Hepatitis C virus dynamics in vivo: Effect of ribavirin and interferon alfa on viral turnover

Treatment of patients with chronic hepatitis C with recombinant interferon alfa (rIFN‐α) can cause a decrease of serum transaminases and hepatitis C virus (HCV) RNA. Recent trials evaluating combination therapy of IFN‐α and ribavirin suggested a potential synergistic effect. From serial measurements of serum HCV RNA concentrations following treatment‐induced perturbation of the balance between virus production and clearance, we compared the antiviral efficacy of both IFN‐α alone and IFN‐α in combination with ribavirin. Chronically HCV‐infected patients were treated with either 3 × 3 MU or 3 × 6 MU rIFN‐α per week or 3 × 6 MU rIFN‐α plus 14 mg/kg of body weight ribavirin per day. The time‐dependent HCV RNA concentrations during antiviral treatment were analyzed by iterative least‐squares regression. After initiation of antiviral therapy, HCV RNA declined exponentially below the detection limit of the reverse‐transcription polymerase chain reaction assay (1,000 HCV RNA molecules per milliliter) in 10 of 26 (39%), 10 of 19 (53%), and 10 of 18 patients (56%) treated with 3 × 3 MU, 3 × 6 MU rIFN‐α without and with ribavirin, respectively. Viral clearance from serum was faster in patients treated with 3 × 6 MU rIFN‐α (t1/2 = 0.23 ± 0.15) compared with patients treated with 3 × 3 MU rIFN‐α per week (0.67 ± 0.36 days) (P < .004). However, half‐lives of viral clearance were similar in patients treated with rIFN‐α or rIFN‐α plus ribavirin. For virus release from infected hepatocytes, absence and presence of ribavirin yielded half‐lives of t1/2= 2.54 ± 2.10 and t1/2 = 1.99 ± 1.70, respectively, indicating that ribavirin does not significantly inhibit HCV production. In conclusion, the data of the present study indicate that higher rIFN‐α doses accelerate viral clearance from serum. Ribavirin (14 mg/kg/d), however, lacks synergistic antiviral effects in the treatment of chronic hepatitis C with 3 × 6 MU rIFN‐α per week.