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Journal of Immunology Research
Volume 2016 (2016), Article ID 1412840, 19 pages
http://dx.doi.org/10.1155/2016/1412840
Review Article

State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization

1Department of Health Sciences, University of Genoa, 16132 Genoa, Italy
2IRCCS AOU San Martino-IST, 16132 Genoa, Italy

Received 30 June 2016; Revised 9 September 2016; Accepted 20 September 2016

Academic Editor: Roberta A. Diotti

Copyright © 2016 Cecilia Trucchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. R. Edlin, “Perspective: test and treat this silent killer,” Nature, vol. 474, no. 7350, pp. S18–S19, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. Center for Disease Control and Prevention (CDC), “Surveillance for Viral Hepatitis-United States,” 2013, http://www.cdc.gov/hepatitis/statistics/2013surveillance/commentary.htm#hepatitisC
  3. E. Gower, C. Estes, S. Blach, K. Razavi-Shearer, and H. Razavi, “Global epidemiology and genotype distribution of the hepatitis C virus infection,” Journal of Hepatology, vol. 61, no. 1, pp. S45–S57, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. I. F. Kretzer, A. do Livramento, J. da Cunha et al., “Hepatitis C worldwide and in Brazil: silent epidemic—data on disease including incidence, transmission, prevention, and treatment,” The Scientific World Journal, vol. 2014, Article ID 827849, 10 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Grebely, K. Page, R. Sacks-Davis et al., “The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection,” Hepatology, vol. 59, no. 1, pp. 109–120, 2014. View at Publisher · View at Google Scholar · View at Scopus
  6. H.-H. Thein, Q. Yi, G. J. Dore, and M. D. Krahn, “Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression,” Hepatology, vol. 48, no. 2, pp. 418–431, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. R. Lozano, M. Naghavi, K. Foreman et al., “Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010,” The Lancet, vol. 380, no. 9859, pp. 2095–2128, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. T. J. Liang, “Current progress in development of hepatitis C virus vaccines,” Nature Medicine, vol. 19, no. 7, pp. 869–878, 2013. View at Publisher · View at Google Scholar
  9. L. Man John Law, A. Landi, W. C. Magee, D. Lorne Tyrrell, and M. Houghton, “Progress towards a hepatitis C virus vaccine,” Emerging Microbes and Infections, vol. 2, article e79, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. M. L. Shiffman, “Universal screening for chronic hepatitis C virus,” Liver International, vol. 36, no. S1, pp. 62–66, 2016. View at Publisher · View at Google Scholar
  11. J. Bottero, C. Brouard, F. Roudot-Thoraval et al., “2014 French guidelines for hepatitis B and C screening. A combined targeted and mass testing strategy of chronic viruses namely HBV, HCV and HIV,” Liver International, vol. 36, no. 10, pp. 1442–1449, 2016. View at Publisher · View at Google Scholar
  12. P. Easterbrook, C. Johnson, C. Figueroa, and R. Baggaley, “HIV and hepatitis testing: global progress, challenges, and future directions,” AIDS Reviews, vol. 18, no. 1, pp. 3–14, 2016. View at Google Scholar
  13. M. M. Denniston, R. M. Klevens, G. M. McQuillan, and R. B. Jiles, “Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001–2008,” Hepatology, vol. 55, no. 6, pp. 1652–1661, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. World Health Organization, “Hepatitis C,” Fact Sheet 164, World Health Organization, Geneva‎, Switzerland, 2015, http://www.who.int/mediacentre/factsheets/fs164/en/. View at Google Scholar
  15. World Health Organization, “Global policy report on the prevention and control of viral hepatitis in WHO Member States,” 2013, http://apps.who.int/iris/bitstream/10665/85397/1/9789241564632_eng.pdf
  16. World Health Organization, “Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection,” http://apps.who.int/iris/bitstream/10665/205035/1/9789241549615_eng.pdf?ua=1
  17. S. Kamili, J. Drobeniuc, A. C. Araujo, and T. M. Hayden, “Laboratory diagnostics for hepatitis C virus infection,” Clinical Infectious Diseases, vol. 55, supplement 1, pp. S43–S48, 2012. View at Publisher · View at Google Scholar
  18. L. M. Villar, H. M. Cruz, C. S. Barbosa Bezerra Jr., M. M. Portilho, and P. Scalioni Lde, “Update on hepatitis B and C virus diagnosis,” World Journal of Virology, vol. 4, no. 4, pp. 323–342, 2015. View at Google Scholar
  19. H. C. Li and S. Y. Lo, “Hepatitis C virus: virology, diagnosis and treatment,” World Journal of Hepatology, vol. 7, no. 10, pp. 1377–1389, 2015. View at Publisher · View at Google Scholar
  20. C. V. Uliana, C. S. Riccardi, and H. Yamanaka, “Diagnostic tests for hepatitis C: recent trends in electrochemical immunosensor and genosensor analysis,” World Journal of Gastroenterology, vol. 20, no. 42, pp. 15476–15491, 2014. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Chevaliez and J.-M. Pawlotsky, “Hepatitis C virus serologic and virologic tests and clinical diagnosis of HCV-related liver disease,” International Journal of Medical Sciences, vol. 3, no. 2, pp. 35–40, 2006. View at Google Scholar · View at Scopus
  22. F. Alborino, A. Burighel, F.-W. Tiller et al., “Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity,” Medical Microbiology and Immunology, vol. 200, no. 2, pp. 77–83, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. C. Colin, D. Lanoir, S. Touzet, L. Meyaud-Kraemer, F. Bailly, and C. Trepo, “Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an analysis of the literature,” Journal of Viral Hepatitis, vol. 8, no. 2, pp. 87–95, 2001. View at Publisher · View at Google Scholar · View at Scopus
  24. J. M. Barrera, B. Francis, G. Ercilla et al., “Improved detection of anti-HCV in post-transfusion hepatitis by a third-generation ELISA,” Vox Sanguinis, vol. 68, no. 1, pp. 15–18, 1995. View at Publisher · View at Google Scholar · View at Scopus
  25. C. L. Mack, R. P. Gonzalez-Peralta, N. Gupta et al., “NASPGHAN Practice guidelines: diagnosis and management of hepatitis c infection in infants, children, and adolescents,” Journal of Pediatric Gastroenterology and Nutrition, vol. 54, no. 6, pp. 838–855, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. M. C. Medici, G. Furlini, A. Rodella et al., “Hepatitis C virus core antigen: analytical performances, correlation with viremia and potential applications of a quantitative, automated immunoassay,” Journal of Clinical Virology, vol. 51, no. 4, pp. 264–269, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. F. V. Cresswell, M. Fisher, D. J. Hughes, S. G. Shaw, G. Homer, and M. O. Hassan-Ibrahim, “Hepatitis C core antigen testing: a reliable, quick, and potentially cost-effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection,” Clinical Infectious Diseases, vol. 60, no. 2, pp. 263–266, 2015. View at Publisher · View at Google Scholar · View at Scopus
  28. B. D. Smith, R. L. Morgan, G. A. Beckett, Y. Falck-Ytter, D. Holtzman, and J. W. Ward, “Hepatitis C virus testing of persons born during 1945–1965: recommendations from the centers for disease control and prevention,” Annals of Internal Medicine, vol. 157, no. 11, pp. 817–822, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. Haute Autorité de Sanitè (HAS), Use of Rapid Point-of-Care First-Line Screening Tests in Hepatitis C Screening Strategy, Haute Autorité de Sanitè (HAS), Saint Denis, France, 2014.
  30. S. Shivkumar, R. Peeling, Y. Jafari, L. Joseph, and N. Pant Pai, “Accuracy of rapid and point-of-care screening tests for hepatitis C: a systematic review and meta-analysis,” Annals of Internal Medicine, vol. 157, no. 8, pp. 558–566, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. L. D. P. Scalioni, H. M. Cruz, V. S. de Paula et al., “Performance of rapid hepatitis C virus antibody assays among high- and low-risk populations,” Journal of Clinical Virology, vol. 60, no. 3, pp. 200–205, 2014. View at Publisher · View at Google Scholar · View at Scopus
  32. M. S. Khuroo, N. S. Khuroo, and M. S. Khuroo, “Diagnostic accuracy of point-of-care tests for hepatitis C virus infection: a systematic review and meta-analysis,” PLoS ONE, vol. 10, no. 3, Article ID e0121450, 2015. View at Publisher · View at Google Scholar · View at Scopus
  33. National Institute for Health and Clinical Excellence (NICE), Hepatitis B and C: Ways to Promote and Offer Testing to People at Increased Risk of Infection, NICE, London, UK, 2012, http://www.nice.org.uk/nicemedia/live/14003/61863/61863.pdf.
  34. Centers for Disease Control and Prevention (CDC), “Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965,” Morbidity and Mortality Weekly Report (MMWR), vol. 61, no. RR04, pp. 1–32, 2012, http://www.cdc.gov/mmwr/pdf/rr/rr6104.pdf View at Google Scholar
  35. AASLD/IDSA HCV Guidance Panel, “Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus,” Hepatology, vol. 62, no. 3, pp. 932–954, 2015. View at Publisher · View at Google Scholar
  36. B. D. Smith, R. L. Morgan, G. A. Beckett et al., “Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965,” MMWR Recommendations and Reports, vol. 61, no. 4, pp. 1–32, 2012. View at Google Scholar · View at Scopus
  37. V. A. Moyer, “Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: U.S. Preventive Services Task Force recommendation statement,” Annals of Internal Medicine, vol. 159, no. 3, pp. 210–218, 2013. View at Google Scholar · View at Scopus
  38. T. M. Shehab, S. S. Sonnad, and A. S. F. Lok, “Management of hepatitis C patients by primary care physicians in the USA: results of a national survey,” Journal of Viral Hepatitis, vol. 8, no. 5, pp. 377–383, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. T. M. Shehab, M. Orrego, R. Chunduri, and A. S. F. Lok, “Identification and management of hepatitis C patients in primary care clinics,” The American Journal of Gastroenterology, vol. 98, no. 3, pp. 639–644, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. R. Mahajan, S. J. Liu, R. M. Klevens, and S. D. Holmberg, “Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004–2010,” American Journal of Public Health, vol. 103, no. 8, pp. 1445–1449, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. L. Hsu, C. L. Bowlus, S. L. Stewart et al., “Electronic messages increase hepatitis B screening in at-risk Asian American patients: a randomized, controlled trial,” Digestive Diseases and Sciences, vol. 58, no. 3, pp. 807–814, 2013. View at Publisher · View at Google Scholar
  42. J. W. Galbraith, R. A. Franco, J. P. Donnelly et al., “Unrecognized chronic hepatitis C virus infection among baby boomers in the emergency department,” Hepatology, vol. 61, no. 3, pp. 776–782, 2015. View at Publisher · View at Google Scholar · View at Scopus
  43. B. J. Turner, B. S. Taylor, J. T. Hanson et al., “Implementing hospital-based baby boomer hepatitis C virus screening and linkage to care: strategies, results, and costs,” Journal of Hospital Medicine, vol. 10, no. 8, pp. 510–516, 2015. View at Publisher · View at Google Scholar · View at Scopus
  44. D. M. Sears, D. C. Cohen, K. Ackerman, J. E. Ma, and J. Song, “Birth cohort screening for chronic hepatitis during colonoscopy appointments,” American Journal of Gastroenterology, vol. 108, no. 6, pp. 981–989, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. R. P. Myers, P. Crotty, S. Town et al., “Acceptability and yield of birth-cohort screening for hepatitis C virus in a Canadian population being screened for colorectal cancer: a cross-sectional study,” CMAJ Open, vol. 3, no. 1, pp. E62–E67, 2015. View at Publisher · View at Google Scholar
  46. N. J. Shire and K. E. Sherman, “Epidemiology of hepatitis C virus: a battle on new frontiers,” Gastroenterology Clinics of North America, vol. 44, no. 4, pp. 699–716, 2015. View at Publisher · View at Google Scholar
  47. J. Nakamura, K. Terajima, Y. Aoyagi, and K. Akazawa, “Cost-effectiveness of the national screening program for hepatitis C virus in the general population and the high-risk groups,” The Tohoku Journal of Experimental Medicine, vol. 215, no. 1, pp. 33–42, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. S. J. M. Hahné, I. K. Veldhuijzen, L. Wiessing, T.-A. Lim, M. Salminen, and M. V. D. Laar, “Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening,” BMC Infectious Diseases, vol. 13, no. 1, article 181, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. A. Kautz, L. Chavdarova, and M. Walker, “Improved hepatitis C screening and treatment in people who inject drugs should be a priority in Europe,” BMC Infectious Diseases, vol. 14, supplement 6, article S3, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. G. Dultz and S. Zeuzem, “Hepatitis C virus: a European perspective,” Gastroenterology Clinics of North America, vol. 44, no. 4, pp. 807–824, 2015. View at Publisher · View at Google Scholar
  51. S. Lubega, U. Agbim, M. Surjadi, M. Mahoney, and M. Khalili, “Formal hepatitis C education enhances HCV care coordination, expedites HCV treatment and improves antiviral response,” Liver International, vol. 33, no. 7, pp. 999–1007, 2013. View at Publisher · View at Google Scholar · View at Scopus
  52. G. Wagner, K. C. Osilla, J. Garnett et al., “Provider and patient correlates of provider decisions to recommend HCV treatment to HIV Co-infected patients,” Journal of the International Association of Physicians in AIDS Care, vol. 11, no. 4, pp. 245–251, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. N. Islam, Y. N. Flores, P. Ramirez, R. Bastani, and J. Salmerón, “Hepatitis and liver disease knowledge and preventive practices among health workers in Mexico: a cross-sectional study,” International Journal of Public Health, vol. 59, no. 2, pp. 381–394, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Grebely, J. Bryant, P. Hull et al., “Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia,” Journal of Viral Hepatitis, vol. 18, no. 4, pp. e104–e116, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. J. A. Aberg, J. E. Gallant, K. G. Ghanem, P. Emmanuel, B. S. Zingman, and M. A. Horberg, “Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the infectious diseases society of America,” Clinical Infectious Diseases, vol. 58, no. 1, pp. 1–10, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. B. P. Linas, A. Y. Wong, B. R. Schackman, A. Y. Kim, and K. A. Freedberg, “Cost-effective screening for acute hepatitis C virus infection in hiv-infected men who have sex with men,” Clinical Infectious Diseases, vol. 55, no. 2, pp. 279–290, 2012. View at Publisher · View at Google Scholar · View at Scopus
  57. G. Wandeler, T. Gsponer, A. Bregenzer et al., “Hepatitis C virus infections in the swiss HIV cohort study: a rapidly evolving epidemic,” Clinical Infectious Diseases, vol. 55, no. 10, pp. 1408–1416, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. M. D. Witt, E. C. Seaberg, A. Darilay et al., “Incident hepatitis C virus infection in men who have sex with men: a prospective cohort analysis, 1984–2011,” Clinical Infectious Diseases, vol. 57, no. 1, pp. 77–84, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. M. J. Bravo, F. Vallejo, G. Barrio et al., “HCV seroconversion among never-injecting heroin users at baseline: no predictors identified other than starting injection,” International Journal of Drug Policy, vol. 23, no. 5, pp. 415–419, 2012. View at Publisher · View at Google Scholar · View at Scopus
  60. I. T. Williams, B. P. Bell, W. Kuhnert, and M. J. Alter, “Incidence and transmission patterns of acute hepatitis C in the United States, 1982–2006,” Archives of Internal Medicine, vol. 171, no. 3, pp. 242–248, 2011. View at Publisher · View at Google Scholar
  61. J. P. Meyer, Y. Moghimi, R. Marcus, J. K. Lim, A. H. Litwin, and F. L. Altice, “Evidence-based interventions to enhance assessment, treatment, and adherence in the chronic Hepatitis C care continuum,” International Journal of Drug Policy, vol. 26, no. 10, pp. 922–935, 2015. View at Publisher · View at Google Scholar · View at Scopus
  62. A. C. Moorman, S. C. Gordon, L. B. Rupp et al., “Baseline characteristics and mortality among people in care for chronic viral hepatitis: the chronic hepatitis cohort study,” Clinical Infectious Diseases, vol. 56, no. 1, pp. 40–50, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. Y. Liu, R. H. Lawrence, Y. Falck-Ytter, B. Watts, and A. A. Hirsch, “Evaluating a hepatitis c quality gap: missed opportunities for HCV-related cares,” American Journal of Managed Care, vol. 20, no. 7, pp. e257–e264, 2014. View at Google Scholar
  64. O. S. Khokhar and J. H. Lewis, “Reasons why patients infected with chronic hepatitis C virus choose to defer treatment: do they alter their decision with time?” Digestive Diseases and Sciences, vol. 52, no. 5, pp. 1168–1176, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Arora, K. Thornton, G. Murata et al., “Outcomes of treatment for hepatitis C virus infection by primary care providers,” New England Journal of Medicine, vol. 364, no. 23, pp. 2199–2207, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. B. T. Clark, G. Garcia-Tsao, and L. Fraenkel, “Patterns and predictors of treatment initiation and completion in patients with chronic hepatitis C virus infection,” Patient Preference and Adherence, vol. 6, pp. 285–295, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. L. L. Seifert, R. B. Perumpail, and A. Ahmed, “Update on hepatitis C: direct-acting antivirals,” World Journal of Hepatology, vol. 7, no. 28, pp. 2829–2833, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. L. Highleyman, “Hepatitis C cascade studies show gaps in testing and treatment,” http://www.hivandhepatitis.com/hepatitis-c/hepatitis-c-topics/hcv-treatment/4693-hepatitis-c-cascade-studies-show-gaps-in-testing-and-treatment
  69. S. D. Holmberg, P. R. Spradling, A. C. Moorman, and M. M. Denniston, “Hepatitis C in the United States,” The New England Journal of Medicine, vol. 368, no. 20, pp. 1859–1861, 2013. View at Publisher · View at Google Scholar
  70. M. Hellard, R. Sacks‐Davis, and J. Gold, “Hepatitis C treatment for injection drug users: a review of the available evidence,” Clinical Infectious Diseases, vol. 49, no. 4, pp. 561–573, 2009. View at Publisher · View at Google Scholar
  71. J. A. Morrill, M. Shrestha, and R. W. Grant, “Barriers to the treatment of hepatitis C: patient, provider, and system factors,” Journal of General Internal Medicine, vol. 20, no. 8, pp. 754–758, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. B. Reilley, J. Leston, J. T. Redd, and R. Geiger, “Lack of access to treatment as a barrier to HCV screening: a facility-based assessment in the Indian health service,” Journal of Public Health Management and Practice, vol. 20, no. 4, pp. 420–423, 2014. View at Publisher · View at Google Scholar
  73. C. E. McGowan, A. Monis, B. R. Bacon et al., “A global view of hepatitis C: physician knowledge, opinions, and perceived barriers to care,” Hepatology, vol. 57, no. 4, pp. 1325–1332, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. M. M. Islam, L. Topp, K. M. Conigrave et al., “Linkage into specialist hepatitis C treatment services of injecting drug users attending a needle syringe program-based primary healthcare centre,” Journal of Substance Abuse Treatment, vol. 43, no. 4, pp. 440–445, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. M. R. Stein, I. J. Soloway, K. S. Jefferson, R. J. Roose, J. H. Arnsten, and A. H. Litwin, “Concurrent group treatment for hepatitis C: implementation and outcomes in a methadone maintenance treatment program,” Journal of Substance Abuse Treatment, vol. 43, no. 4, pp. 424–432, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. P. Bruggmann and A. H. Litwin, “Models of care for the management of hepatitis C virus among people who inject drugs: one size does not fit all,” Clinical Infectious Diseases, vol. 57, supplement 2, pp. S56–S61, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. S. B. Ho, N. Bräu, R. Cheung et al., “Integrated care increases treatment and improves outcomes of patients with chronic hepatitis C virus infection and psychiatric illness or substance abuse,” Clinical Gastroenterology and Hepatology, vol. 13, no. 11, pp. 2005–2014, 2015. View at Publisher · View at Google Scholar · View at Scopus
  78. L. Rossaro, C. Torruellas, S. Dhaliwal et al., “Clinical outcomes of hepatitis C treated with pegylated interferon and ribavirin via telemedicine consultation in Northern California,” Digestive Diseases and Sciences, vol. 58, no. 12, pp. 3620–3625, 2013. View at Publisher · View at Google Scholar · View at Scopus
  79. L. Miller, S.-A. Fluker, M. Osborn, X. Liu, and A. Strawder, “Improving access to hepatitis C care for urban, underserved patients using a primary care-based hepatitis C clinic,” Journal of the National Medical Association, vol. 104, no. 5-6, pp. 244–250, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. S. B. Trooskin, J. Poceta, C. M. Towey et al., “Results from a geographically focused, community-based HCV screening, linkage-to-care and patient navigation program,” Journal of General Internal Medicine, vol. 30, no. 7, pp. 950–957, 2015. View at Publisher · View at Google Scholar · View at Scopus
  81. C. Coyle, K. Viner, E. Hughes et al., “Identification and linkage to care of HCV-infected persons in five health centers—Philadelphia, Pennsylvania, 2012–2014,” Morbidity and Mortality Weekly Report, vol. 64, no. 17, pp. 459–463, 2015. View at Google Scholar · View at Scopus
  82. S. Zopf, A. E. Kremer, M. F. Neurath, and J. Siebler, “Advances in hepatitis C therapy: what is the current state—what come's next?” World Journal of Hepatology, vol. 8, no. 3, pp. 139–147, 2016. View at Publisher · View at Google Scholar · View at Scopus
  83. J. M. Pawlotsky, “Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens,” Gastroenterology, vol. 151, no. 1, pp. 70–86, 2016. View at Publisher · View at Google Scholar
  84. M. Jiménez-Pérez, R. González-Grande, P. España Contreras, I. Pinazo Martínez, J. de la Cruz Lombardo, and R. Olmedo Martín, “Treatment of chronic hepatitis C with direct-acting antivirals: the role of resistance,” World Journal of Gastroenterology, vol. 22, no. 29, pp. 6573–6581, 2016. View at Publisher · View at Google Scholar
  85. S. Kattakuzhy, R. Levy, E. Rosenthal, L. Tang, E. Wilson, and S. Kottilil, “Hepatitis C genotype 3 disease,” Hepatology International, 2016. View at Publisher · View at Google Scholar
  86. J. Dietz, S. Susser, C. Berkowski, D. Perner, S. Zeuzem, and C. Sarrazin, “Consideration of viral resistance for optimization of direct antiviral therapy of hepatitis C virus genotype 1-infected patients,” PLoS ONE, vol. 10, no. 8, article e0134395, 2015. View at Publisher · View at Google Scholar · View at Scopus
  87. D. J. Bartels, J. C. Sullivan, E. Z. Zhang et al., “Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment,” Journal of Virology, vol. 87, no. 3, pp. 1544–1553, 2013. View at Publisher · View at Google Scholar · View at Scopus
  88. M. D. Schneider and C. Sarrazin, “Antiviral therapy of hepatitis C in 2014: do we need resistance testing?” Antiviral Research, vol. 105, no. 1, pp. 64–71, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. O. Lenz, T. Verbinnen, B. Fevery et al., “Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies,” Journal of Hepatology, vol. 62, no. 5, pp. 1008–1014, 2015. View at Publisher · View at Google Scholar · View at Scopus
  90. S. M. Horner, S. Naggie, and R. C. Condit, “Successes and challenges on the road to cure hepatitis C,” PLoS Pathogens, vol. 11, no. 6, article e1004854, 2015. View at Publisher · View at Google Scholar
  91. I. Vicenti, F. Falasca, L. Sticchi, B. Bruzzone, O. Turriziani, and M. Zazzi, “Evaluation of a commercial real-time PCR kit for the detection of the Q80K polymorphism in plasma from HCV genotype 1a infected patients,” Journal of Clinical Virology, vol. 76, pp. 20–23, 2016. View at Publisher · View at Google Scholar · View at Scopus
  92. I. M. Jacobson, G. J. Dore, G. R. Foster et al., “Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial,” The Lancet, vol. 384, no. 9941, pp. 403–413, 2014. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Manns, P. Marcellin, F. Poordad et al., “Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial,” The Lancet, vol. 384, no. 9941, pp. 414–426, 2014. View at Publisher · View at Google Scholar · View at Scopus
  94. X. Forns, E. Lawitz, S. Zeuzem et al., “Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial,” Gastroenterology, vol. 146, no. 7, pp. 1669.e3–1679.e3, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. C. Moreno, C. Hezode, P. Marcellin et al., “Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4,” Journal of Hepatology, vol. 62, no. 5, pp. 1047–1055, 2015. View at Publisher · View at Google Scholar · View at Scopus
  96. C. Sarrazin, E. Lathouwers, M. Peeters et al., “Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region,” Antiviral Research, vol. 116, pp. 10–16, 2015. View at Publisher · View at Google Scholar · View at Scopus
  97. L. L. Vidãl, A. F. Santos, and M. A. Soares, “Worldwide distribution of the NS3 gene 80K polymorphism among circulating hepatitis C genotype 1 viruses: implication for simeprevir usage,” Journal of Antimicrobial Chemotherapy, vol. 70, no. 7, Article ID dkv081, pp. 2024–2027, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Hajji, S. Aherfi, A. Motte et al., “Diversity of 1,213 hepatitis C virus NS3 protease sequences from a clinical virology laboratory database in Marseille university hospitals, southeastern France,” Journal of Medical Virology, vol. 87, no. 11, pp. 1921–1933, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. E. Lawitz, G. Matusow, E. DeJesus et al., “Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: a phase 3 study (OPTIMIST-2),” Hepatology, vol. 64, no. 2, pp. 360–369, 2016. View at Publisher · View at Google Scholar
  100. C. Sarrazin, “The importance of resistance to direct antiviral drugs in HCV infection in clinical practice,” Journal of Hepatology, vol. 64, no. 2, pp. 486–504, 2016. View at Publisher · View at Google Scholar · View at Scopus
  101. R. A. Fridell, D. Qiu, C. Wang, L. Valera, and M. Gao, “Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 9, pp. 3641–3650, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. Y. Suzuki, K. Ikeda, F. Suzuki et al., “Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options,” Journal of Hepatology, vol. 58, no. 4, pp. 655–662, 2013. View at Publisher · View at Google Scholar · View at Scopus
  103. F. Suzuki, H. Sezaki, N. Akuta et al., “Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b,” Journal of Clinical Virology, vol. 54, no. 4, pp. 352–354, 2012. View at Publisher · View at Google Scholar · View at Scopus
  104. N. Coppola, C. Minichini, M. Starace, C. Sagnelli, and E. Sagnelli, “Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals,” Journal of Medical Virology, vol. 88, no. 10, pp. 1659–1671, 2016. View at Publisher · View at Google Scholar
  105. P. Krishnan, R. Tripathi, G. Schnell et al., “Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir/r-, ombitasvir- and dasabuvir-based regimens,” Journal of Hepatology, vol. 62, supplement 2, p. S220, 2015. View at Publisher · View at Google Scholar
  106. F. Mcphee, D. Hernandez, F. Yu et al., “Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir,” Hepatology, vol. 58, no. 3, pp. 902–911, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. H. Dvory-Sobol, D. Wyles, W. Ouyang et al., “Long-term persistence of HCV NS5A variants after treatment with NS5A inhibitor ledipasvir,” Journal of Hepatology, vol. 62, supplement 2, p. S221, 2015. View at Publisher · View at Google Scholar
  108. V. Cento, S. Chevaliez, and C. F. Perno, “Resistance to direct-acting antiviral agents: clinical utility and significance,” Current Opinion in HIV and AIDS, vol. 10, no. 5, pp. 381–389, 2015. View at Publisher · View at Google Scholar · View at Scopus
  109. M. Buti, M. Riveiro-Barciela, and R. Esteban, “Management of direct-acting antiviral agent failures,” Journal of Hepatology, vol. 63, no. 6, pp. 1511–1522, 2015. View at Publisher · View at Google Scholar · View at Scopus
  110. S. Duffy, L. A. Shackelton, and E. C. Holmes, “Rates of evolutionary change in viruses: patterns and determinants,” Nature Reviews Genetics, vol. 9, no. 4, pp. 267–276, 2008. View at Publisher · View at Google Scholar
  111. J. Bukh, R. H. Miller, and R. H. Purcell, “Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes,” Seminars in Liver Disease, vol. 15, no. 1, pp. 41–63, 1995. View at Publisher · View at Google Scholar · View at Scopus
  112. P. Simmonds, “Viral heterogeneity of the hepatitis C virus,” Journal of Hepatology, vol. 31, supplement 1, pp. 54–60, 1999. View at Publisher · View at Google Scholar · View at Scopus
  113. D. G. Bowen and C. M. Walker, “Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man,” Journal of Experimental Medicine, vol. 201, no. 11, pp. 1709–1714, 2005. View at Publisher · View at Google Scholar · View at Scopus
  114. T. von Hahn, J. C. Yoon, H. Alter et al., “Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo,” Gastroenterology, vol. 132, no. 2, pp. 667–678, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. B. Rehermann, “Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses,” Seminars in Liver Disease, vol. 27, no. 2, pp. 152–160, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. A. Penna, M. Pilli, A. Zerbini et al., “Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection,” Hepatology, vol. 45, no. 3, pp. 588–601, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. J. R. Larrubia, M. U. Lokhande, S. García-Garzõn et al., “Persistent hepatitis C virus (HCV) infection impairs HCV-specific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation,” Journal of Viral Hepatitis, vol. 20, no. 2, pp. 85–94, 2013. View at Publisher · View at Google Scholar · View at Scopus
  118. J. M. Timpe, Z. Stamataki, A. Jennings et al., “Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies,” Hepatology, vol. 47, no. 1, pp. 17–24, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. F. Ghasemi, S. Rostami, and Z. Meshkat, “Progress in the development of vaccines for hepatitis C virus infection,” World Journal of Gastroenterology, vol. 21, no. 42, pp. 11984–12002, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. L. Mailly, E. Robinet, P. Meuleman, T. F. Baumert, and M. B. Zeisel, “Hepatitis C virus infection and related liver disease: the quest for the best animal model,” Frontiers in Microbiology, vol. 4, article 213, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. J. Bukh, “Animal models for the study of hepatitis C virus infection and related liver disease,” Gastroenterology, vol. 142, no. 6, pp. 1279.e3–1287.e3, 2012. View at Publisher · View at Google Scholar · View at Scopus
  122. F. Ansaldi, A. Orsi, L. Sticchi, B. Bruzzone, and G. Icardi, “Hepatitis C virus in the new era: perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy,” World Journal of Gastroenterology, vol. 20, no. 29, pp. 9633–9652, 2014. View at Publisher · View at Google Scholar · View at Scopus
  123. G. Leroux-Roels, E. Depla, F. Hulstaert et al., “A candidate vaccine based on the hepatitis C E1 protein: tolerability and immunogenicity in healthy volunteers,” Vaccine, vol. 22, no. 23-24, pp. 3080–3086, 2004. View at Publisher · View at Google Scholar · View at Scopus
  124. S. E. Frey, M. Houghton, S. Coates et al., “Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults,” Vaccine, vol. 28, no. 38, pp. 6367–6373, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. D. Drane, E. Maraskovsky, R. Gibson et al., “Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: a phase I study in healthy volunteers,” Human Vaccines, vol. 5, no. 3, pp. 151–157, 2009. View at Publisher · View at Google Scholar · View at Scopus
  126. C. Firbas, B. Jilma, E. Tauber et al., “Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects,” Vaccine, vol. 24, no. 20, pp. 4343–4353, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. C. Firbas, T. Boehm, V. Buerger et al., “Immunogenicity and safety of different injection routes and schedules of IC41, a Hepatitis C virus (HCV) peptide vaccine,” Vaccine, vol. 28, no. 12, pp. 2397–2407, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. E. Barnes, A. Folgori, S. Capone et al., “Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man,” Science Translational Medicine, vol. 4, no. 115, Article ID 115ra1, 2012. View at Publisher · View at Google Scholar · View at Scopus
  129. K. S. Abdelwahab and Z. N. A. Said, “Status of hepatitis C virus vaccination: recent update,” World Journal of Gastroenterology, vol. 22, no. 2, pp. 862–873, 2016. View at Publisher · View at Google Scholar · View at Scopus
  130. C. S. Klade, H. Wedemeyer, T. Berg et al., “Therapeutic vaccination of chronic hepatitis C nonresponder patients with the peptide vaccine IC41,” Gastroenterology, vol. 134, no. 5, pp. 1385.e1–1395.e1, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. H. Wedemeyer, E. Schuller, V. Schlaphoff et al., “Therapeutic vaccine IC41 as late add-on to standard treatment in patients with chronic hepatitis C,” Vaccine, vol. 27, no. 37, pp. 5142–5151, 2009. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Yutani, A. Yamada, K. Yoshida et al., “Phase I clinical study of a personalized peptide vaccination for patients infected with hepatitis C virus (HCV) 1b who failed to respond to interferon-based therapy,” Vaccine, vol. 25, no. 42, pp. 7429–7435, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. F. Habersetzer, G. Honnet, C. Bain et al., “A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C,” Gastroenterology, vol. 141, no. 3, pp. 890.e4–899.e4, 2011. View at Publisher · View at Google Scholar · View at Scopus
  134. G. A. Sautto, R. A. Diotti, and M. Clementi, “New therapeutic options for HCV infection in the monoclonal antibody era,” New Microbiologica, vol. 35, no. 4, pp. 387–397, 2012. View at Google Scholar · View at Scopus
  135. M. Flego, A. Ascione, M. Cianfriglia, and S. Vella, “Clinical development of monoclonal antibody-based drugs in HIV and HCV diseases,” BMC Medicine, vol. 11, article 4, 2013. View at Publisher · View at Google Scholar · View at Scopus
  136. E. Galun, N. A. Terrault, R. Eren et al., “Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: safety and antiviral activity,” Journal of Hepatology, vol. 46, no. 1, pp. 37–44, 2007. View at Publisher · View at Google Scholar · View at Scopus
  137. T. D. Schiano, M. Charlton, Z. Younossi et al., “Monoclonal antibody HCV-AbXTL68 in patients undergoing liver transplantation for HCV: results of a phase 2 randomized study,” Liver Transplantation, vol. 12, no. 9, pp. 1381–1389, 2006. View at Publisher · View at Google Scholar · View at Scopus
  138. R. T. Chung, F. D. Gordon, M. P. Curry et al., “Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study,” American Journal of Transplantation, vol. 13, no. 4, pp. 1047–1054, 2013. View at Publisher · View at Google Scholar · View at Scopus
  139. D. Gardiner, J. Lalezari, E. Lawitz et al., “A Randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection,” PLoS ONE, vol. 8, no. 5, Article ID e63818, 2013. View at Publisher · View at Google Scholar · View at Scopus
  140. B. Sangro, C. Gomez-Martin, M. De La Mata et al., “A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C,” Journal of Hepatology, vol. 59, no. 1, pp. 81–88, 2013. View at Publisher · View at Google Scholar · View at Scopus
  141. W. Halota, P. Ferenci, D. Kozielewicz et al., “Oral anti-CD3 immunotherapy for HCV-nonresponders is safe, promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase-2a placebo-controlled trial,” Journal of Viral Hepatitis, vol. 22, no. 8, pp. 651–657, 2015. View at Publisher · View at Google Scholar · View at Scopus
  142. T. Kuntzen, J. Timm, A. Berical et al., “Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients,” Hepatology, vol. 48, no. 6, pp. 1769–1778, 2008. View at Publisher · View at Google Scholar · View at Scopus
  143. J. A. Howe, J. Long, S. Black et al., “Clinical implications of detectable baseline hepatitis C virus-genotype 1 NS3/4A-protease variants on the efficacy of boceprevir combined with peginterferon/ribavirin,” Open Forum Infectious Diseases, vol. 1, no. 2, 2014. View at Publisher · View at Google Scholar
  144. E. Lontok, P. Harrington, A. Howe et al., “Hepatitis C virus drug resistance-associated substitutions: state of the art summary,” Hepatology, vol. 62, no. 5, pp. 1623–1632, 2015. View at Publisher · View at Google Scholar · View at Scopus
  145. B. Bartolini, M. Selleri, A. R. Garbuglia et al., “HCV NS3 quasispecies in liver and plasma and dynamics of telaprevir-resistant variants in breakthrough patients assessed by UDPS: A Case Study,” Journal of Clinical Virology, vol. 72, pp. 60–65, 2015. View at Publisher · View at Google Scholar · View at Scopus
  146. A. Beloukas, S. King, K. Childs et al., “Detection of the NS3 Q80K polymorphism by Sanger and deep sequencing in hepatitis C virus genotype 1a strains in the UK,” Clinical Microbiology and Infection, vol. 21, no. 11, pp. 1033–1039, 2015. View at Publisher · View at Google Scholar · View at Scopus
  147. L. Boglione, A. De Nicolò, C. S. Cardellino et al., “Relationship between the early Boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy,” Clinical Microbiology and Infection, vol. 21, no. 2, pp. 205.e1–205.e3, 2015. View at Publisher · View at Google Scholar · View at Scopus
  148. S. Vallet, F. Viron, C. Henquell et al., “NS3 protease polymorphism and natural resistance to protease inhibitors in French patients infected with HCV genotypes 1–5,” Antiviral Therapy, vol. 16, no. 7, pp. 1093–1102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  149. S. Gaudieri, A. Rauch, K. Pfafferott et al., “Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy,” Hepatology, vol. 49, no. 4, pp. 1069–1082, 2009. View at Publisher · View at Google Scholar · View at Scopus
  150. N. Palanisamy, A. Danielsson, C. Kokkula et al., “Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a,” Antiviral Research, vol. 99, no. 1, pp. 12–17, 2013. View at Publisher · View at Google Scholar · View at Scopus
  151. N. Nagpal, S. Goyal, D. Wahi et al., “Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease,” Gene, vol. 570, no. 1, pp. 115–121, 2015. View at Publisher · View at Google Scholar · View at Scopus
  152. S. Larrat, S. Vallet, S. David-Tchouda et al., “Naturally occurring resistance-associated variants of hepatitis C virus protease inhibitors in poor responders to pegylated interferon-ribavirin,” Journal of Clinical Microbiology, vol. 53, no. 7, pp. 2195–2202, 2015. View at Publisher · View at Google Scholar · View at Scopus
  153. T. Ruggiero, A. Proietti, L. Boglione et al., “Predominance of hepatitis C virus Q80K among NS3 baseline-resistance-associated amino acid variants in direct-antiviral-agent-naïve patients with chronic hepatitis: single-centre experience,” Archives of Virology, vol. 160, no. 11, pp. 2881–2885, 2015. View at Publisher · View at Google Scholar · View at Scopus
  154. S. Paolucci, L. Fiorina, B. Mariani et al., “Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients,” Virology Journal, vol. 10, article 355, 2013. View at Publisher · View at Google Scholar · View at Scopus
  155. V. Cento, C. Mirabelli, R. Salpini et al., “HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors,” PLoS ONE, vol. 7, article e39652, 2012. View at Publisher · View at Google Scholar · View at Scopus
  156. C. Sarrazin, H. Dvory-Sobol, E. S. Svarovskaia et al., “Baseline and post-baseline resistance analyses of phase 2/3 studies of ledipasvir/sofosbuvir +/− RBV,” Hepatology, vol. 60, no. 1, p. 1128a, 2014. View at Google Scholar
  157. K. M. Kitrinos, D. Wyles, H. Dvory-Sobol, A. Worth, B. Han, and D. Brainard, “Evaluation of the resistance profile of ledipasvir, a nonstructural protein 5A inhibitor, in genotype 1 chronically infected HCV subjects treated with ledipasvir-containing regimens without sofosbuvir,” Hepatology, vol. 60, pp. 1143a–1144a, 2014. View at Google Scholar
  158. Z. Plaza, V. Soriano, E. Vispo et al., “Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor,” Antiviral Therapy, vol. 17, no. 5, pp. 921–926, 2012. View at Publisher · View at Google Scholar · View at Scopus
  159. R. Liu, S. Curry, P. McMonagle et al., “Susceptibilities of genotype 1a, 1b, and 3 hepatitis C virus variants to the NS5A inhibitor elbasvir,” Antimicrobial Agents and Chemotherapy, vol. 59, no. 11, pp. 6922–6929, 2015. View at Publisher · View at Google Scholar · View at Scopus
  160. C. Premoli and A. Aghemo, “Directly acting antivirals against hepatitis C virus: mechanisms of action and impact of resistant associated variants,” Minerva Gastroenterologica e Dietologica, vol. 62, no. 1, pp. 76–87, 2016. View at Google Scholar
  161. R. A. Fridell, C. Wang, J.-H. Sun et al., “Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations,” Hepatology, vol. 54, no. 6, pp. 1924–1935, 2011. View at Publisher · View at Google Scholar · View at Scopus
  162. E. J. Lawitz, D. Gruener, J. M. Hill et al., “A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C,” Journal of Hepatology, vol. 57, no. 1, pp. 24–31, 2012. View at Publisher · View at Google Scholar
  163. L. Cuypers, G. Li, P. Libin, S. Piampongsant, A.-M. Vandamme, and K. Theys, “Genetic diversity and selective pressure in hepatitis C virus genotypes 1–6: significance for direct-acting antiviral treatment and drug resistance,” Viruses, vol. 7, no. 9, pp. 5018–5039, 2015. View at Publisher · View at Google Scholar · View at Scopus
  164. S. Nakamoto, T. Kanda, S. Wu, H. Shirasawa, and O. Yokosuka, “Hepatitis C virus NS5A inhibitors and drug resistance mutations,” World Journal of Gastroenterology, vol. 20, no. 11, pp. 2902–2912, 2014. View at Publisher · View at Google Scholar · View at Scopus
  165. P. Krishnan, R. Tripathi, G. Schnell, T. Reisch, J. Beyer, and M. Irvin, “Pooled analysis of resistance in patients treated with ombitasvir/ABT-450/r and dasabuvir with or without ribavirin in Phase 2 and Phase 3 clinical trials,” Hepatology, vol. 60, no. 1, pp. 1134a–1135a, 2014. View at Google Scholar
  166. C. Wang, L. Jia, H. Huang et al., “In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A,” Antimicrobial Agents and Chemotherapy, vol. 56, no. 3, pp. 1588–1590, 2012. View at Publisher · View at Google Scholar · View at Scopus
  167. D. Hernandez, N. Zhou, J. Ueland, A. Monikowski, and F. McPhee, “Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors,” Journal of Clinical Virology, vol. 57, no. 1, pp. 13–18, 2013. View at Publisher · View at Google Scholar · View at Scopus
  168. F. McPhee, J. Friborg, S. Levine et al., “Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir,” Antimicrobial Agents and Chemotherapy, vol. 56, no. 7, pp. 3670–3681, 2012. View at Publisher · View at Google Scholar · View at Scopus
  169. Y. Karino, J. Toyota, K. Ikeda et al., “Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir,” Journal of Hepatology, vol. 58, no. 4, pp. 646–654, 2013. View at Publisher · View at Google Scholar · View at Scopus
  170. F. McPhee, D. Hernandez, N. Zhou et al., “Virological escape in HCV genotype-1-infected patients receiving daclatasvir plus ribavirin and peginterferon alfa-2a or alfa-2b,” Antiviral Therapy, vol. 19, no. 5, pp. 479–490, 2014. View at Publisher · View at Google Scholar · View at Scopus
  171. J. Itakura, M. Kurosaki, H. Takada et al., “Naturally occurring, resistance-associated hepatitis C virus NS5A variants are linked to interleukin-28B genotype and are sensitive to interferon-based therapy,” Hepatology Research, vol. 45, no. 10, pp. E115–E121, 2015. View at Publisher · View at Google Scholar · View at Scopus
  172. Y. Kai, H. Hikita, T. Tatsumi et al., “Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice,” Journal of Gastroenterology, vol. 50, no. 11, pp. 1145–1151, 2015. View at Publisher · View at Google Scholar · View at Scopus
  173. C. Wang, L. Jia, D. R. O'Boyle II et al., “Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: Implications for cross-genotype activity,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 9, pp. 5155–5163, 2014. View at Publisher · View at Google Scholar · View at Scopus
  174. I. Lindström, M. Kjellin, N. Palanisamy et al., “Prevalence of polymorphisms with significant resistance to NS5A inhibitors in treatment-naive patients with hepatitis C virus genotypes 1a and 3a in Sweden,” Infectious Diseases, vol. 47, no. 8, pp. 555–562, 2015. View at Publisher · View at Google Scholar
  175. F. Poordad, C. Hezode, R. Trinh et al., “ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis,” The New England Journal of Medicine, vol. 370, no. 21, pp. 1973–1982, 2014. View at Publisher · View at Google Scholar · View at Scopus
  176. E. S. Svarovskaia, H. Dvory Sobol, N. Parkin et al., “Infrequent development of resistance in genotype 1-6 hepatitis c virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials,” Clinical Infectious Diseases, vol. 59, no. 12, pp. 1666–1674, 2014. View at Publisher · View at Google Scholar · View at Scopus
  177. S. Zeuzem, G. M. Dusheiko, R. Salupere et al., “Sofosbuvir and ribavirin in HCV genotypes 2 and 3,” The New England Journal of Medicine, vol. 370, no. 21, pp. 1993–2001, 2014. View at Publisher · View at Google Scholar · View at Scopus
  178. M. Charlton, E. Gane, M. P. Manns et al., “Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation,” Gastroenterology, vol. 148, no. 1, pp. 108–117, 2015. View at Publisher · View at Google Scholar · View at Scopus
  179. X. Tong, S. Le Pogam, L. Li et al., “In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir,” Journal of Infectious Diseases, vol. 209, no. 5, pp. 668–675, 2014. View at Publisher · View at Google Scholar · View at Scopus
  180. S. Chopp, R. Vanderwall, A. Hult, and M. Klepser, “Simeprevir and sofosbuvir for treatment of hepatitis C infection,” American Journal of Health-System Pharmacy, vol. 72, no. 17, pp. 1445–1455, 2015. View at Publisher · View at Google Scholar · View at Scopus
  181. V. C. Di Maio, V. Cento, C. Mirabelli et al., “Hepatitis c virus genetic variability and the presence of ns5b resistance-Associated mutations as natural polymorphisms in selected genotypes could affect the response to ns5b inhibitors,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 5, pp. 2781–2797, 2014. View at Publisher · View at Google Scholar · View at Scopus
  182. P. Krishnan, R. Tripathi, M. Irvin et al., “P1230 lack of impact of baseline resistance-associated variants (RAVS) on treatment outcome in the aviator study with ABT-450/R, ABT-333 AND ABT-267, +/– Ribavirin,” Journal of Hepatology, vol. 60, no. 1, article S498, 2014. View at Publisher · View at Google Scholar