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Science 2 October 1998:
Vol. 282. no. 5386, pp. 103 - 107
DOI: 10.1126/science.282.5386.103
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Reports

Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-alpha Therapy

Avidan U. Neumann, *dagger Nancy P. Lam, *ddagger Harel Dahari, David R. Gretch, Thelma E. Wiley, Thomas J. Layden, Alan S. Perelson

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha -2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 1012 virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

A. U. Neumann, Department of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel, and Santa Fe Institute, Santa Fe, NM 87501, USA. N. P. Lam, Department of Pharmacy Practice, University of Illinois, Chicago, IL 60612, USA. H. Dahari, Department of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. D. R. Gretch, Hepatitis Laboratory, University of Washington, Seattle, WA 98144, USA. T. E. Wiley and T. J. Layden, Section of Digestive and Liver Diseases, Department of Medicine, University of Illinois, Chicago, IL 60612, USA. A. S. Perelson, Theoretical Division, Los Alamos National Laboratory, NM 87545, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence and questions regarding mathematical modeling and analysis should be addressed. E-mail: neumann{at}macs.biu.ac.il

ddagger    To whom correspondence should be addressed. E-mail: NancyLam{at}uic.edu

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   Abstract »    Full Text »    PDF »
Alpha Interferon Inhibits Hepatitis C Virus Replication in Primary Human Hepatocytes Infected In Vitro.
V. Castet, C. Fournier, A. Soulier, R. Brillet, J. Coste, D. Larrey, D. Dhumeaux, P. Maurel, and J.-M. Pawlotsky (2002)
J. Virol. 76, 8189-8199
   Abstract »    Full Text »    PDF »
Needlestick Transmission of Hepatitis C.
M. S. Sulkowski, S. C. Ray, and D. L. Thomas (2002)
JAMA 287, 2406-2413
   Abstract »    Full Text »    PDF »
Performance of the New Bayer VERSANT HCV RNA 3.0 Assay for Quantitation of Hepatitis C Virus RNA in Plasma and Serum: Conversion to International Units and Comparison with the Roche COBAS Amplicor HCV Monitor, Version 2.0, Assay.
M. Beld, R. Sentjens, S. Rebers, C. Weegink, J. Weel, C. Sol, and R. Boom (2002)
J. Clin. Microbiol. 40, 788-793
   Abstract »    Full Text »    PDF »
Dynamics of bacterial phenotype selection in a colonized host.
G. F. Webb and M. J. Blaser (2002)
PNAS
   Abstract »    Full Text »    PDF »
Evolutionary trends of the first hypervariable region of the hepatitis C virus E2 protein in individuals with differing liver disease severity.
R. Curran, C. L. Jameson, J. K. Craggs, A. M. Grabowska, B. J. Thomson, A. Robins, W. L. Irving, and J. K. Ball (2002)
J. Gen. Virol. 83, 11-23
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Dynamics of Persistent TT Virus Infection, as Determined in Patients Treated with Alpha Interferon for Concomitant Hepatitis C Virus Infection.
F. Maggi, M. Pistello, M. Vatteroni, S. Presciuttini, S. Marchi, P. Isola, C. Fornai, S. Fagnani, E. Andreoli, G. Antonelli, et al. (2001)
J. Virol. 75, 11999-12004
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Longitudinal Evaluation of the Structure of Replicating and Circulating Hepatitis C Virus Quasispecies in Nonprogressive Chronic Hepatitis C Patients.
B. Cabot, M. Martell, J. I. Esteban, M. Piron, T. Otero, R. Esteban, J. Guardia, and J. Gomez (2001)
J. Virol. 75, 12005-12013
   Abstract »    Full Text »    PDF »
Hepatitis C Virus Infection.
G. M. Lauer and B. D. Walker (2001)
N. Engl. J. Med. 345, 41-52
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Vitamin B12 and hepatitis C: Molecular biology and human pathology.
W. B. Lott, S. S. Takyar, J. Tuppen, D. H. G. Crawford, M. Harrison, T. P. Sloots, and E. J. Gowans (2001)
PNAS
   Abstract »    Full Text »
Release of Virus from Lymphoid Tissue Affects Human Immunodeficiency Virus Type 1 and Hepatitis C Virus Kinetics in the Blood.
V. Müller, A. F. M. Marée, and R. J. De Boer (2001)
J. Virol. 75, 2597-2603
   Abstract »    Full Text »
Characterization of Hepatitis C Virus Core-Specific Immune Responses Primed in Rhesus Macaques by a Nonclassical ISCOM Vaccine.
N. K. Polakos, D. Drane, J. Cox, P. Ng, M. J. Selby, D. Chien, D. T. O'Hagan, M. Houghton, and X. Paliard (2001)
J. Immunol. 166, 3589-3598
   Abstract »    Full Text »    PDF »
Investigation of CMV disease in immunocompromised patients.
V C Emery (2001)
J. Clin. Pathol. 54, 84-88
   Abstract »    Full Text »    PDF »
Peginterferon Alfa-2a in Patients with Chronic Hepatitis C.
S. Zeuzem, S. V. Feinman, J. Rasenack, E. J. Heathcote, M.-Y. Lai, E. Gane, J. O'Grady, J. Reichen, M. Diago, A. Lin, et al. (2000)
N. Engl. J. Med. 343, 1666-1672
   Abstract »    Full Text »    PDF »
Conquering Hepatitis C, Step by Step.
D. F. Schafer and M. F. Sorrell (2000)
N. Engl. J. Med. 343, 1723-1724
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Estimating Relative Fitness in Viral Competition Experiments.
A. F. M. Marée, W. Keulen, C. A. B. Boucher, and R. J. De Boer (2000)
J. Virol. 74, 11067-11072
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Replication of hepatitis C virus.
R. Bartenschlager and V. Lohmann (2000)
J. Gen. Virol. 81, 1631-1648
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Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy.
V. C. Emery and P. D. Griffiths (2000)
PNAS
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Quantitative Molecular Analysis of Virus Expression and Replication.
M. Clementi (2000)
J. Clin. Microbiol. 38, 2030-2036
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Translational Control of Viral Gene Expression in Eukaryotes.
M. Gale Jr., S.-L. Tan, and M. G. Katze (2000)
Microbiol. Mol. Biol. Rev. 64, 239-280
   Abstract »    Full Text »    PDF »
Dominant Role of Host Selective Pressure in Driving Hepatitis C Virus Evolution in Perinatal Infection.
A. Manzin, L. Solforosi, M. Debiaggi, F. Zara, E. Tanzi, L. Romanò, A. R. Zanetti, and M. Clementi (2000)
J. Virol. 74, 4327-4334
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Pathogenesis, Natural History, Treatment, and Prevention of Hepatitis C.
T. J. Liang, B. Rehermann, L. B. Seeff, and J. H. Hoofnagle (2000)
Ann Intern Med 132, 296-305
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Genetic Heterogeneity of Hypervariable Region 1 of the Hepatitis C Virus (HCV) Genome and Sensitivity of HCV to Alpha Interferon Therapy.
K. Sandres, M. Dubois, C. Pasquier, J. L. Payen, L. Alric, M. Duffaut, J. P. Vinel, J. P. Pascal, J. Puel, and J. Izopet (2000)
J. Virol. 74, 661-668
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Antiapoptotic and Oncogenic Potentials of Hepatitis C Virus Are Linked to Interferon Resistance by Viral Repression of the PKR Protein Kinase.
M. Gale Jr., B. Kwieciszewski, M. Dossett, H. Nakao, and M. G. Katze (1999)
J. Virol. 73, 6506-6516
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The Dynamics of Human Cytomegalovirus Replication In Vivo.
V. C. Emery, A. V. Cope, E. F. Bowen, D. Gor, and P. D. Griffiths (1999)
J. Exp. Med. 190, 177-182
   Abstract »    Full Text »    PDF »


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