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

Abstract

Hepatitis C virus (HCV) is known to infect and replicate within peripheral blood mononuclear cells (PBMC), thereby enabling the direct evaluation of antiviral mechanisms by analyzing HCV dynamics in PBMC. To address potential molecular differences associated with distinct antiviral regimens, we studied HCV dynamics in both serum and PBMC in 44 patients with HCV genotype 1b and high viral load who were randomly assigned to the following 4 different treatment groups: 1) combination therapy with 6 MU daily of interferon alfa 2b (IFN‐α2b) plus 800 mg of ribavirin; 2) monotherapy with 6 MU daily of IFN‐α2b; 3) monotherapy with twice‐daily intravenous administration with 3MU of IFN‐β; and 4) monotherapy with daily intravenous administration with 6 MU of IFN‐β. HCV‐RNA levels were measured serially using highly sensitive real‐time detection polymerase chain reaction (PCR). HCV dynamics in both the serum and PBMC showed a “biphasic” pattern. The exponential decay slopes of the second phase were significantly higher in the combination or twice‐daily dosing regimen groups compared with groups 2 or 4 (0.10 ± 0.08 vs. 0.02 ± 0.09 or 0.16 ± 0.09 vs. 0.02 ± 0.04 day−1; P < .05 or P < .0005, respectively). Moreover, the viral half‐lives in the second phase were significantly shorter in these groups (73.2 ± 42.5 vs. 240.1 ± 120.7 or 56.0 ± 44.6 vs. 361.6 ± 293.5 hours; P < .05 or P < .05, respectively). Additionally, the slope of HCV decline in PBMC tended to be higher in the combination regimens, as compared with monotherapy. Taken together, our data on HCV dynamics provide molecular insight into utilization of combination or twice‐daily dosing regimens to increase rates of sustained viral eradication of HCV.

Safety of interferon β treatment for chronic HCV hepatitis

“…Several studies comparing the safety of IFNβ and IFNα have been performed [29,30,[38][39][40][41][42] . Frosi et al [38] compared IFNα and IFNβ in 20 naïve patients treated for 6 months and did not observe any significant differences between the two treatment groups in terms of the frequency of adverse events.…”

Differential distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells

“…Interestingly, considering viral dynamics such as virus half-life, the suppressing effect on viral replication observed through treatment appears consistently slower in PBMCs than in serum. 20 On the basis of these studies, one can argue that a specific replicative dynamics of HCV exists in PBMCs.…”

“…Interestingly, considering viral dynamics such as virus half-life, the suppressing effect on viral replication observed through treatment appears consistently slower in PBMCs than in serum. 20 On the basis of these studies, one can argue that a specific replicative dynamics of HCV exists in PBMCs.The relationship between quasispecies and replication in PBMCs is unclear. In a previous study we demonstrated, in the serum of a patient chronically infected with HCV, 21 the coexistence of internal ribosome entry site (IRES) quasispecies segregating according to their respective translation efficiencies in lymphoid and nonlymphoid optimal IRES.…”

Prediction of a sustained viral response in chronic hepatitis C patients who undergo induction therapy with double filtration plasmapheresis plus interferon-β/ribavirin

“…These observations demonstrate that while the half-life of venously-administered IFN-β in the blood is very short, the blood levels are maintained in the effective treatment range with twice daily administration (15). In addition, Asahina et al analyzed HCV dynamics in serum and peripheral blood mononuclear cells and demonstrated that twice daily administration of IFN-β exhibited a strong antiviral effect until the second phase (16).…”