Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

Ferenci, Péter; Laferl, Hermann; Scherzer, Thomas–Matthias; Gschwantler, Michael; Maieron, A; Brünner, H.; Stauber, Rudolf; Bischof, Martin; Bauer, B. L.; Datz, Christian; Löschenberger, Karin; Formann, E.; Staufer, Katharina; Steindl–Munda, Petra

doi:10.1053/j.gastro.2008.04.015

Cited by 235 publications

(237 citation statements)

References 19 publications

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“…The 50% SVR rate achieved was similar to that reported in previous studies while the independent baseline prognostic factors identified in multivariate analyses including age, sex, histological stage, and viral load were consistent with prognostic factors identified previously in patients infected with genotype 1. An RVR, achieved in around one-quarter of patients in the standard arm, had a positive predictive value for SVR of 80%, similar to that recently reported in patients treated with 24 weeks of standard therapy 19 although somewhat lower than the 89% reported from a retrospective analysis of a large international phase III registration study. 15 Consistent with other studies, EVR was the most reliable predictor of nonresponse with a negative predictive value of 98% in the standard therapy group.…”

Section: Discussionsupporting

confidence: 84%

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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Section: Discussionsupporting

confidence: 84%

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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“…For instance, in one study where 240 patients were treated with DAAs for 12 weeks, of the 86 patients available for follow‐up, 22 had detectable viremia at the EOT and 20 of the latter patients eventually achieved SVR 12. This observation is in striking contrast to PR treatment, where detectable viremia at the EOT typically implies treatment failure and results in viral rebound 13. The achievement of SVR despite detectable viremia at the EOT, a phenomenon termed EOT + /SVR, suggests that DAA treatments can be terminated much earlier than the currently prescribed duration of 12 weeks, even if virus is detectable, at least in some patient subpopulations.…”

Section: Introductionmentioning

confidence: 95%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT +/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT +/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT +/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT +/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT +/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.

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“…5 Other studies have demonstrated that the percentage of RVR in patients with hepatitis C genotype 1 was 16%-26.7%. 4,[6][7][8] We have recently reported a RVR rate of 43.5% (87/200) among Taiwanese patients infected with HCV genotype 1 in our randomized trial. 9 The rates of RVR in patients with hepatitis C genotype 1 differ greatly from different areas.…”

Section: Replymentioning

confidence: 63%

Rapid virological response in hepatitis C virus genotype 1 and early ribavirin exposure

Chuang

Huang

et al. 2008

Hepatology

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Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

Cited by 235 publications

References 19 publications

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

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

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Rapid virological response in hepatitis C virus genotype 1 and early ribavirin exposure

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