Clinical implications of hepatitis C viral kinetics

Antiviral treatment of patients with chronic hepatitis C can perturb the steady-state of virus production and clearance. From serial measurements of changes in viremia, kinetic information on the dynamics of hepatitis C virus (HCV) replication can be obtained. After a delay of about 9 h due to interferon-alpha pharmacokinetics, the decline of viremia in patients treated with interferon-alpha is characterized by a concave shape. In the first phase (day 1) a rapid dose-dependent decline in viral load is observed. The second phase viral decline (greater than or equal to day 2) shows a much slower decline with no or less pronounced differences between the applied interferon-alpha schedules. While a first phase decline can be observed in almost all patients treated with interferon-alpha, non-responders typically reveal no further decline of viremia during the second phase. Kinetic analysis showed that combination therapy with interferon-alpha plus ribavirin has no direct synergistic antiviral effect in the initial 4 weeks of treatment of HCV-infected patients with 6 MU IFN alpha three times per week. Calculations revealed a minimum virus production and clearance per day in patients with chronic hepatitis C of approximately 10(10)-10(12) virions per day and an in vivo half-life of the virus in the order of a few hours. The high turnover rates of HCV explain the rapid generation of viral diversity and the opportunity for viral escape from the host immune surveillance and antiviral therapy. The implications derived from HCV kinetics comprise the consideration of more aggressive initial dosing regimens (especially daily doses), the possibility to optimize therapy individually not only according to pretreatment parameters but also according to the initial decline of viral load and the perception that eradication of the virus will rely on the half-life of infected cells.