Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon

Abstract

A dynamic equilibrium between viral production and clearance characterizes untreated chronic hepatitis C viral infection. After initiating antiviral treatment, a typical multiphasic decay of viremia can be observed and analyzed using mathematical models. To elucidate the antiviral mechanism of ribavirin when used in combination with (pegylated) interferon alfa, we investigated kinetic parameters in patients with chronic hepatitis C treated with either peginterferon ␣-2a with or without ribavirin and standard interferon ␣-2b plus ribavirin for 48 weeks. Serum HCV RNA was measured frequently before, during, and at the end-of-treatment and the follow-up period. By using an appropriate model for viral dynamics, kinetic parameters were derived from nonlinear, least square fitting of serum HCV RNA quantifications. The first phase of viral decay (day 1) and the second phase of viral decay (days 2 to 21) were similar for all treatment groups. After about 7 to 28 days, a third phase of viral decay was seen in several patients, and this phase of decay was significantly faster in patients treated with peginterferon ␣-2a plus ribavirin compared with those treated with peginterferon ␣-2a alone. The decay of this third phase was associated with the virologic end-of-treatment response and sustained virologic response. In conclusion, the third-phase decay of initial viral kinetics, which may represent a treatment-enhanced degradation of infected cells, was more pronounced in patients treated with peginterferon ␣-2a plus ribavirin. This finding suggests that combination treatment leads to a better restoration of the patient's immune response. C hronic infection with hepatitis C virus (HCV) is characterized by a dynamic equilibrium between virus production and clearance. 1,2 A characteristic biphasic or multiphasic initial decline of serum HCV RNA is observed when this equilibrium is disturbed by interferon alfa and can be analyzed mathematically. 1-3 Viral kinetic models estimated a very short half-life of free hepatitis C virions in vivo (Ͻ5 hours) and suggested that a rapid first phase (day 1) of viral decline relates to the decay of free viral particles, whereas the much slower second phase (days 2 to 14) of viral decline reflects the clearance of productively infected cells. Moreover, a typical biphasic decay could be explained if interferon has a single therapeutic effect of partially blocking viral production. 1-3 Kinetic analyses were central to our current understanding of antiviral therapy and have influenced approaches toward treatment of patients with chronic hepatitis C. 4 New results indicate that a third phase of viral decay can be present and may be due to suppression of the immune response during chronic HCV infection and a restoration of the cellular immune response that occurs when the serum viral load declines below an individual threshold. 5 Wide fluctuations in the plasma concentration of interferon are seen because of its short elimination half-life (4 to 10 hours) and render mathematical modeling of HCV ki...

Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C

“…The study was designed to explore the effect of telaprevir in combination with peginterferon on HCV kinetics, and the safety and pharmacokinetics of this combination. The median change in HCV RNA from baseline to day 15 in patients who received placebo and peginterferon alfa-2a was Ϫ1.09 log 10 ; this result is consistent with other studies of interferon monotherapy in patients with genotype 1 hepatitis C. 6,7,11 As in the prior phase 1b study, 4 telaprevir demonstrated substantial antiviral activity: in the 8 patients who received telaprevir alone, the median change from baseline to day 15 was Ϫ3.99 log 10 , and 1 patient achieved undetectable HCV RNA levels. The median change from baseline in HCV RNA of Ϫ5.5 log 10 in the telaprevir and peginterferon alfa-2a group and the undetectable HCV RNA levels in 4 patients in this group confirmed the hypothesis that telaprevir in combination with peginterferon would result in a greater antiviral effect than telaprevir alone.…”

Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

“…23,24 Similarly, declines ranging from 0.86 log 10 to 1.08 log 10 have been reported for HCV patients injected once with 180 g pegylated IFN-␣-2a. 24,25 Therefore, comparison of immune and antiviral activities induced by CPG 10101 and IFN suggests that CPG 10101 may provide similar antiviral effects and modulation of the innate immune response.…”

Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels

“…[15][16][17]23,25,26 Here, viral kinetics in 20 patients with chronic hepatitis C and persistently normal ALT levels and 19 patients with elevated ALT levels were analyzed. The first-phase decline of the viral load is mainly determined by the clearance rate of free viral particles c and the effectiveness of blocking virus production ⑀.…”

“…Viral Kinetic Model. Viral kinetics were calculated according to the kinetic model described by Herrmann et al 15 Compartments were used for the free viral load, productively infected, and uninfected hepatocytes. Constant rates were assumed for clearance of free virus (c), infected cell loss (␦), virus production, and de novo infection.…”

“…[15][16][17] Therefore, in the present study, viral kinetics were analyzed in patients with chronic hepatitis C and persistently normal ALT levels to obtain information about the efficacy of combination therapy in blocking viral production (⑀), the clearance rate (c), the pretreatment infected cell loss (␦), and the infected cell loss during therapy (m␦). 15 Viral kinetic parameters were compared with data obtained from patients with chronic hepatitis C and elevated ALT levels.…”