Current Hepatitis Reports

, Volume 10, Issue 3, pp 214–227

Hepatitis C Viral Kinetics in the Era of Direct Acting Antiviral Agents and Interleukin-28B

  • Harel Dahari
  • Jeremie Guedj
  • Alan S. Perelson
  • Thomas J. Layden
Article

Abstract

In the last decade, hepatitis C virus (HCV) kinetics has become an important clinical tool for the optimization of therapy with pegylated-interferon-α (PEG-IFN) and ribavirin (RBV). Mathematical models have generated important insights into HCV pathogenesis, HCV-host dynamics, as well as IFN and RBV modes of action. Clinical trials with direct-acting antiviral agents (DAAs) against various steps of the HCV-life cycle have revealed new viral-kinetic patterns that have not been observed with (PEG)-IFN+RBV. Very recently, studies have shown that single nucleotide polymorphisms (SNPs) in the interleukin-28B (IL28B) gene region were associated with race/ethnicity, and with response to PEG-IFN+RBV. Here, we review our current knowledge of HCV kinetics and related mathematical models during (PEG)-IFN+RBV and/or DAA-based therapies, HCV pathogenesis, and the role of IL28B polymorphism on early HCV kinetics. Better understanding of the mode of actions of drugs and viral kinetics may help to develop new, individualized therapeutic regimens that include DAAs in combination with PEG-IFN+RBV.

Keywords

Mathematical modeling Viral kinetics Direct acting antiviral agents Pegylated interferon-α Ribavirin IL28B polymorphism Hepatitis C virus Interleukin 28B 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hepatitis C fact sheet. Available from: Accessed July 13, 2009. [http://www.who.int/mediacentre/factsheets/fs164/en/]
  2. 2.
    Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2009;138(2):513–21.PubMedCrossRefGoogle Scholar
  3. 3.
    TenCate V, Sainz B Jr, Cotler SJ, Uprichard SL. Potential treatment options and future research to increase hepatitis C virus treatment response rate. Hepat Med. 2010;(2):125–145.Google Scholar
  4. 4.
    Pawlotsky JM, Dahari H, Neumann AU, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. 2004;126(3):703–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Nguyen TT, Sedghi-Vaziri A, Wilkes LB, et al. Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection. J Viral Hepat. 1996;3(2):75–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Nainan OV, Alter MJ, Kruszon-Moran D, et al. Hepatitis C virus genotypes and viral concentrations in participants of a general population survey in the United States. Gastroenterology. 2006;131(2):478–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Zeuzem S, Fried MW, Reddy KR, et al. Improving the clinical relevance of pre-treatment viral load as a predictor of sustained virological response (SVR) in patients infected with hepatitis C genotype 1 treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®). Hepatology. 2006;44 Suppl 1:267A–8A.Google Scholar
  10. 10.
    Zehnter E, Mauss S, John C, et al. Better prediction of SVR in patients with HCV genotype 1 (G1) with peginterferon alfa-2a (PEGASYS) plus ribavirin: Improving differentiation between low (LVL) and high baseline viral load (HVL). Hepatology. 2006;44 Suppl 1:328A.Google Scholar
  11. 11.
    Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282(5386):103–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Dahari H, Sainz Jr B, Perelson AS, Uprichard SL. Modeling subgenomic hepatitis C virus RNA kinetics during treatment with alpha interferon. J Virol. 2009;83(13):6383–90.PubMedCrossRefGoogle Scholar
  13. 13.
    Neumann AU, Lam NP, Dahari H, et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J Infect Dis. 2000;182(1):28–35.PubMedCrossRefGoogle Scholar
  14. 14.
    Guedj J, Rong L, Dahari H, Perelson AS. A perspective on modelling hepatitis C virus infection. J Viral Hepat. 2010;17:825–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Rong L, Perelson AS. Treatment of hepatitis C virus infection with interferon and small molecule direct antivirals: viral kinetics and modeling. Crit Rev Immunol. 2010;30(2):131–48.PubMedGoogle Scholar
  16. 16.
    Dahari H, Layden-Almer JE, Perelson AS, Layden TJ. Hepatitis C viral kinetics in special populations. Curr Hepat Rep. 2008;7(3):97–105.PubMedCrossRefGoogle Scholar
  17. 17.
    • Adiwijaya BS, Hare B, Caron PR, et al. Rapid decrease of wild-type hepatitis C virus on telaprevir treatment. Antivir Ther. 2009;14(4):591–5. Using the biphasic decline model (Eq. 1), the authors suggested that telaprevir effectiveness in blocking HCV production/release and the loss rate of infected cells are significantly higher than with IFN-based therapy.PubMedGoogle Scholar
  18. 18.
    • Dahari H, Araújo ES, Haagmans BL, et al. Pharmacodynamics of PEG-IFN-alpha-2a in HIV/HCV co-infected patients: implications for treatment outcomes. J Hepatol. 2010;53(3):460–7. This is the first modeling paper that couples PEG-IFN-α-2a plasma concentrations with its effectiveness in blocking HCV production, and treatment outcome.PubMedCrossRefGoogle Scholar
  19. 19.
    Dahari H, Lo A, Ribeiro RM, Perelson AS. Modeling hepatitis C virus dynamics: liver regeneration and critical drug efficacy. J Theor Biol. 2007;247(2):371–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Dahari H, Ribeiro RM, Perelson AS. Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology. 2007;46(1):16–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Dahari H, Major M, Zhang X, et al. Mathematical modeling of primary hepatitis C infection: noncytolytic clearance and early blockage of virion production. Gastroenterology. 2005;128(4):1056–66.PubMedCrossRefGoogle Scholar
  22. 22.
    •• Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med. 2010;2(30):30ra32. This theoretical study explains the observed rapid emergence of telaprevir resistant strains during monotherapy.PubMedGoogle Scholar
  23. 23.
    Dahari H, Layden-Almer JE, Kallwitz E, et al. A mathematical model of hepatitis C virus dynamics in patients with high baseline viral loads or advanced liver disease. Gastroenterology. 2009;136(4):1402–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 2006;130(4):1086–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131(2):451–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Brouwer JT, Nevens F, Bekkering FC, et al. Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients. J Hepatol. 2004;40(4):689–95.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferenci P, Laferl H, Scherzer TM, et al. Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response. Gastroenterology. 2010;138(2):503–12. 512 e501.PubMedCrossRefGoogle Scholar
  28. 28.
    Buti M, Lurie Y, Zakharova NG, et al. Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response. Hepatology. 2010;52(4):1201–7.PubMedCrossRefGoogle Scholar
  29. 29.
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292–303.PubMedCrossRefGoogle Scholar
  30. 30.
    • Snoeck E, Chanu P, Lavielle M, et al. A comprehensive hepatitis C viral kinetic model explaining cure. Clin Pharmacol Ther. 2010;87(6):706–13. This study models various observed HCV kinetics (including late viral rebounds, such as viral breakthrough) during SOC and predicts SVR. Some features of the model are discussed in [31].PubMedCrossRefGoogle Scholar
  31. 31.
    Dahari H, Rong L, Layden TJ, Cotler SJ. Hepatocyte proliferation and hepatitis C virus (HCV) kinetics during treatment. Clin Pharmacol Ther. 2011;89(3):353–4Google Scholar
  32. 32.
    Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature. 2005;436(7053):933–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhong J, Gastaminza P, Cheng G, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA. 2005;102(26):9294–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11(7):791–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Lindenbach BD, Evans MJ, Syder AJ, et al. Complete replication of hepatitis C virus in cell culture. Science. 2005;309(5734):623–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Einav S, Gerber D, Bryson PD, et al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol. 2008;26(9):1019–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Yu X, Uprichard SL. Cell-based hepatitis C virus infection fluorescence resonance energy transfer (FRET) assay for antiviral compound screening. Curr Protoc Microbiol. 2010;Chapter 17(17):Unit 17 15.Google Scholar
  38. 38.
    Cho NJ, Dvory-Sobol H, Lee C, et al. Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci Transl Med. 2010;2(15):15ra16.Google Scholar
  39. 39.
    • Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010;465(7294):96–100. This study provides the first clinical validation of an inhibitor of HCV NS5A (BMS-790052). Viral kinetics after one dose of BMS-790052 was characterized by a rapid biphasic decline that persisted in some patients given a 100 mg dose for as long as 6 days. Using the biphasic decline model, Eq. 1, it has been shown that the HCV clearance rate under BMS-790052, is significantly higher than under telaprevir or IFN.PubMedCrossRefGoogle Scholar
  40. 40.
    Pawlotsky JM. Hepatitis virus resistance. In: Fong I, Drlica K, editors. Antimicrobial resistance and implications for the 21st century. Springer; New York, NY, USA, 2008. Pp. 291–323.Google Scholar
  41. 41.
    Thompson AJ, McHutchison JG. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). J Viral Hepat. 2009;16(6):377–87.PubMedCrossRefGoogle Scholar
  42. 42.
    Forestier N, Reesink HW, Weegink CJ, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology. 2007;46(3):640–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology. 2007;46(3):631–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of phase 3 ADVANCE study. Hepatology. 2010;52(Suppl):427A.Google Scholar
  45. 45.
    Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: final results of phase 3 ILLUMINATE study. Hepatology. 2010;52(Suppl):401A.Google Scholar
  46. 46.
    Kieffer TL, Bartels DJ, Sullivan J, et al. Clinical virology results from telaprevir phase 3 study ADVANCE. Hepatology. 2010;52(Suppl):879A.Google Scholar
  47. 47.
    Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705–16.PubMedCrossRefGoogle Scholar
  48. 48.
    Vierling J, Poordad F, Lawitz E, et al. Once daily narlaprevir (SCH 900518) in combination with peginterferon alfa-2b/ribavirin for treatment-naive patients with genotype-1 chronic hepatitis C: interim results from the NEXT-1 study. Hepatology 2009;50(6):3A–4A.Google Scholar
  49. 49.
    Sulkowski M, Bourliere M, Bronowicki J-P, et al. SILEN-C2: early antiviral activity and safety of BI 201335 combined with pegintergeron alfa-2a and ribavirin (PEGIFN/RBV) in chronic HCV genotype-1 patients with non-response to PEGIFN/RBV. J Hepatol. 2010;52 Suppl 1:S462–3.CrossRefGoogle Scholar
  50. 50.
    Sulkowski MS, Ferenci P, Emanoil C, et al. SILEN-C1: early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype 1 HCV infection. In: The 60th meeting of the American Association for the Study of Liver Diseases (AASLD); Boston, MA, USA, 2009. Abstract LB3.Google Scholar
  51. 51.
    Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010;138(2):447–62.PubMedCrossRefGoogle Scholar
  52. 52.
    Reesink HW, Fanning GC, Farha KA, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138(3):913–21.PubMedCrossRefGoogle Scholar
  53. 53.
    Morcos PN, Kulkarni R, Ipe D, et al. Pharmacokinetics/pharmacodynamics (PK/PD) of combination R7227 and R7128 therapy from INFORM-1 demonstrates similar early HCV viral dynamics when R7227 is combined with either PEG-IFN/Ribavirin (SOC) or R7128. Hepatology. 2009;50(S4):1041A.Google Scholar
  54. 54.
    Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132(5):1767–77.PubMedCrossRefGoogle Scholar
  55. 55.
    Herrmann E, Zeuzem S, Sarrazin C, et al. Viral kinetics in patients with chronic hepatitis C treated with the serine protease inhibitor BILN 2061. Antivir Ther. 2006;11(3):371–6.PubMedGoogle Scholar
  56. 56.
    Panorchan P, Nachbar R, Saltzman J, et al. Evaluation of the dose-response relationship to short-term monotherapy with the hcv protease inhibitor, mk-7009. In: 2nd American Conference on Pharmacometrics (ACoP). 2009.Google Scholar
  57. 57.
    Ramratnam B, Bonhoeffer S, Binley J, et al. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet. 1999;354(9192):1782–5.PubMedCrossRefGoogle Scholar
  58. 58.
    • Dahari H, Guedj J, Cotler SJ, et al. Higher hepatitis C virus (HCV) clearance rates during treatment with direct acting agents compared to interferon-alpha. Hepatology 2010;52(Suppl)718A–9A. This study shows that the HCV clearance rate in serum is higher than previuosly estimated under IFN-based treatments and suggests that in the era of DAAs, intracellular features of HCV dynamics are needed to be included in models in order to explain these new HCV kinetics.Google Scholar
  59. 59.
    Dahari H, Shudo E, Cotler SJ, et al. Modelling hepatitis C virus kinetics: the relationship between the infected cell loss rate and the final slope of viral decay. Antivir Ther. 2009;14(3):459–64.PubMedGoogle Scholar
  60. 60.
    • Guedj J, Neumann AU. Understanding hepatitis C viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics. J Theor Biol. 2010;267(3):330–40. This theoretical paper explores the possibility that the new patterns of viral kinetics observed with DAAs (rapid decline of wild-type virus and drug resistance related viral breakthrough) may be attributed to the dynamics of intracellular HCV RNA.PubMedCrossRefGoogle Scholar
  61. 61.
    Adiwijaya BS, Herrmann E, Hare B, et al. A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants. PLoS Comput Biol. 2010;6(4):e1000745.PubMedCrossRefGoogle Scholar
  62. 62.
    Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–50.PubMedCrossRefGoogle Scholar
  63. 63.
    McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827–38.PubMedCrossRefGoogle Scholar
  64. 64.
    Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399–401.PubMedCrossRefGoogle Scholar
  65. 65.
    Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41(10):1100–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138(4):1338–45. 1345 e1331–1337.PubMedCrossRefGoogle Scholar
  68. 68.
    Rauch A, Rohrbach J, Bochud PY. REVIEW: the recent breakthroughs in the understanding of host genomics in hepatitis C. Eur J Clin Invest. 2010;40(10):950–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Ahlenstiel G, Booth DR, George J. IL28B in hepatitis C virus infection: translating pharmacogenomics into clinical practice. J Gastroenterol. 2010;45(9):903–10.PubMedCrossRefGoogle Scholar
  70. 70.
    Imazeki F, Yokosuka O, Omata M. Impact of IL-28B SNPs on control of hepatitis C virus infection: a genome-wide association study. Expert Rev Anti Infect Ther. 2010;8(5):497–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Akkarathamrongsin S, Sugiyama M, Matsuura K, et al. High sensitivity assay using serum sample for IL28B genotyping to predict treatment response in chronic hepatitis C patients. Hepatol Res. 2010;40(10):956–62.PubMedCrossRefGoogle Scholar
  72. 72.
    McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138(7):2307–14.PubMedCrossRefGoogle Scholar
  73. 73.
    Stattermayer AF, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2010, In press.Google Scholar
  74. 74.
    Askarieh G, Alsio A, Pugnale P, et al. Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepatology. 2010;51(5):1523–30.PubMedCrossRefGoogle Scholar
  75. 75.
    Darling JM, Aerssens J, Fanning GC, et al. Quantitation of pretreatment serum IP-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response. Hepatology. 2010;52(Suppl):382A–3A.Google Scholar
  76. 76.
    Howell CD, Thompson AJ, Ryan K, et al. IL28B genetic variation association with early viral kinetics and SVR in HCV henotype 1 the VIRAHEP-C study. J Hepatol. 2010;52 Suppl 1:S451.CrossRefGoogle Scholar
  77. 77.
    Neumann AU, Bibert S, Haagmans B, et al. IL28B polymorphism is significantly correlated with IFN anti-viral effectiveness already on first day of pegylated interferon-a and ribavirin therapy of chronic HCV infection. J Hepatol. 2010;52 Suppl 1:S468.CrossRefGoogle Scholar
  78. 78.
    Trippler M, Schumacher S, Poggenpohi L, et al. Immediate and early antiviral responses to Peg-IFN or consensus IFN and ribavirin therapy for HCV correlate with the “upstream-of-IL28B” SNP (rs12979860). Hepatology. 2010;52(Suppl):1229A.Google Scholar
  79. 79.
    • Araújo ES, Dahari H, Cotler SJ, et al. Pharmacodynamics of PEG-IFN alpha-2a and HCV response as a function of IL28B polymorphism in HIV/HCV co-infected patients. J Acquir Immune Defic Syndr. 2011;56(2):95–9. This is the first paper that explores the association among early viral kinetic and PEG-IFN-α-2a pharmacodynamic parameters and IL28B genotypes.Google Scholar
  80. 80.
    Araújo ES, Dahari H, Neumann AU, et al. Very early prediction of response to HCV treatment with peg-IFN-alfa-2a and ribavirin in HIV/HCV coinfected patients. J Viral Hepat. 2011;18(4):e52–60.Google Scholar
  81. 81.
    Marcello T, Grakoui A, Barba-Spaeth G, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131(6):1887–98.PubMedCrossRefGoogle Scholar
  82. 82.
    Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010;139(2):499–509.PubMedCrossRefGoogle Scholar
  83. 83.
    Thompson AJ, Muir AJ, Sulkowski MS, et al. IL28B Polymorphism Improves Viral Kinetics and Is the Strongest Pre-treatment Predictor of SVR in HCV-1 Patients. Gastroenterology 2010:15.Google Scholar
  84. 84.
    Zeuzem S, Herrmann E, Lee JH, et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology. 2001;120(6):1438–47.PubMedCrossRefGoogle Scholar
  85. 85.
    Pilli M, Zerbini A, Penna A, et al. HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV project). Gastroenterology. 2007;133(4):1132–43.PubMedCrossRefGoogle Scholar
  86. 86.
    Thompson AJ, Clark PJ, Zhu M, et al. Genome wide-association study identifies IL28B polymorphism to be associated with baseline ALT and hepatic necro-inflammatory activity in chronic hepatitis C patients enrolled in the IDEAL study. Hepatology. 2010;52(Suppl):1220A.Google Scholar
  87. 87.
    Thompson AJ, Clark PJ, Fellay J, et al. IL28B genotype is not associated with advanced hepatic fibrosis in chronic hepatitis C patients enrolled in the IDEAL study. Hepatology. 2010;52(Suppl):437A.Google Scholar
  88. 88.
    Barreiro P, Pineda JA, Rallon N, et al. Influence of Interleukin-28B Single Nucleotide Polymorphisms (SNP) on Progression to Liver Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients In: ICAAC: September 12–15 2010; Boston; 2010.Google Scholar
  89. 89.
    Rallon NI, Naggie S, Benito JM, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS. 2010;24(8):F23–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Montes-Cano MA, Garcia-Lozano JR, Abad-Molina C, et al. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology 2010;52(1):33–7.Google Scholar
  91. 91.
    Pang PS, Planet PJ, Glenn JS. The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy. PLoS One. 2009;4(8):e6579.PubMedCrossRefGoogle Scholar
  92. 92.
    Araújo ES, Melo CE, Martins LP, et al. Brazilian profile of IL28-B Single Nucleotide Polymorphism (SNP): a retrospective analysis and possible consequences for Interferon-alpha based therapies. Hepatology. 2010;52(Suppl):779A.Google Scholar
  93. 93.
    McHutchison JG, Goldstein DB, Shianna K, et al. IL28B SNP geographical distribution and antiviral responses in a 28-day Phase 2a trial of PSI-7977 daily dosing plus PEG-IFN/RBV. Hepatology. 2010;52(Suppl):711A.Google Scholar
  94. 94.
    Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52(2):421–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Muir AJ, Lawitz E, Rodriguez-Torres M, et al. IL28B polymorphism and kinetics of antiviral activity for ANA598 in combination with pegylated interferon α2A plus ribavirin in treatment-naïve genotype-1 chronic HCV patients. Hepatology. 2010;52(Suppl):1200A.Google Scholar
  96. 96.
    Layden JE, Layden TJ, Reddy KR, et al. First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline. J Viral Hepat. 2002;9(5):340–5.PubMedCrossRefGoogle Scholar
  97. 97.
    Cotler SJ, Layden JE, Neumann AU, Jensen DM. First phase hepatitis c viral kinetics in previous nonresponders patients. J Viral Hepat. 2003;10(1):43–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Colombatto P, Civitano L, Oliveri F, et al. Sustained response to interferon-ribavirin combination therapy predicted by a model of hepatitis C virus dynamics using both HCV RNA and alanine aminotransferase. Antivir Ther. 2003;8(6):519–30.PubMedGoogle Scholar
  99. 99.
    Colombatto P, Ciccorossi P, Maina AM, et al. Early and accurate prediction of Peg-IFNs/ribavirin therapy outcome in the individual patient with chronic hepatitis C by modeling the dynamics of the infected cells. Clin Pharmacol Ther. 2008;84(2):212–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Herrmann E, Lee JH, Marinos G, et al. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology. 2003;37(6):1351–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Reluga TC, Dahari H, Perelson AS. Analysis of hepatitis C virus infection models with hepatocyte homeostasis. SIAM J Appl Math. 2009;69(4):999–1023.PubMedCrossRefGoogle Scholar
  102. 102.
    Talal AH, Ribeiro RM, Powers KA, et al. Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders. Hepatology. 2006;43(5):943–53.PubMedCrossRefGoogle Scholar
  103. 103.
    Rozenberg L, Haagmans BL, Neumann AU, et al. Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics. AIDS. 2009;23(18):2439–50.PubMedCrossRefGoogle Scholar
  104. 104.
    Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004;432(7019):922–4.PubMedCrossRefGoogle Scholar
  105. 105.
    Brunetto MR, Colombatto P, Bonino F. Bio-mathematical models of viral dynamics to tailor antiviral therapy in chronic viral hepatitis. World J Gastroenterol. 2009;15(5):531–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Sarrazin C, Schwendy S, Moeller B, et al. Completely individualized treatment durations with peginterferon-alfa-2b and ribavirin in HCV genotype 1-infected patients and importance of IL28B genotype (INDIV-2 study). Hepatology. 2010;52(Suppl):384A.Google Scholar
  107. 107.
    Mangia A, Thompson AJ, Santoro R, et al. Rapid virological response (RVR) vs IL28B CC genotype in HCV-1 infected patients treated with an individualized course of peginterferon and weight based ribavirin. Hepatology. 2010;52(Suppl):750A.Google Scholar
  108. 108.
    Poordad F, McCone J, Bacon BR, et al. Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin(P/R) for treatment-naive patients with hepatitis C virus (HCV) genotype (G) 1: SPRINT-2 final results. Hepatology. 2010;52(Suppl):402A.Google Scholar
  109. 109.
    Kannan RP, Hensley LL, Evers LE, et al. Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Entry to Mitosis. J Virol, 2011; in press.Google Scholar
  110. 110.
    Chevaliez S, Hézode C, Soulier A, et al. High-Dose Pegylated Interferon-α and Ribavirin in Nonresponder Hepatitis C Patients and Relationship With IL-28B Genotype (SYREN Trial). Gasteroenterology, 2011; in press.Google Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA)  2011

Authors and Affiliations

  • Harel Dahari
    • 1
    • 2
  • Jeremie Guedj
    • 2
  • Alan S. Perelson
    • 2
  • Thomas J. Layden
    • 1
  1. 1.Department of Medicine, Section of HepatologyThe University of Illinois at ChicagoChicagoUSA
  2. 2.Theoretical Biology and Biophysics, MS-K710, Los Alamos National LaboratoryLos AlamosUSA

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