al.. Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages.  Blood. 2004;  103 (10) 3854-3859
    Search in Google Scholar
  • 68 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 (10) 3841-3849
    Search in Google Scholar
  • 69 Di Liberto G, Roque-Afonso A M, Kara R et al.. Clinical and therapeutic implications of hepatitis C virus compartmentalization.  Gastroenterology. 2006;  131 (1) 76-84
    Search in Google Scholar
  • 70 Pham T N, Mulrooney-Cousins P M, Mercer S E et al.. Antagonistic expression of hepatitis C virus and alpha interferon in lymphoid cells during persistent occult infection.  J Viral Hepat. 2007;  14 (8) 537-548
    Search in Google Scholar
  • 71 Radkowski M, Gallegos-Orozco J F, Jablonska J et al.. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.  Hepatology. 2005;  41 (1) 106-114
    Search in Google Scholar
  • 72 Pham T N, MacParland S A, Mulrooney P M et al.. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C.  J Virol. 2004;  78 (11) 5867-5874
    Search in Google Scholar
  • 73 Natarajan V, Kottilil S, Hazen A et al.. HCV in peripheral blood mononuclear cells are predominantly carried on the surface of cells in HIV/HCV co-infected individuals.  J Med Virol. 2010;  82 (12) 2032-2037
    Search in Google Scholar
  • 74 Ramirez S, Perez-Del-Pulgar S, Carrion J A et al.. Hepatitis C virus compartmentalization and infection recurrence after liver transplantation.  Am J Transplant. 2009;  9 (7) 1591-1601
    Search in Google Scholar
  • 75 Maggi F, Fornai C, Vatteroni M L et al.. Differences in hepatitis C virus quasispecies composition between liver, peripheral blood mononuclear cells and plasma.  J Gen Virol. 1997;  78 (Pt 7) 1521-1525
    Search in Google Scholar
  • 76 Revie D, Salahuddin S Z. Human cell types important for hepatitis C virus replication in vivo and in vitro: old assertions and current evidence.  Virol J. 2011;  8 346
    Search in Google Scholar
  • 77 Martínez J L, Rojo F. Metabolic regulation of antibiotic resistance.  FEMS Microbiol Rev. 2011;  35 (5) 768-789
    Search in Google Scholar
  • 78 Klepper A, Eng F, Walewski J et al.. Contrary to published models of HCV RNA replication, heat denaturation reveals that much of the HCV in natural infections is in double-stranded form. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 79 Jones C T, Murray C L, Eastman D K, Tassello J, Rice C M. Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus.  J Virol. 2007;  81 (16) 8374-8383
    Search in Google Scholar
  • 80 Pedersen I M, Cheng G, Wieland S et al.. Interferon modulation of cellular microRNAs as an antiviral mechanism.  Nature. 2007;  449 (7164) 919-922
    Search in Google Scholar
  • 81 Chang J, Guo J T, Jiang D, Guo H, Taylor J M, Block T M. Liver-specific microRNA miR-122 enhances the replication of hepatitis C virus in nonhepatic cells.  J Virol. 2008;  82 (16) 8215-8223
    Search in Google Scholar
  • 82 Jopling C L. Regulation of hepatitis C virus by microRNA-122.  Biochem Soc Trans. 2008;  36 (Pt 6) 1220-1223
    Search in Google Scholar
  • 83 Randall G, Panis M, Cooper J D et al.. Cellular cofactors affecting hepatitis C virus infection and replication.  Proc Natl Acad Sci U S A. 2007;  104 (31) 12884-12889
    Search in Google Scholar
  • 84 Henke J I, Goergen D, Zheng J et al.. microRNA-122 stimulates translation of hepatitis C virus RNA.  EMBO J. 2008;  27 (24) 3300-3310
    Search in Google Scholar
  • 85 Jangra R K, Yi M, Lemon S M. Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122.  J Virol. 2010;  84 (13) 6615-6625
    Search in Google Scholar
  • 86 Roberts A P, Lewis A P, Jopling C L. miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components.  Nucleic Acids Res. 2011;  39 (17) 7716-7729
    Search in Google Scholar
  • 87 Sagan S, Sarnow P. Stabilization of the HCV RNA genome by miR-122. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 88 Shimakami T, Yamane D, Jangra R K et al.. miR-122 stabilizes hepatitis C virus RNA by an Ago2-dependent mechanism. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 89 Negro F. Mechanisms of hepatitis C virus-related insulin resistance.  Clin Res Hepatol Gastroenterol. 2011;  35 (5) 358-363
    Search in Google Scholar
  • 90 Rasmussen A L, Diamond D L, McDermott J E et al.. Systems virology identifies a mitochondrial Fatty Acid oxidation enzyme, dodecenoyl coenzyme a delta isomerase, required for hepatitis C virus replication and likely pathogenesis.  J Virol. 2011;  85 (22) 11646-11654
    Search in Google Scholar
  • 91 Diamond D L, Syder A J, Jacobs J M et al.. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics.  PLoS Pathog. 2010;  6 (1) e1000719
    Search in Google Scholar
  • 92 Berger K L, Randall G. Potential roles for cellular cofactors in hepatitis C virus replication complex formation.  Commun Integr Biol. 2009;  2 (6) 471-473
    Search in Google Scholar
  • 93 Estrabaud E, De Muynck S, Asselah T. Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response.  J Hepatol. 2011;  55 (5) 1150-1153
    Search in Google Scholar
  • 94 Ke P Y, Chen S S. Autophagy: a novel guardian of HCV against innate immune response.  Autophagy. 2011;  7 (5) 533-535
    Search in Google Scholar
  • 95 Ke P Y, Chen S S. Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro.  J Clin Invest. 2011;  121 (1) 37-56
    Search in Google Scholar
  • 96 Zeuzem S, Poordad F, Gordon S C et al.. Boceprevir resistance-associated variants (RAVs) are observed more frequently in HCV (GT1)-infected patients with poor response to peginterferon alfa-2b/ribavirin. Paper presented at: European Association for the Study of the Liver 46th Annual Meeting March 30–April 3, 2011. Berlin, Germany;
    Search in Google Scholar
  • 97 Jiang M, Vijgen L, Sullivan J et al.. Phenotypic characterization of HCV NS3 protease from patient isolates in phase 2 clinical trials of telaprevir. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 98 Shimakami T, Welsch C, Yamane D et al.. Protease inhibitor-resistant hepatitis C virus mutants with reduced fitness from impaired production of infectious virus.  Gastroenterology. 2011;  140 (2) 667-675
    Search in Google Scholar
  • 99 Kieffer T L, Sarrazin C, Miller J S et al.. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.  Hepatology. 2007;  46 (3) 631-639
    Search in Google Scholar
  • 100 Le Pogam S, Seshaadri A, Ewing A et al.. RG7128 alone or in combination with pegylated interferon-α2a and ribavirin prevents hepatitis C virus (HCV) Replication and selection of resistant variants in HCV-infected patients.  J Infect Dis. 2010;  202 (10) 1510-1519
    Search in Google Scholar
  • 101 Lawitz E, Nguyen T, Younes Z et al.. Valopicitabine NM283 plus PEGinterferon in treatment-naive hepatitis C patients with HCV genotype 1 infection: HCV RNA clearance during 24 weeks of treatment.  Hepatology. 2007;  44 223A
    Search in Google Scholar
  • 102 Ali S, Leveque V, Le Pogam S et al.. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479.  Antimicrob Agents Chemother. 2008;  52 (12) 4356-4369
    Search in Google Scholar
  • 103 Fridell R A, Qiu D, Valera L, Wang C, Rose R E, Gao M. Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A inhibitor BMS-790052.  J Virol. 2011;  85 (14) 7312-7320
    Search in Google Scholar
  • 104 Lok A, Gardiner D, Lawitz E et al.. Quadruple therapy with BMS-790052, BMS-650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders (Abstract 1356).  J Hepatol. 2011;  54 S536
    Search in Google Scholar
  • 105 Fried M W, Hadziyannis S J, Shiffman M L, Messinger D, Zeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection.  J Hepatol. 2011;  55 (1) 69-75
    Search in Google Scholar
  • 106 Guedj J, Bazzoli C, Neumann A U, Mentré F. Design evaluation and optimization for models of hepatitis C viral dynamics.  Stat Med. 2011;  30 (10) 1045-1056
    Search in Google Scholar
  • 107 Guedj J, Dahari H, Shudo E, Smith S, Perelson A. Hepatitis C viral kinetics with the nucleoside polymerase inhibitor RG7128. Paper presented at: 18th International Symposium on Hepatitis C Virus and Related Viruses September 8–12, 2011. Seattle, WA;
    Search in Google Scholar
  • 108 Pearson J E, Krapivsky P, Perelson A S. Stochastic theory of early viral infection: continuous versus burst production of virions.  PLOS Comput Biol. 2011;  7 (2) e1001058
    Search in Google Scholar
  • 109 Zeuzem S, Schmidt J M, Lee J H, von Wagner M, Teuber G, Roth W K. Hepatitis C virus dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover.  Hepatology. 1998;  28 (1) 245-252
    Search in Google Scholar
  • 110 Zeuzem S, Lee J H, Franke A et al.. Quantification of the initial decline of serum hepatitis C virus RNA and response to interferon alfa.  Hepatology. 1998;  27 (4) 1149-1156
    Search in Google Scholar
  • 111 Dusheiko G, Main J, Thomas H et al.. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study.  J Hepatol. 1996;  25 (5) 591-598
    Search in Google Scholar
  • 112 Pawlotsky J M, Dahari H, Neumann A U et al.. Antiviral action of ribavirin in chronic hepatitis C.  Gastroenterology. 2004;  126 (3) 703-714
    Search in Google Scholar
  • 113 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 (13) 975-982
    Search in Google Scholar
  • 114 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 (9286) 958-965
    Search in Google Scholar
  • 115 Hézode C, Forestier N, Dusheiko G PROVE2 Study Team et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.  N Engl J Med. 2009;  360 (18) 1839-1850
    Search in Google Scholar
  • 116 McHutchison J G, Everson G T, Gordon S C PROVE1 Study Team et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.  N Engl J Med. 2009;  360 (18) 1827-1838
    Search in Google Scholar

Robert RalstonPh.D. 

Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri

1201 E. Rollins Drive, Columbia, MO 65211

Email: ralstonr@missouri.edu