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Gastroenterology Research and Practice
Volume 2015, Article ID 579147, 14 pages
http://dx.doi.org/10.1155/2015/579147
Review Article

A New Twist to a Chronic HCV Infection: Occult Hepatitis C

1Division of Gastroenterology and Hepatology, Cook County Health and Hospitals System, 1901 West Harrison Street, Chicago, IL 60612, USA
2Rush University Medical Center, Chicago, IL 60612, USA
3Advanced Liver and Gastrointestinal Disease Center, Berwyn, IL 60402, USA

Received 23 November 2014; Revised 15 April 2015; Accepted 24 May 2015

Academic Editor: Tatsuya Toyokawa

Copyright © 2015 Bashar M. Attar and David Van Thiel. 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. J.-M. Pawlotsky, “Therapy of hepatitis C: from empiricism to eradication,” Hepatology, vol. 43, no. 2, pp. S207–S220, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. B. Hajarizadeh, J. Grebely, and G. J. Dore, “Epidemiology and natural history of HCV infection,” Nature Reviews Gastroenterology and Hepatology, vol. 10, no. 9, pp. 553–562, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. J.-M. Pawlotsky, “New hepatitis C therapies: the toolbox, strategies, and challenges,” Gastroenterology, vol. 146, no. 5, pp. 1176–1192, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. E. R. Feeney and R. T. Chung, “Antiviral treatment of hepatitis C,” The British Medical Journal, vol. 348, Article ID g3308, 2014. View at Publisher · View at Google Scholar
  5. A. Slomski, “WHO issues guidelines on HCV amid drug cost controversy,” The Journal of the American Medical Association, vol. 311, no. 22, pp. 2262–2263, 2014. View at Publisher · View at Google Scholar
  6. R. Chou, D. Hartung, B. Rahman, N. Wasson, E. B. Cottrell, and R. Fu, “Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review,” Annals of Internal Medicine, vol. 158, no. 2, pp. 114–123, 2013. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Bourlière, A. Wendt, H. Fontaine, C. Hézode, S. Pol, and J. P. Bronowicki, “How to optimize HCV therapy in genotype 1 patients with cirrhosis,” Liver International, vol. 33, no. 1, pp. 46–55, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. L. Wei and A. S. F. Lok, “Impact of new hepatitis c treatments in different regions of the world,” Gastroenterology, vol. 146, no. 5, pp. 1145–1150, 2014. View at Publisher · View at Google Scholar · View at Scopus
  9. T. N. Q. Pham, S. A. MacParland, P. M. Mulrooney, H. Cooksley, N. V. Naoumov, and T. I. Michalak, “Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C,” Journal of Virology, vol. 78, no. 11, pp. 5867–5874, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. I. Castillo, M. Pardo, J. Bartolomé et al., “Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver function tests is unknown,” Journal of Infectious Diseases, vol. 189, no. 1, pp. 7–14, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. L. de Marco, A. Gillio-Tos, V. Fiano et al., “Occult HCV infection: an unexpected finding in a population unselected for hepatic disease,” PLoS ONE, vol. 4, no. 12, Article ID e8128, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. M.-W. Welker and S. Zeuzem, “Occult hepatitis C: how convincing are the current data?” Hepatology, vol. 49, no. 2, pp. 665–675, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. V. Carreño, J. Bartolomé, I. Castillo, and J. A. Quiroga, “New perspectives in occult hepatitis C virus infection,” World Journal of Gastroenterology, vol. 18, no. 23, pp. 2887–2894, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. I. Castillo, E. Rodríguez-Iñigo, J. Bartolomé et al., “Hepatitis C virus replicates in peripheral blood mononuclear cells of patients with occult hepatitis C virus infection,” Gut, vol. 54, no. 5, pp. 682–685, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. T. N. Q. Pham and T. I. Michalak, “Occult hepatitis C virus infection and its relevance in clinical practice,” Journal of Clinical and Experimental Hepatology, vol. 1, no. 3, pp. 185–189, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. V. Carreño, M. Pardo, J. M. López-Alcorocho, E. Rodríguez-Iñigo, J. Bartolomé, and I. Castillo, “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,” Journal of Infectious Diseases, vol. 194, no. 1, pp. 53–60, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. F. Bernardin, L. Tobler, I. Walsh, J. D. Williams, M. Busch, and E. Delwart, “Clearance of hepatitis C virus RNA from the peripheral blood mononuclear cells of blood donors who spontaneously or therapeutically control their plasma viremia,” Hepatology, vol. 47, no. 5, pp. 1446–1452, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. B. Pinarbasi, M. Bozaci, F. Akyuz et al., “The presence of HCVRNA in the peripheral blood mononuclear cells of the individuals with isolated anti HCV positivity: is HCV hiding out?” Journal of Hepatology, vol. 48, supplement 2, p. S222, 2008. View at Publisher · View at Google Scholar
  19. T. N. Q. Pham, C. S. Coffin, and T. I. Michalak, “Occult hepatitis C virus infection: what does it mean?” Liver International, vol. 30, no. 4, pp. 502–511, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. G. H. Haydon, L. M. Jarvis, C. S. Blair et al., “Clinical significance of intrahepatic hepatitis C virus levels in patients with chronic HCV infection,” Gut, vol. 42, no. 4, pp. 570–575, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Barrett, N. Kieran, E. Ryan, J. C. O'Keane, and J. Crowe, “Intrahepatic hepatitis C viral RNA status of serum polymerase chain reaction-negative individuals with histological changes on liver biopsy,” Hepatology, vol. 33, no. 6, pp. 1496–1502, 2001. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. Sugiyasu, N. Yuki, T. Nagaoka et al., “Histological improvement of chronic liver disease after spontaneous serum hepatitis C virus clearance,” Journal of Medical Virology, vol. 69, no. 1, pp. 41–49, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Tomimatsu, H. Endou, H. Takahashi et al., “Negative strand of hepatitis C virus RNA in the liver of patients with chronic hepatitis C after interferon treatment,” Journal of Gastroenterology and Hepatology, vol. 12, no. 9-10, pp. 629–632, 1997. View at Publisher · View at Google Scholar · View at Scopus
  24. T. N. Q. Pham, S. E. Mercer, and T. I. Michalak, “Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles,” Journal of Viral Hepatitis, vol. 16, no. 8, pp. 547–556, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. T. N. Q. Pham, D. King, S. A. MacParland et al., “Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection,” Gastroenterology, vol. 134, no. 3, pp. 812–822, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Hoare, W. T. H. Gelson, S. M. Rushbrook et al., “Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection,” Hepatology, vol. 48, no. 6, pp. 1737–1745, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. T. N. Q. Pham, P. M. Mulrooney-Cousins, S. E. Mercer et al., “Antagonistic expression of hepatitis C virus and alpha interferon in lymphoid cells during persistent occult infection,” Journal of Viral Hepatitis, vol. 14, no. 8, pp. 537–548, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Radkowski, J. F. Gallegos-Orozco, J. Jablonska et al., “Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C,” Hepatology, vol. 41, no. 1, pp. 106–114, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. I. Castillo, E. Rodríguez-Iñigo, J. M. López-Alcorocho, M. Pardo, J. Bartolomé, and V. Carreño, “Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment,” Clinical Infectious Diseases, vol. 43, no. 10, pp. 1277–1283, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Ciancio, A. Smedile, C. Giordanino et al., “Long-term follow-up of previous hepatitis C virus positive nonresponders to interferon monotherapy successfully retreated with combination therapy: are they really cured?” American Journal of Gastroenterology, vol. 101, no. 8, pp. 1811–1816, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. J. A. Quiroga, S. Llorente, I. Castillo et al., “Virus-specific T-cell responses associated with hepatitis C virus (HCV) persistence in the liver after apparent recovery from HCV infection,” Journal of Medical Virology, vol. 78, no. 9, pp. 1190–1197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. J. F. Gallegos-Orozco, J. Rakela, M. J. Rosati, H. E. Vargas, and V. Balan, “Persistence of hepatitis C virus in peripheral blood mononuclear cells of sustained viral responders to pegylated interferon and ribavirin therapy,” Digestive Diseases and Sciences, vol. 53, no. 9, pp. 2564–2568, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Di Liberto, A.-M. Roque-Afonso, R. Kara et al., “Clinical and therapeutic implications of hepatitis C virus compartmentalization,” Gastroenterology, vol. 131, no. 1, pp. 76–84, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. N. Tsuda, N. Yuki, K. Mochizuki et al., “Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy,” Journal of Medical Virology, vol. 74, no. 3, pp. 406–413, 2004. View at Publisher · View at Google Scholar · View at Scopus
  35. T. N. Q. Pham, S. A. MacParland, C. S. Coffin, S. S. Lee, F. R. Bursey, and T. I. Michalak, “Mitogen-induced upregulation of hepatitis C virus expression in human lymphoid cells,” Journal of General Virology, vol. 86, no. 3, pp. 657–666, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. T. N. Q. Pham and T. I. Michalak, “Hepatitis C virus in peripheral blood mononuclear cells of individuals with isolated anti-hepatitis C virus antibody reactivity,” Hepatology, vol. 48, no. 1, pp. 350–351, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. S. A. MacParland, T. N. Q. Pham, C. S. Guy, and T. I. Michalak, “Hepatitis C virus persisting after clinically apparent sustained virological response to antiviral therapy retains infectivity in vitro,” Hepatology, vol. 49, no. 5, pp. 1431–1441, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. K. Katayama, J. Kumagai, Y. Komiya et al., “Titration of hepatitis C virus in chimpanzees for determining the copy number required for transmission,” Intervirology, vol. 47, no. 1, pp. 57–64, 2004. View at Publisher · View at Google Scholar · View at Scopus
  39. P. Halfon, M. Bourlière, D. Ouzan et al., “Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay,” Journal of Clinical Microbiology, vol. 46, no. 6, pp. 2106–2108, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. S. L. George, B. R. Bacon, E. M. Brunt, K. L. Mihindukulasuriya, J. Hoffman, and A. M. Di Bisceglie, “Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients,” Hepatology, vol. 49, no. 3, pp. 729–738, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Maylin, M. Martinot-Peignoux, R. Moucari et al., “Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C,” Gastroenterology, vol. 135, no. 3, pp. 821–829, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. S. Naga, S. H. T. Raghuraman, and J. R. B. Liang, “Minute levels of HCV RNA persist for an extended period of time after clinical recovery from hepatitis C but are ultimately cleared,” in Proceedings of the 15th International Symposium on Hepatitis C Virus and Related Viruses, p. 66, San Antonio, Tex, USA, October 2008.
  43. P. Marcellin, N. Boyer, A. Gervais et al., “Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-α therapy,” Annals of Internal Medicine, vol. 127, no. 10, pp. 875–881, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. A.-M. Roque-Afonso, D. Ducoulombier, G. Di Liberto et al., “Compartmentalization of hepatitis C virus genotypes between plasma and peripheral blood mononuclear cells,” Journal of Virology, vol. 79, no. 10, pp. 6349–6357, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. I. Castillo, J. Bartolomé, J. A. Quiroga, G. Barril, and V. Carreño, “Hepatitis C virus infection in the family setting of patients with occult hepatitis C,” Journal of Medical Virology, vol. 81, no. 7, pp. 1198–1203, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Y. Chen, M. Zeremski, R. Chauhan, I. M. Jacobson, A. H. Talal, and T. I. Michalak, “Persistence of hepatitis C virus during and after otherwise clinically successful treatment of chronic hepatitis C with standard pegylated interferon α-2b and ribavirin therapy,” PLoS ONE, vol. 8, no. 11, Article ID e80078, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Inokuchi, T. Ito, H. Nozawa et al., “Lymphotropic hepatitis C virus has an interferon-resistant phenotype,” Journal of Viral Hepatitis, vol. 19, no. 4, pp. 254–262, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. A. L. Zignego, C. Giannini, M. Monti, and L. Gragnani, “Hepatitis C virus lymphotropism: lessons from a decade of studies,” Digestive and Liver Disease, vol. 39, supplement 1, pp. S38–S45, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Bartolomé, J. M. López-Alcorocho, I. Castillo et al., “Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C,” Journal of Virology, vol. 81, no. 14, pp. 7710–7715, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. T. N. Q. Pham, C. S. Coffin, N. D. Churchill, S. J. Urbanski, S. S. Lee, and T. I. Michalak, “Hepatitis C virus persistence after sustained virological response to antiviral therapy in patients with or without past exposure to hepatitis B virus,” Journal of Viral Hepatitis, vol. 19, no. 2, pp. 103–111, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. J. T. Blackard, N. Kemmer, and K. E. Sherman, “Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences,” Hepatology, vol. 44, no. 1, pp. 15–22, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. V. Falcón, N. Acosta-Rivero, M. Shibayama et al., “Evidences of hepatitis C virus replication in hepatocytes and peripheral blood mononuclear cells from patients negative for viral RNA in serum,” American Journal of Infectious Diseases, vol. 1, pp. 34–42, 2005. View at Publisher · View at Google Scholar
  53. I. Castillo, J. Bartolomé, J. A. Quiroga, G. Barril, and V. Carreño, “Diagnosis of occult hepatitis C without the need for a liver biopsy,” Journal of Medical Virology, vol. 82, no. 9, pp. 1554–1559, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. A. G. Muazzam, S. Qureshi, A. Mansoor et al., “Occult HCV or delayed viral clearance from lymphocytes of Chronic HCV genotype 3 patients after interferon therapy,” Genetic Vaccines and Therapy, vol. 9, no. 1, article 14, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. P. B. Sugden, B. Cameron, R. Bull, P. A. White, and A. R. Lloyd, “Occult infection with hepatitis C virus: friend or foe,” Immunology and Cell Biology, vol. 90, no. 8, pp. 763–773, 2012. View at Publisher · View at Google Scholar · View at Scopus
  56. P. B. Sugden, T. N. Q. Pham, S. Ratnarajah et al., “Rare occurrence of occult hepatitis C virus in apparently uninfected injecting drug users: a two-centre, masked, case-control study,” Journal of Viral Hepatitis, vol. 20, no. 10, pp. 725–728, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. F. Ansaldi, B. Bruzzone, S. Salmaso et al., “Different seroprevalence and molecular epidemiology patterns of hepatitis C virus infection in Italy,” Journal of Medical Virology, vol. 76, no. 3, pp. 327–332, 2005. View at Publisher · View at Google Scholar · View at Scopus
  58. P. M. Kopko and P. V. Holland, “Universal leukocyte reduction,” Current Opinion in Hematology, vol. 7, no. 6, pp. 397–401, 2000. View at Publisher · View at Google Scholar · View at Scopus
  59. L. De Marco, P. Manzini, M. Trevisan et al., “Prevalence and follow-up of occult HCV infection in an Italian population free of clinically detectable infectious liver disease,” PLoS ONE, vol. 7, no. 8, Article ID e43541, 2012. View at Publisher · View at Google Scholar
  60. G. Barril, I. Castillo, M. D. Arenas et al., “Occult hepatitis C virus infection among hemodialysis patients,” Journal of the American Society of Nephrology, vol. 19, pp. 2248–2250, 2008. View at Publisher · View at Google Scholar
  61. I. Castillo, J. Bartolomé, J. A. Quiroga, G. Barril, and V. Carreño, “Long-term virological follow up of patients with occult hepatitis C virus infection,” Liver International, vol. 31, no. 10, pp. 1519–1524, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. F. Bokharaei-Salim, H. Keyvani, S. H. R. Monavari et al., “Occult hepatitis C virus infection in Iranian patients with cryptogenic liver disease,” Journal of Medical Virology, vol. 83, no. 6, pp. 989–995, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. H. Zaghloul and W. El-Sherbiny, “Detection of occult hepatitis C and hepatitis B virus infections from peripheral blood mononuclear cells,” Immunological Investigations, vol. 39, no. 3, pp. 284–291, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. J. M. Cruzado, T. Casanovas-Taltavull, J. Torras, C. Baliellas, S. Gil-Vernet, and J. M. Grinyó, “Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance,” The American Journal of Transplantation, vol. 3, no. 3, pp. 357–360, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Baid-Agrawal, R. Schindler, P. Reinke et al., “Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients,” Journal of Hepatology, vol. 60, no. 5, pp. 928–933, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. P. Halfon, M. Martinot-Peignoux, and P. Cacoub, “The myth of occult hepatitis C infection,” Hepatology, vol. 50, no. 5, article 1675, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. N. Coppola, M. Pisaturo, S. Guastafierro et al., “Absence of occult hepatitis C virus infection in patients under immunosupressive therapy for oncohematological diseases,” Hepatology, vol. 54, no. 4, pp. 1487–1489, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. F. Nicot, N. Kamar, B. Mariamé, L. Rostaing, C. Pasquier, and J. Izopet, “No evidence of occult hepatitis C virus (HCV) infection in serum of HCV antibody-positive HCV RNA-negative kidney-transplant patients,” Transplant International, vol. 23, no. 6, pp. 594–601, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. L. Richiardi, L. de Marco, A. Gillio-Tos et al., “Persistent infection by HCV and EBV in peripheral blood mononuclear cells and risk of non-Hodgkin's lymphoma,” Cancer Epidemiology, vol. 34, no. 6, pp. 709–712, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Casato, D. Lilli, G. Donato et al., “Occult hepatitis C virus infection in type II mixed cryoglobulinaemia,” Journal of Viral Hepatitis, vol. 10, no. 6, pp. 455–459, 2003. View at Publisher · View at Google Scholar · View at Scopus
  71. C. Giannini, F. Giannelli, and A. L. Zignego, “Association between mixed cryogtobulinemia, translocation (14;18), and persistence of occult HCV lymphoid infection after treatment,” Hepatology, vol. 43, no. 5, pp. 1166–1167, 2006. View at Publisher · View at Google Scholar · View at Scopus
  72. S. S. Youssef, A. S. Nasr, T. El Zanaty, R. S. El Rawi, and M. M. Mattar, “Prevalence of occult hepatitis C virus in Egyptian patients with chronic lymphoproliferative disorders,” Hepatitis Research and Treatment, vol. 2012, Article ID 429784, 6 pages, 2012. View at Publisher · View at Google Scholar
  73. M. Farahani, F. Bokharaei-Salim, M. Ghane, A. Basi, P. Meysami, and H. Keyvani, “Prevalence of occult hepatitis C virus infection in Iranian patients with lymphoproliferative disorders,” Journal of Medical Virology, vol. 85, no. 2, pp. 235–240, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. I. Castillo, J. Martinez-Ara, T. Olea et al., “High prevalence of occult hepatitis C virus infection in patients with primary and secondary glomerular nephropathies,” Kidney International, vol. 86, pp. 619–624, 2014. View at Publisher · View at Google Scholar · View at Scopus
  75. J. D. Scott and D. R. Gretch, “Molecular diagnostics of hepatitis C virus infection: a systematic review,” Journal of the American Medical Association, vol. 297, no. 7, pp. 724–732, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. E. Kisiel, M. Radkowski, A. Pawelczyk et al., “Seronegative hepatitis C virus infection in patients with lymphoproliferative disorders,” Journal of Viral Hepatitis, vol. 21, no. 6, pp. 424–429, 2014. View at Publisher · View at Google Scholar · View at Scopus
  77. J. A. Quiroga, S. Llorente, I. Castillo, E. Rodríguez-Iñigo, M. Pardo, and V. Carreño, “Cellular immune responses associated with occult hepatitis C virus infection of the liver,” Journal of Virology, vol. 80, no. 22, pp. 10972–10979, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. V. Carreño, J. Bartolomé, I. Castillo, and J. A. Quiroga, “Occult hepatitis B virus and hepatitis C virus infections,” Reviews in Medical Virology, vol. 18, no. 3, pp. 139–157, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. M. C. Roque-Cuéllar, B. Sánchez, J. R. García-Lozano et al., “Hepatitis C virus-specific cellular immune responses in sustained virological responders with viral persistence in peripheral blood mononuclear cells,” Liver International, vol. 34, no. 6, pp. e80–e88, 2014. View at Publisher · View at Google Scholar · View at Scopus
  80. Y. S. Choi, J. E. Lee, S. J. Nam et al., “Two distinct functional patterns of hepatitis C Virus (HCV)-specific T cell responses in seronegative, aviremic patients,” PLoS ONE, vol. 8, no. 4, Article ID e62319, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. H. R. Rosen, “Emerging concepts in immunity to hepatitis C virus infection,” Journal of Clinical Investigation, vol. 123, no. 10, pp. 4121–4130, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Grakoui, N. H. Shoukry, D. J. Woollard et al., “HCV persistence and immune evasion in the absence of memory T cell help,” Science, vol. 302, no. 5645, pp. 659–662, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. N. H. Shoukry, A. Grakoui, M. Houghton et al., “Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection,” Journal of Experimental Medicine, vol. 197, no. 12, pp. 1645–1655, 2003. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Y. Kim, T. Kuntzen, J. Timm et al., “Spontaneous control of HCV is associated with expression of HLA-B*57 and preservation of targeted epitopes,” Gastroenterology, vol. 140, no. 2, pp. 686–696, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. P. A. Knolle and R. Thimme, “Hepatic immune regulation and its involvement in viral hepatitis infection,” Gastroenterology, vol. 146, no. 5, pp. 1193–1207, 2014. View at Publisher · View at Google Scholar · View at Scopus
  86. Y. Z. Gad, N. Mouas, A. Abdel-Aziz, N. Abousmra, and M. Elhadidy, “Distinct immunoregulatory cytokine pattern in Egyptian patients with occult Hepatitis C infection and unexplained persistently elevated liver transaminases,” Asian Journal of Transfusion Science, vol. 6, no. 1, pp. 24–28, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. N. Mousa, W. Eldars, H. Eldegla et al., “Cytokine profiles and hepatic injury in occult hepatitis C versus chronic hepatitis C virus infection,” International Journal of Immunopathology and Pharmacology, vol. 27, no. 1, pp. 87–96, 2014. View at Google Scholar · View at Scopus
  88. J. K. Flynn, G. J. Dore, M. Hellard et al., “Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment,” Journal of Gastroenterology and Hepatology, vol. 28, no. 11, pp. 1770–1781, 2013. View at Publisher · View at Google Scholar · View at Scopus
  89. L. Zhang, C. Q. Hao, L. Miao, and X. Dou, “Role of Th1/Th2 cytokines in serum on the pathogenesis of chronic hepatitis C and the outcome of interferon therapy,” Genetics and Molecular Research, vol. 13, no. 4, pp. 9747–9755, 2014. View at Publisher · View at Google Scholar
  90. J. J. Feld, J. Grebely, G. V. Matthews et al., “Plasma interferon-gamma-inducible protein-10 levels are associated with early, but not sustained virological response during treatment of acute or early chronic HCV infection,” PLoS ONE, vol. 8, no. 11, Article ID e80003, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. V. Natarajan, S. Kottilil, A. Hazen et al., “HCV in peripheral blood mononuclear cells are predominantly carried on the surface of cells in HIV/HCV co-infected individuals,” Journal of Medical Virology, vol. 82, no. 12, pp. 2032–2037, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. K. Fujiwara, R. D. Allison, R. Y. Wang et al., “Investigation of residual hepatitis C virus in presumed recovered subjects,” Hepatology, vol. 57, no. 2, pp. 483–491, 2013. View at Publisher · View at Google Scholar · View at Scopus
  93. T. Laskus, M. Radkowski, A. Piasek et al., “Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes,” Journal of Infectious Diseases, vol. 181, no. 2, pp. 442–448, 2000. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Ramirez, S. Perez-Del-Pulgar, J. A. Carrion et al., “Hepatitis C virus compartmentalization and infection recurrence after liver transplantation,” American Journal of Transplantation, vol. 9, no. 7, pp. 1591–1601, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. S. V. Kotenko, “IFN-λs,” Current Opinion in Immunology, vol. 23, no. 5, pp. 583–590, 2011. View at Publisher · View at Google Scholar
  96. J. Vera-Otarola, M. I. Barría, U. León et al., “Hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cells of treatment naïve chronically infected patients,” Journal of Viral Hepatitis, vol. 16, no. 9, pp. 633–643, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. P. K. Chandra, L. Bao, K. Song et al., “HCV infection selectively impairs type i but not type III IFN signaling,” American Journal of Pathology, vol. 184, no. 1, pp. 214–229, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Angulo, K. Pino, C. Pavez et al., “Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells-associated hepatitis C virus RNA in chronically infected patients,” Journal of Viral Hepatitis, vol. 20, no. 4, pp. 263–272, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. M. T. Dill, F. H. T. Duong, J. E. Vogt et al., “Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C,” Gastroenterology, vol. 140, no. 3, pp. 1021–1031, 2011. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Marukian, L. Andrus, T. P. Sheahan et al., “Hepatitis C virus induces interferon-lambda and interferon-stimulated genes in primary liver cultures,” Hepatology, vol. 54, no. 6, pp. 1913–1923, 2011. View at Publisher · View at Google Scholar · View at Scopus
  101. O. Bauhofer, A. Ruggieri, B. Schmid, P. Schirmacher, and R. Bartenschlager, “Persistence of HCV in quiescent hepatic cells under conditions of an interferon-induced antiviral response,” Gastroenterology, vol. 143, no. 2, pp. 429–438, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Amanzada, A. Goralczyk, F. Moriconi et al., “Ultra-rapid virological response, young age, low γ-GT/ALT-ratio, and absence of steatosis identify a subgroup of HCV genotype 3 patients who achieve SVR with IFN-α2a monotherapy,” Digestive Diseases and Sciences, vol. 56, no. 11, pp. 3296–3304, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. S. S. Youssef, A. M. Abd El-Aal, A. Saad, M. Hassan Omran, T. El Zanaty, and S. M. Seif, “Impact of IL12B gene rs 3212227 polymorphism on fibrosis, liver inflammation, and response to treatment in genotype 4 Egyptian hepatitis C patients,” Disease Markers, vol. 35, no. 5, pp. 431–437, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. F. Bellanti, G. Vendemiale, E. Altomare, and G. Serviddio, “The impact of interferon lambda 3 gene polymorphism on natural course and treatment of hepatitis C,” Clinical and Developmental Immunology, vol. 2012, Article ID 849373, 9 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. K. D. Ibarra, M. K. Jain, and J. K. Pfeiffer, “Host-based ribavirin resistance influences hepatitis C virus replication and treatment response,” Journal of Virology, vol. 85, no. 14, pp. 7273–7283, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. R. M. Zinkernagel, “Immunology taught by viruses,” Science, vol. 271, no. 5246, pp. 173–178, 1996. View at Publisher · View at Google Scholar · View at Scopus
  107. R. M. Zinkernagel, M. F. Bachmann, T. M. Kündig, S. Oehen, H. Pirchet, and H. Hengartner, “On immunological memory,” Annual Review of Immunology, vol. 14, no. 1, pp. 333–367, 1996. View at Publisher · View at Google Scholar
  108. R. M. Zinkernagel, S. Ehl, P. Aichele, S. Oehen, T. Kündig, and H. Hengartner, “Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity,” Immunological Reviews, vol. 156, pp. 199–209, 1997. View at Publisher · View at Google Scholar · View at Scopus
  109. T. E. Starzl and R. M. Zinkernagel, “Antigen localization and migration in immunity and tolerance,” The New England Journal of Medicine, vol. 339, no. 26, pp. 1905–1913, 1998. View at Publisher · View at Google Scholar · View at Scopus
  110. J. T. Blackard, L. Smeaton, Y. Hiasa et al., “Detection of hepatitis C virus (HCV) in serum and peripheral-blood mononuclear cells from HCV-monoinfected and HIV/HCV-coinfected persons,” Journal of Infectious Diseases, vol. 192, no. 2, pp. 258–265, 2005. View at Publisher · View at Google Scholar · View at Scopus
  111. P. Baré, “Hepatitis C virus and peripheral blood mononuclear cell reservoirs Patricia Baré,” World Journal of Hepatology, vol. 1, no. 1, p. 67, 2009. View at Publisher · View at Google Scholar
  112. M. C. Roque-Cuéllar, B. Sánchez, J. R. García-Lozano, J. M. Praena-Fernández, A. Núñez-Roldán, and J. Aguilar-Reina, “Cellular immune responses and occult infection in seronegative heterosexual partners of chronic hepatitis C patients,” Journal of Viral Hepatitis, vol. 18, no. 10, pp. e541–e549, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. H. Keyvani, F. Bokharaei-Salim, S. H. Monavari et al., “Occult hepatitis C virus infection in candidates for liver transplant with cryptogenic cirrhosis,” Hepatitis Monthly, vol. 13, no. 8, Article ID e11290, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. P. Dzekova Vidimliski, I. Nikolov, N. Matevska Geshkovska, A. Dimovski, L. Rostaing, and A. Sikole, “Occult hepatitis C virus infection: still remains a controversy,” Journal of Medical Virology, vol. 86, no. 9, pp. 1491–1498, 2014. View at Publisher · View at Google Scholar · View at Scopus
  115. L. Gatserelia, L. Sharvadze, M. Karchava et al., “Occurrence of occult HCV infection among HIV infected patients in Georgia,” Georgian Medical News, no. 226, pp. 37–41, 2014. View at Google Scholar
  116. T. Laskus, E. A. Operskalski, M. Radkowski et al., “Negative-strand hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells from anti-HCV-positive/HIV-infected women,” The Journal of Infectious Diseases, vol. 195, no. 1, pp. 124–133, 2007. View at Google Scholar
  117. A. Pawełczyk, N. Kubisa, J. Jabłońska et al., “Detection of hepatitis C virus (HCV) negative strand RNA and NS3 protein in peripheral blood mononuclear cells (PBMC): CD3+, CD14+ and CD19+,” Virology Journal, vol. 10, article 46, 2013. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Z. Rahman, D. S. Ahmed, H. Masud et al., “Sustained virological response after treatment in patients with chronic hepatitis C infection—a five year follow up,” Bangladesh Medical Research Council Bulletin, vol. 39, no. 1, pp. 11–13, 2013. View at Google Scholar · View at Scopus
  119. A. Sood, V. Midha, V. Mehta et al., “How sustained is sustained viral response in patients with hepatitis C virus infection?” Indian Journal of Gastroenterology, vol. 29, no. 3, pp. 112–115, 2010. View at Publisher · View at Google Scholar · View at Scopus
  120. K. Rutter, H. Hofer, S. Beinhardt et al., “Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral,” Alimentary Pharmacology and Therapeutics, vol. 38, no. 2, pp. 118–123, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. C. E. Gordon, K. Uhlig, C. H. Schmid, A. S. Levey, and J. B. Wong, “Long-term viral negativity after Interferon for chronic hepatitis C virus infection in hemodialysis,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 9, pp. 2226–2234, 2011. View at Publisher · View at Google Scholar · View at Scopus
  122. E. G. Giannini, M. Basso, V. Savarino, and A. Picciotto, “Sustained virological response to pegylated interferon and ribavirin is maintained during longterm follow up of chronic hepatitis C patients,” Alimentary Pharmacology & Therapeutics, vol. 31, pp. 502–508, 2010. View at Google Scholar
  123. F. M. Cortés-Mancera, J. C. Restrepo, G. Osorio, S. Hoyos, G. Correa, and M. C. Navas, “Occult hepatitis C virus infection in a re-transplanted patient with liver failure of unknown etiology,” Revista Colombiana de Gastroenterologia, vol. 25, no. 1, pp. 76–85, 2010. View at Google Scholar · View at Scopus
  124. J. A. Quiroga, I. Castillo, M. Pardo, E. Rodríguez-Iñigo, and V. Carreño, “Combined hepatitis C virus (HCV) antigen-antibody detection assay does not improve diagnosis for seronegative individuals with occult HCV infection,” Journal of Clinical Microbiology, vol. 44, no. 12, pp. 4559–4560, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. M. Comar, G. Dal Molin, P. D'Agaro, S. L. Crocè, C. Tiribelli, and C. Campello, “HBV, HCV, and TTV detection by in situ polymerase chain reaction could reveal occult infection in hepatocellular carcinoma: comparison with blood markers,” Journal of Clinical Pathology, vol. 59, no. 5, pp. 526–529, 2006. View at Publisher · View at Google Scholar · View at Scopus
  126. J. A. Quiroga, S. Llorente, I. Castillo et al., “Tracking intrafamilial spread of serologically silent occult HCV infection through humoral and cellular HCV-specific responses,” Journal of Hepatology, vol. 50, supplement 1, p. S149, 2009. View at Google Scholar
  127. F. Fabrizi and P. Martin, “Occult hepatitis C virus infection in hemodialysis,” Journal of the American Society of Nephrology, vol. 19, no. 12, pp. 2248–2250, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. H. Lerat and F. B. Hollinger, “Hepatitis C virus (HCV) occult infection or occult HCV RNA detection?” Journal of Infectious Diseases, vol. 189, no. 1, pp. 3–6, 2004. View at Publisher · View at Google Scholar · View at Scopus
  129. J. W. Ward, “The hidden epidemic of hepatitis C virus infection in the United States: occult transmission and burden of disease,” Topics in Antiviral Medicine, vol. 21, no. 1, pp. 15–19, 2013. View at Google Scholar · View at Scopus
  130. H. S. Dhaliwal and R. V. Nampoothiri, “Daclatasvir plus sofosbuvir for HCV infection,” The New England Journal of Medicine, vol. 370, no. 16, pp. 1560–1561, 2014. View at Publisher · View at Google Scholar · View at Scopus
  131. C. Berasain, M. Betés, A. Panizo et al., “Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology,” Gut, vol. 47, no. 3, pp. 429–435, 2000. View at Publisher · View at Google Scholar · View at Scopus
  132. M. P. Manns, P. J. Pockros, G. Norkrans et al., “Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin,” Journal of Viral Hepatitis, vol. 20, no. 8, pp. 524–529, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. Roche Diagnostics, COBAS AmpliPrep/COBAS TaqMan HCV Test, http://www.roche-diagnostics.us.
  134. Abbott Molecular, http://www.abbottmolecular.com/.
  135. BayerMaterialScience, 2014, http://www.bayermaterialsciencenafta.com/.
  136. G. Li, K. Li, A. S. Lea et al., “In situ hybridization for the detection of hepatitis C virus RNA in human liver tissue,” Journal of Viral Hepatitis, vol. 20, no. 3, pp. 183–192, 2013. View at Publisher · View at Google Scholar · View at Scopus