Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis c patients: a case control study

Abstract

BackgroundHigh dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied.MethodsA new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction.ResultsDose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group.ConclusionsThese findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.

Triphasic decline of hepatitis C virus RNA during antiviral therapy

“…Agreement of the model with experimental data. To show that the extended model agrees with experimental data (•) exhibiting triphasic viral decays, we digitized HCV RNA levels of 2 patients (figures 2A and 2B from Hermann et al 12 ) treated with (A) pegylated IFN-␣2a alone and (B) pegylated IFN-␣2a plus RBV and (C) 1 patient (figure 2A from Bekkering et al 13 ) treated with IFN-␣2b. The analytical solution for V(t) (i.e., equation 4 in Neumann et al 9 ) was first fitted to the HCV RNA using Berkeley-Madonna software, version 7.0.2, to estimate the delay time before viral decay begins (t 0 ), the IFN-␣ effectiveness (⑀), and the viral clearance rate constant (c).…”

“…Thus, RBV is not necessary for a triphasic decline. Other studies [13][14][15] have also observed triphasic viral decays. In particular, Bergmann et al 15 observed triphasic viral declines in a large fraction (30%-40%) of IFN-␣-treated patients (n ϭ 200).…”

“…[9][10][11][12] In some patients, a triphasic decline has been observed in which there is a rapid initial decline in viral load, followed by a "shoulder phase" lasting 4-28 days in which HCV RNA decays slowly or remains constant, and a third phase of renewed viral decay. [12][13][14][15] For example, Herrmann et al 12 observed triphasic declines in 8 of 10 patients treated with pegylated IFN-␣ plus RBV, in 9 of 17 patients treated with pegylated IFN-␣ alone, and in 4 of 7 patients treated with IFN-␣ plus RBV. Why some patients respond to therapy with a biphasic decline whereas others respond in a triphasic manner has not been addressed previously and is the subject of our report.…”

New Kinetic Models for the Hepatitis C Virus *

“…Because the effectiveness of a drug depends on its dose, a model with variations in the efficiency of blocking viral production is needed. Thus, Bekkering et al 5 introduced a model in which ⑀ was changed starting at the time of dose reduction from a level ⑀ 1 to a lower level ⑀ 2 with a smooth transition between these values. The model provided a good fit to the viral load data and showed that models are capable of mimicking non-biphasic viral load patterns.…”

“…[1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, [7][8][9] stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production.…”