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

Abstract

Treatment of patients with chronic hepatitis C with recombinant interferon alfa (rIFN-␣) can achieve clearance of the hepatitis C virus (HCV) from serum and liver. However, the overall sustained virological response to IFN-␣ monotherapy is less than 20%. 1,2 Additional clinical trials have been conducted to evaluate alternative treatment modalities in chronic hepatitis C, including therapy with ribavirin. While ribavirin monotherapy revealed no consistent effect on HCV RNA relative to placebo, 3,4 results of combination therapy with subcutaneously administered rIFN-␣ and orally administered ribavirin suggested a potential synergistic effect. [5][6][7] Ribavirin (1-␤-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is a synthetic purine nucleoside that is structurally similar to guanosine. The drug rapidly enters eukaryotic cells, and after intracellular phosphorylation exhibits virustatic activity against a broad spectrum of DNA and RNA viruses. Several possible mechanisms of action have been proposed, including depletion of the intracellular guanosine triphosphate pools, synthesis of RNA with abnormal 5Јcap structures, and inhibition of viral polymerase activity. Furthermore, ribavirin has detectable effects on host immune responses. The detailed mechanism of action, however, is unknown. 4,8 In the present study, we treated patients chronically infected with HCV with either 3 ϫ 3 MU rIFN-␣ per week, 3 ϫ 6 MU rIFN-␣ per week, or 3 ϫ 6 MU rIFN-␣ per week plus 14 mg/kg of body weight ribavirin per day to perturb the balance between virus production and clearance. From serial measurements of changes in viremia in patients responding to antiviral therapy, we obtained kinetic information on the dynamics of HCV replication in vivo. Numerical data modeling was performed to compare the direct antiviral efficacy of the three different treatment schedules. PATIENTS AND METHODSIn this study, 26 patients chronically infected with HCV were treated with 3 MU rIFN-␣ three times per week subcutaneously. In a different cohort of 37 patients, we administered 6 MU rIFN-␣ three times per week subcutaneously. Eighteen patients of this cohort were randomized to receive ribavirin (14 mg per kg of body weight, i.e., 900-1,200 mg) in two divided doses orally per day. Duration of treatment is scheduled for 12 months; the trials are ongoing. All patients were previously untreated, and the diagnosis of chronic hepatitis C was based on elevated serum transaminase levels, histological examination, and the consistent detection of anti-HCV antibodies (third-generation assay) and HCV RNA. All patients were hepatitis B surface antigen-negative and negative for the antibody to the human immunodeficiency virus type 1 and type 2. Blood samples were obtained 4 and 1 week before initiation of treatment and subsequently at days 0, 1, 3, 7, 14, 21, 28, and 56. Serum was prepared under a laminar flow bench and frozen at Ϫ80°C. Serum HCV RNA levels were quantified as recently described in detail. [9][10][11] Abbreviations: rIFN-␣, recombinant interferon ...

A Potent Antiviral Effect on Hepatitis C Viral Dynamics in Serum and Peripheral Blood Mononuclear Cells During Combination Therapy With High–Dose Daily Interferon Alfa Plus Ribavirin and Intravenous Twice–Daily Treatment With Interferon Beta

“…36 Those reports differ from ours in several fundamental ways, including: 1) the clinical characteristics of the cases selected as the subjects; 2) sensitivity and linearity of HCV-RNA quantitation used in the HCV dynamics analysis; and 3) the IFN treatment regimens (doses and intervals). First, while previous studies included virologically heterogeneous patients as the subjects, 36 we selected virologically homogenous cases assessed by viral genotype, baseline viral load, and the number of ISDR mutations in the NS5A region of the HCV genome. In our subjects, no significant difference in the number of ISDR mutations was found among the different treatment groups.…”

Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence

“…[11][12][13][14][15] Although these studies have undoubtedly provided insight into HCV kinetics, the reported half life (t 1/2 ) of hepatitis C virions has varied greatly among studies. Neumann et al reported the virion t 1/2 to be 2.7 hours, with production and clearance rates of 10 12 virions/day.…”

Comparison of Serum Hepatitis C Virus (HCV) RNA and Core Antigen Levels in Patients Coinfected with Human Immunodeficiency Virus and HCV and Treated with Interferon plus Ribavirin

“…Two early phases of viral elimination were observed with SVR, as previously described for HCV-infected, treated patients: a very early phase with a rapid viral decline, before W4, and a second phase with a slower decline, between W4 and W12 (15,26). In RR, the first phase of decrease was slower than that of SVR and was prolonged up to W12.…”

“…In RR, the first phase of decrease was slower than that of SVR and was prolonged up to W12. Indeed, it was shown that the rate of the phase 2 decay correlated closely with that of SVR to IFN-based treatment regimens (26). Especially for NR, a very weak decline was observed before W12.…”