Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy.
The balance of virus production and clearance for untreated patients with chronic hepatitis C changes into a decline of viraemia when initiating effective anti-viral treatment. During the first phase of interferon-alpha (IFN-a) therapy, the kinetics of the viral load is characterised by a rapid dose-dependent decline starting after a delay of about eight to nine hours. This early response can be observed for almost all patients treated with IFN-a. After about 24 to 48 hours, the viral decline slows down leading to a second phase with a relatively stable exponential decay. Some non-responding patients show a nearly constant viraemia and some even a rebound throughout this second phase. Kinetic models allow the estimation of rates of viral production and clearance and reveal high turnover rates of hepatitis C virus (HCV) and an in vivo half-life of hepatitis C virions of a few hours, only. Due to the continuous and high replication rate in vivo, the low fidelity of the ribonucleic acid (RNA)-dependent RNA polymerase, and the immune surveillance of the host, HCV exists in an individual patient as a heterogeneous population of related viruses (quasispecies). A high degree of quasispecies variability correlates with a lower response to IFN-a therapy. Changes of the quasispecies population are more pronounced after initiation of treatment with IFN-a or interleukin-12 than during the natural course of disease. Ribavirin, however, has not been found to affect the HCV quasispecies population. Identification of a specific region within an envelope-encoding gene as the most variable region of HCV and as a critical neutralisation domain suggests that viral escape mechanisms are a possible cause for chronification and poses a major challenge for the development of a broadly reactive vaccine against HCV.
Zeuzem
S
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Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universit t, Frankfurt am Main, Germany.
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005814:Genes, Viral / Q000235:genetics; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D018664:Interleukin-12 / Q000627:therapeutic use; D007700:Kinetics; D012254:Ribavirin / Q000627:therapeutic use; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000235:genetics; D014761:Viral Hepatitis Vaccines; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy; D014771:Virion / Q000187:drug effects / Q000235:genetics
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D016898:Interferon-alpha; D014759:Viral Envelope Proteins; D014761:Viral Hepatitis Vaccines; D018664:Interleukin-12; D012254:Ribavirin