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-alpha) can cause a decrease of serum transaminases and hepatitis C virus (HCV) RNA. Recent trials evaluating combination therapy of IFN-alpha 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-alpha alone and IFN-alpha in combination with ribavirin. Chronically HCV-infected patients were treated with either 3 x 3 MU or 3 x 6 MU rIFN-alpha per week or 3 x 6 MU rIFN-alpha 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 x 3 MU, 3 x 6 MU rIFN-alpha without and with ribavirin, respectively. Viral clearance from serum was faster in patients treated with 3 x 6 MU rIFN-alpha (t1/2 = 0.23 +/- 0.15) compared with patients treated with 3 x 3 MU rIFN-alpha per week (0.67 +/- 0.36 days) (P < .004). However, half-lives of viral clearance were similar in patients treated with rIFN-alpha or rIFN-alpha 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-alpha 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 x 6 MU rIFN-alpha per week.
Zeuzem
S
S
Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt a.M., Germany.
Schmidt
J M
JM
Lee
J H
JH
von Wagner
M
M
Teuber
G
G
Roth
W K
WK
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D015331:Cohort Studies; D004338:Drug Combinations; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006526:Hepatitis C / Q000097:blood / Q000628:therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004338:Drug Combinations; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase