Hepatitis C (HCV), a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is the most common indication for liver transplantation in the United States. Although annual incidence of infection has declined since the 1980s, aging of the currently infected population is expected to result in an increase in HCV burden. HCV is prone to develop resistance to antiviral drugs, and despite considerable efforts to understand the virus for effective treatments, our knowledge remains incomplete. This paper reviews HCV resistance mechanisms, the traditional treatment with and the new standard of care for hepatitis C treatment. Although these new treatments remain PEG-IFN-α- and ribavirin-based, they add one of the newly FDA approved direct antiviral agents, telaprevir or boceprevir. This new “triple therapy” has resulted in greater viral cure rates, although treatment failure remains a possibility. The future may belong to nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of HCV may ultimately parallel that of HIV. However, research should focus not only on effective treatments, but also on the development of a HCV vaccine, as this may prove to be the most cost-effective method of eradicating this disease. 1. Introduction: Burden of Hepatitis C Hepatitis C (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in the United States. The annual incidence of infection in the USA has declined from about 230,000 cases per year in the 1980s to an estimated 17,000 cases in 2007 [1, 2]. This decline has been largely attributed to changes in injection practices motivated by a concern for human immunodeficiency virus (HIV) risk [3]. Approximately 3.2 million persons have chronic HCV infection in the United States; however, the reservoir of chronically infected persons is still estimated at approximately 2.35%, representing approximately 160 million worldwide infected individuals [4]. Aging of the currently infected population is expected to result in an increase in the burden of hepatitis C in the next decade [5]. During that period, the number of HCV-related cirrhosis cases is estimated to increase by 31% and that of hepatocellular carcinoma (HCC) cases is estimated to increase by approximately 50% [5]. Estimates of hepatitis C prevalence range from <0.5% in very low endemic countries (e.g., northern European countries) to staggering rates of approximately 20% in
References
[1]
A. Wasley, S. Grytdal, and D. Daniels, “Surveillance for acute viral hepatitis—United States, 2007,” MMWR. Surveillance Summaries, vol. 58, no. 3, pp. 1–27, 2009.
[2]
Centers for Disease Control and Prevention, “Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease,” MMWR Recommendations and Reports, vol. 47, no. RR-19, pp. 1–39, 1998.
[3]
M. J. Alter, “Epidemiology of hepatitis C,” Hepatology, vol. 26, no. 3, pp. 62S–65S, 1997.
[4]
D. Lavanchy, “Evolving epidemiology of hepatitis C virus,” Clinical Microbiology and Infection, vol. 17, no. 2, pp. 107–115, 2011.
[5]
G. L. Davis, M. J. Alter, H. El-Serag, T. Poynard, and L. W. Jennings, “Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression,” Gastroenterology, vol. 138, no. 2, pp. 513–521, 2010.
[6]
Centers for Disease Control and Prevention, CDC Health Information for International Travel 2012, Oxford University Press, New York, NY, USA, 2012, http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm.
[7]
D. Moradpour, F. Penin, and C. M. Rice, “Replication of hepatitis C virus,” Nature Reviews Microbiology, vol. 5, no. 6, pp. 453–463, 2007.
[8]
A. O. De Beeck and J. Dubuisson, “Topology of hepatitis C virus envelope glycoproteins,” Reviews in Medical Virology, vol. 13, no. 4, pp. 233–241, 2003.
[9]
Q. L. Choo, K. H. Richman, J. H. Han et al., “Genetic organization and diversity of the hepatitis C virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 6, pp. 2451–2455, 1991.
[10]
R. Jubin, “Hepatitis C IRES: translating translation into a therapeutic target,” Current Opinion in Molecular Therapeutics, vol. 3, no. 3, pp. 278–287, 2001.
[11]
J. Dubuisson, “Hepatitis C virus proteins,” World Journal of Gastroenterology, vol. 13, no. 17, pp. 2406–2415, 2007.
[12]
M. B. Zeisel, H. Barth, C. Schuster, and T. F. Baumert, “Hepatitis C virus entry: molecular mechanisms and targets for antiviral therapy,” Frontiers in Bioscience, vol. 14, no. 9, pp. 3274–3285, 2009.
[13]
I. Kohaar, A. Ploss, E. Korol et al., “Splicing diversity of the human OCLN gene and its biological significance for hepatitis C virus entry,” Journal of Virology, vol. 84, no. 14, pp. 6987–6994, 2010.
[14]
G. H. Syed, Y. Amako, and A. Siddiqui, “Hepatitis C virus hijacks host lipid metabolism,” Trends in Endocrinology and Metabolism, vol. 21, no. 1, pp. 33–40, 2010.
[15]
J. M. Pawlotsky, “Hepatitis C virus genetic variability: pathogenic and clinical implications,” Clinics in Liver Disease, vol. 7, no. 1, pp. 45–66, 2003.
[16]
J. M. Pawlotsky, “Hepatitis C virus population dynamics during infection,” Current Topics in Microbiology and Immunology, vol. 299, pp. 261–284, 2006.
[17]
T. Kuntzen, J. Timm, A. Berical et al., “Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-na？ve patients,” Hepatology, vol. 48, no. 6, pp. 1769–1778, 2008.
[18]
D. J. Bartels, Y. Zhou, E. Z. Zhang et al., “Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-na？ve subjects,” Journal of Infectious Diseases, vol. 198, no. 6, pp. 800–807, 2008.
[19]
M. Lataillade, J. Chiarella, R. Yang et al., “Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-na？ve subjects in the CASTLE study,” PloS ONE, vol. 5, no. 6, Article ID e10952, 2010.
[20]
C. Rodriguez, S. Chevaliez, P. Bensadoun, et al., “Ultra-deep pyrosequencing, a powerful new tool to study HBV resistance to nucleoside/nucleotide analogues, identifies preexisting HBV variants bearing resistance mutations and characterizes their on-treatment kinetics,” Hepatology, vol. 52, pp. 441A–442A, 2010.
[21]
T. Verbinnen, H. Van Marck, I. Vandenbroucke et al., “Tracking the evolution of multiple in vitro hepatitis C virus replicon variants under protease inhibitor selection pressure by 454 deep sequencing,” Journal of Virology, vol. 84, no. 21, pp. 11124–11133, 2010.
[22]
S. Chevaliez and J. M. Pawlotsky, “Interferons and their use in persistent viral infections,” Handbook of Experimental Pharmacology, vol. 189, pp. 203–241, 2009.
[23]
C. S. Kim, J. H. Jung, T. Wakita, K. Y. Seung, and K. J. Sung, “Monitoring the antiviral effect of alpha interferon on individual cells,” Journal of Virology, vol. 81, no. 16, pp. 8814–8820, 2007.
[24]
F. Porteu, M. Brockhaus, D. Wallach, H. Engelmann, and C. F. Nathan, “Human neutrophil elastase releases a ligand-binding fragment from the 75-kDa tumor necrosis factor (TNF) receptor: comparison with the proteolytic activity responsible for shedding of TNF receptors from stimulated neutrophils,” The Journal of Biological Chemistry, vol. 266, no. 28, pp. 18846–18853, 1991.
[25]
E. Lien, N. B. Liabakk, A. C. Johnsen, U. Nonstad, A. Sundan, and T. Espevik, “Polymorphonuclear granulocytes enhance lipopolysaccharide-induced soluble p75 tumor necrosis factor receptor release from mononuclear cells,” European Journal of Immunology, vol. 25, no. 9, pp. 2714–2717, 1995.
[26]
M. Lantz, S. Malik, M. L. Slevin, and I. Olsson, “Infusion of tumor necrosis factor (TNF) causes an increase in circulating TNF-binding protein in humans,” Cytokine, vol. 2, no. 6, pp. 402–406, 1990.
[27]
D. A. Joyce, D. P. Gibbons, P. Green, J. H. Steer, M. Feldmann, and F. M. Brennan, “Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes,” European Journal of Immunology, vol. 24, no. 11, pp. 2699–2705, 1994.
[28]
H. Tilg, W. Vogel, and C. A. Dinarello, “Interferon-α induces circulating tumor necrosis factor receptor p55 in humans,” Blood, vol. 85, no. 2, pp. 433–435, 1995.
[29]
A. U. Neumann, S. Zeuzem, C. Ferrari, 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,” Journal of Hepatology, vol. 36, supplement 1, article 121, 2002.
[30]
J. M. Pawlotsky, C. Hezode, B. Pellegrin, 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, vol. 36, article 291A, 2002.
[31]
J. M. Pawlotsky, “Treating hepatitis C in “difficult-to-treat” patients,” The New England Journal of Medicine, vol. 351, no. 5, pp. 422–423, 2004.
[32]
J. Y. N. Lau, R. C. Tam, T. J. Liang, and Z. Hong, “Mechanism of action of ribavirin in the combination treatment of chronic HCV infection,” Hepatology, vol. 35, no. 5, pp. 1002–1009, 2002.
[33]
J. P. Bronowicki, D. Ouzan, T. Asselah et al., “Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin,” Gastroenterology, vol. 131, no. 4, pp. 1040–1048, 2006.
[34]
A. M. Contreras, Y. Hiasa, W. He, A. Terella, E. V. Schmidt, and R. T. Chung, “Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system,” Journal of Virology, vol. 76, no. 17, pp. 8505–8517, 2002.
[35]
S. Chevaliez, R. Brillet, E. Lázaro, C. Hézode, and J. M. Pawlotsky, “Analysis of ribavirin mutagenicity in human hepatitis C virus infection,” Journal of Virology, vol. 81, no. 14, pp. 7732–7741, 2007.
[36]
G. Lutchman, S. Danehower, B. C. Song et al., “Mutation rate of the hepatitis C virus NS5b in patients undergoing treatment with ribavirin mono-therapy,” Gastroenterology, vol. 132, no. 5, pp. 1757–1766, 2007.
[37]
S. H. Fang, L. H. Hwang, D. S. Chen, and B. L. Chiang, “Ribavirin enhancement of hepatitis C virus core antigen-specific type 1 T helper cell response correlates with the increased IL-12 level,” Journal of Hepatology, vol. 33, no. 5, pp. 791–798, 2000.
[38]
J. J. Feld, S. Nanda, Y. Huang et al., “Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response,” Hepatology, vol. 46, no. 5, pp. 1548–1563, 2007.
[39]
K. H. Tang, E. Herrmann, H. Cooksley et al., “Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy,” Journal of Hepatology, vol. 43, no. 5, pp. 776–782, 2005.
[40]
J. J. Feld and J. H. Hoofnagle, “Mechanism of action of interferon and ribavirin in treatment of hepatitis C,” Nature, vol. 436, no. 7053, pp. 967–972, 2005.
[41]
X. Ji, R. Cheung, S. Cooper, et al., “Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C,” Hepatology, vol. 37, no. 3, pp. 610–621, 2003.
[42]
E. S. Araújo, C. Courtouké, and A. A. Barone, “Hepatitis C treatment: shorter and better?” Brazilian Journal of Infectious Diseases, vol. 11, no. 1, pp. 118–124, 2007.
[43]
A. U. Neumann, N. P. Lam, H. Dahari et al., “Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy,” Science, vol. 282, no. 5386, pp. 103–107, 1998.
[44]
C. Hézode, N. Forestier, G. Dusheiko et al., “Telaprevir and peginterferon with or without ribavirin for chronic HCV infection,” The New England Journal of Medicine, vol. 360, no. 18, pp. 1839–1850, 2009.
[45]
L. Rong, H. Dahari, R. M. Ribeiro, and A. S. Perelson, “Rapid emergence of protease inhibitor resistance in hepatitis C virus,” Science Translational Medicine, vol. 2, pp. 1–20, 2010.
[46]
F. Clavel and A. J. Hance, “HIV drug resistance,” The New England Journal of Medicine, vol. 350, no. 10, pp. 1023–1035, 2004.
[47]
J. M. Pawlotsky, “Therapeutic implications of hepatitis C virus resistance to antiviral drugs,” Therapeutic Advances in Gastroenterology, vol. 2, no. 4, pp. 205–219, 2009.
[48]
B. S. Adiwijaya, E. Herrmann, B. Hare et al., “A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants,” PLoS Computational Biology, vol. 6, no. 4, Article ID e1000745, 2010.
[49]
Y. He, M. S. King, D. J. Kempf et al., “Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 3, pp. 1101–1110, 2008.
[50]
C. Lin, C. A. Gates, B. G. Rao et al., “In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061,” The Journal of Biological Chemistry, vol. 280, no. 44, pp. 36784–36791, 2005.
[51]
C. Lin, K. Lin, Y. P. Luong et al., “In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms,” The Journal of Biological Chemistry, vol. 279, no. 17, pp. 17508–17514, 2004.
[52]
X. Tong, R. Chase, A. Skelton, T. Chen, J. Wright-Minogue, and B. A. Malcolm, “Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034,” Antiviral Research, vol. 70, no. 2, pp. 28–38, 2006.
[53]
X. Tong, S. Bogen, R. Chase et al., “Characterization of resistance mutations against HCV ketoamide protease inhibitors,” Antiviral Research, vol. 77, no. 3, pp. 177–185, 2008.
[54]
C. Welsch, F. S. Domingues, S. Susser et al., “Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus,” Genome Biology, vol. 9, no. 1, article R16, 2008.
[55]
Y. Zhou, U. Müh, B. L. Hanzelka et al., “Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon α,” The Journal of Biological Chemistry, vol. 282, no. 31, pp. 22619–22628, 2007.
[56]
Y. Zhou, D. J. Bartels, B. L. Hanzelka et al., “Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 1, pp. 110–120, 2008.
[57]
K. P. Romano, A. Ali, W. E. Royer, and C. A. Schiffer, “Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 49, pp. 20986–20991, 2010.
[58]
T. L. Kieffer, C. Sarrazin, J. S. Miller et al., “Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients,” Hepatology, vol. 46, no. 3, pp. 631–639, 2007.
[59]
C. Sarrazin, T. L. Kieffer, D. Bartels et al., “Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir,” Gastroenterology, vol. 132, no. 5, pp. 1767–1777, 2007.
[60]
D. J. Bartels, S. DeMeyer, J. Sullivan, et al., “Summary of clinical virology findings from clinical trials of telaprevir,” in Proceedings of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, Calif, USA, November 2011, Abstract 1328.
[61]
“Incivek [package insert],” Vertex Pharmaceuticals Incorporated, Cambridge, Mass, USA, 2011.
[62]
“Incivo [telaprevir],” European Medicines Agency http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf.
[63]
S. Zeuzem, M. S. Sulkowski, F. Zoulim, et al., “Long-term follow-up of patients with chronic hepatitis C treated with telaprevir in combination with peginterferonalfa-2a and ribavirin: interim analysis of the EXTEND study,” in Proceedings of the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD '10), Boston, Mass, USA, October 2010, Abstract 227.
[64]
K. E. Sherman, M. S. Sulkowski, F. Zoulim, et al., “Follow-up of SVR durability and viral resistance in patients with chronic hepatitis C treated with telaprevir-based regimens: interim analysis from the EXTEND study,” in Proceedings of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, Calif, USA, November 2011, Abstract 248.
[65]
S. Susser, C. Welsch, Y. Wang et al., “Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients,” Hepatology, vol. 50, no. 6, pp. 1709–1718, 2009.
[66]
L. Lu, T. J. Pilot-Matias, K. D. Stewart et al., “Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 6, pp. 2260–2266, 2004.
[67]
M. Sulkowski, F. Poordad, J. McCone, et al., “BOC combined with P/R for treatment-na？ve patients with HCV genotype-1: SPRINT-2 final results,” in Proceedings of the 18th Conference on Retroviruses and Opportunistic Infections (CROI '11), Boston, Mass, USA, February 2011.
[68]
S. Gordon, B. Bacon, E. Lawitz, et al., “HCV RESPOND-2 final results: high sustained virologicresponse among genotype-1 previous non-responders and relapsers to pegIFN/RBV when re-treated with BO EGINTRON/RBV,” in Proceedings of the 18th Conference on Retroviruses and Opportunistic Infections (CROI '11), Boston, Mass, USA, February 2011.
[69]
“Victrelis [package insert],” Merck & Company Incorporated, Whitehouse Station, NJ, USA, 2011.
[70]
“Victrelis [boceprevir],” European Medicines Agency http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf.
[71]
R. J. Barnard, S. Zeuzem, J. M. Vierling, et al., “Analysis of resistance-associated amino acid variants (RAVs) in non-SVR patients enrolled in a retrospective long-term follow-up analysis of boceprevir phase III clinical studies,” in Proceedings of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, Calif, USA, November 2011, Abstract 164.
[72]
J. M. Pawlotsky, “Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus,” Hepatology, vol. 53, no. 5, pp. 1742–1751, 2011.
[73]
C. J. Baidick, D. J. Tenney, C. E. Mazzucco et al., “Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance,” Hepatology, vol. 47, no. 5, pp. 1473–1482, 2008.
[74]
C. Pallier, L. Castéra, A. Soulier et al., “Dynamics of hepatitis B virus resistance to lamivudine,” Journal of Virology, vol. 80, no. 2, pp. 643–653, 2006.
[75]
C. Palleir, C. Rodriguez, R. Brillet, P. Nordmann, C. Hézode, and J. M. Pawlotsky, “Complex dynamics of hepatitis B virus resistance to adefovir,” Hepatology, vol. 49, no. 1, pp. 50–59, 2009.
[76]
P. Kwo, J. Lawitz, J. McCone, et al., “HCV SPRINT-1 final results: SVR 24 from a phase II study of boceprevir plus peginterferon alfa-2b/ribavirin in treatment-na？ve subjects with genotype 1 chronic hepatitis C,” in Proceedings of the 44th Annual Meeting of the European Association for the Study of the Liver, Copenhagen, Denmark, April 2009.
[77]
J. G. McHutchison, M. P. Manns, A. J. Muir et al., “Telaprevir for previously treated chronic HCV infection,” The New England Journal of Medicine, vol. 362, no. 14, pp. 1292–1303, 2010.
[78]
S. Zeuzem, P. Andreone, S. Pol, et al., “REALIZE trial final results: telaprevir-based regimen for genotype 1 hepatitis C virus infection in patients with prior null response, partial response or relapse to peginterferon/ribavirin,” in Proceedings of the EASL 46th Annual Meeting, Berlin, Germany, March 2011.
[79]
I. M. Jacobson, J. G. McHutchison, G. Dusheiko et al., “Telaprevir for previously untreated chronic hepatitis C virus infection,” The New England Journal of Medicine, vol. 364, no. 25, pp. 2405–2416, 2011.
[80]
D. Ge, J. Fellay, A. J. Thompson et al., “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance,” Nature, vol. 461, no. 7262, pp. 399–401, 2009.
[81]
A. J. Thompson, A. J. Muir, M. S. Sulkowski et al., “Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus,” Gastroenterology, vol. 139, no. 1, pp. 120–129, 2010.
[82]
E. J. Gane, C. A. Stedman, R. J. Hyland, et al., “ELECTRON: once daily PSI-7977 plus RBV in HCV GT1/2/3,” in Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona, Spain, April 2012.
[83]
E. Lawitz, F. Poordad, K. V. Kowdley, et al., “A 12-week interferon-free regimen of ABT-450/r, ABT-072, and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-na？ve HCV IL28B-CC genotype-1-infected subject,” in Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona, Spain, April 2012, Abstract 1187.
[84]
F. Poordad, E. Lawitz, K. V. Kowdley, et al., “12-week interferon-free regimen of ABT-450/ritonavi BT-333+ribavirin achieved SVR12 in more than 90% of treatment-na？ve HCV genotype-1-infected subjects and 47% of previous non-responders,” in Proceedings of the 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona, Spain, April 2012, Abstract 1399.
