Estimation of Early Hepatitis C Viral Clearance in Patients Receiving Daily Interferon and Ribavirin Therapy Using A Mathematical Model

Bekkering, Frank C.; Stalgis, Carlos; McHutchison, John G.; Brouwer, Johannes T.; Perelson, Alan S.

doi:10.1053/jhep.2001.21552

Cited by 74 publications

(46 citation statements)

References 25 publications

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“…An improved prediction of SVR as well as non-SVR would therefore be important, and it has been proposed that the viral kinetics during treatment might be clinically useful for this purpose (1,2,4,5,16,18,20,22,25,26). For example, the magnitude of HCV RNA reduction after only one dose of interferon is clearly associated with an SVR (10,15), as is the rate of decline in viremia between day 7 and week 12 (second-phase slope) (1,8). However, it has been difficult to include kinetic parameters in clinical practice, partly because the reliability of predictions for individual patients has been uncertain and partly due to concerns regarding the robustness of HCV RNA quantification.…”

Section: Discussionmentioning

confidence: 99%

Response Prediction and Treatment Tailoring for Chronic Hepatitis C Virus Genotype 1 Infection

et al. 2007

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We monitored early viral response during the treatment of hepatitis C virus (HCV) infection with the aim of identifying predictors of treatment outcome. We studied 53 patients with genotype 1 infection who received 180 g/week pegylated interferon alfa-2a and 1,000 or 1,200 mg/day ribavirin depending on body weight and serially assessed HCV RNA in serum, using the Cobas TaqMan assay. Thirty-one patients (58%) achieved sustained viral response (SVR). SVR was obtained in 100% (10/10) of patients with pretreatment viremia concentrations below 400,000 IU/ml, in 100% (14/14) of patients with more than 1.5 log reduction of HCV RNA after 4 days of treatment, and in 95% (22/23) of patients with a rate of decline in viremia higher than 0.70 log units/week during the second phase. Non-SVR was seen in all patients with a second-phase decline rate lower than 0.35 log units/week. Patients with slopes between 0.50 and 0.80 log units/week achieved SVR (4/4) unless the treatment dose was modified (3/3). We conclude that the second-phase slope appears to be an accurate and useful predictor of treatment response. On the basis of these findings, we propose a model of tailored treatment which takes into account the second-phase slope and the amount of HCV RNA after 21 days of treatment.

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Section: Discussionmentioning

confidence: 99%

Response Prediction and Treatment Tailoring for Chronic Hepatitis C Virus Genotype 1 Infection

et al. 2007

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“…In this regard, a recent mathematical study has shown that, theoretically, the induction period of antiviral therapy should be longer than 4 to 8 weeks. 44 Clearly, a prospective clinical trial will be required to address these important clinical and therapeutic questions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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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.

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“…[4][5][6][7][8][9][10][11] The rationale for this so-called induction strategy is that high-dose interferon may improve SVR by inducing a more rapid initial decline in HCV RNA. The relationships between interferon dose and early phase HCV kinetics, including phase I and II slope and time to undetectable HCV RNA, 12,13 and early virological responses and SVR support such a rationale. 1,[14][15][16] Studies utilizing induction therapy with (peg)interferon in patients with genotype 1 CHC have yielded mixed results, with some patients demonstrating an enhanced SVR 4,5 and others not.…”

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confidence: 91%

Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: A randomized controlled trial

Roberts¹,

Weltman²,

Crawford³

et al. 2009

Hepatology

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This study tested the hypothesis that high-dose peginterferon alfa-2a (PEG-IFN␣-2a) for the first 12 weeks would increase early and sustained virological response (SVR) rates in patients with chronic hepatitis C genotype 1. Eight hundred ninety-six patients were randomized 1:1 to 360 g (n ‫؍‬ 448) or 180 g (n ‫؍‬ 448) PEG-IFN␣-2a weekly plus ribavirin at 1000-1200 mg/day for 12 weeks, followed by 36 weeks of 180 g PEG-IFN␣-2a weekly plus ribavirin at 1000-1200 mg/day with 871 patients evaluable for the intention-to-treat analysis. Virological responses were assessed by TaqMan (limit of detection 15 IU/mL) at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (SVR). Undetectable hepatitis C virus RNA rates were significantly higher among patients receiving high-dose induction therapy at week 4 (36% versus 26%, P < 0.005), week 8 (61% versus 50%, P < 0.005), and week 12 (74% versus 62%, P < 0.005). However, SVR was not significantly different between patients receiving high-dose (53%) and standard (50%) therapy. Significant baseline prognostic factors for SVR included age, sex, race, histological stage, and viral load. SVR was considerably higher among patients with no or minimal fibrosis (64% and 60%, respectively) compared to those with severe fibrosis/cirrhosis (28% and 24%, respectively). The frequency of serious adverse events and drug discontinuations were similar in both groups, whereas PEG-IFN dose modification, weight and appetite reduction, and grade IV neutropenia were significantly higher in the induction arm.

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Estimation of Early Hepatitis C Viral Clearance in Patients Receiving Daily Interferon and Ribavirin Therapy Using A Mathematical Model

Cited by 74 publications

References 25 publications

Response Prediction and Treatment Tailoring for Chronic Hepatitis C Virus Genotype 1 Infection

Response Prediction and Treatment Tailoring for Chronic Hepatitis C Virus Genotype 1 Infection

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

Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: A randomized controlled trial

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