Randomized, controlled trial with IFN-α combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C

Teuber, G.; Pascu, Maria; Berg, Thomas; Lafrenz, Michael; Pausch, Jürgen; Kullmann, Frank; Ramadori, Giuliano; Arnold, R.; Weidenbach, H; Musch, E.; Junge, Ulrich; Wiedmann, K. H.; Herrmann, Eva; Zankel, M.; Zeuzem, Stefan

doi:10.1016/s0168-8278(03)00298-8

Cited by 36 publications

(33 citation statements)

References 29 publications

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“…Results, however, are conflicting. 7,8,10,11,14 A recent meta-analysis 6 reported a significant effect of triple combination therapy with AMA in non-responders, but no effect upon naive patients or relapsers. However, most of the patients included in the meta-analysis had failed IFN monotherapy rather than IFN + RBV combination treatment and the definition of previous non-response was not homogeneous between studies.…”

Section: Discussionmentioning

confidence: 99%

“…The role of AMA in the retreatment of non-responders to combined therapy is even more debated due to the low number of full reports on this topic. 10,11 In order to establish whether patients previously unresponsive to combined therapy with conventional IFN-based treatment regimens benefit from therapy with Peg-IFN/RBV-based regimens with or without AMA, we conducted a randomized-controlled trial; the study was designed to compare the efficacy and safety of Peg-IFN-a2a given at 180 lg dose once weekly plus RBV 1000-1200 mg/daily with or without AMA 200 mg given daily for 12 months.…”

Section: Introductionmentioning

confidence: 99%

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A randomized trial of pegylated‐interferon‐α2a plus ribavirin with or without amantadine in the re‐treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin

Ciancio

Picciotto

Giordanino

et al. 2006

Aliment Pharmacol Ther

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A randomized trial of pegylated‐interferon‐α2a plus ribavirin with or without amantadine in the re‐treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin

Ciancio

Picciotto

Giordanino

et al. 2006

Aliment Pharmacol Ther

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“…Meta-analyses of all studies with IFN-␣ in combination with amantadine showed contradictory results (22,81). Triple therapy with PEG-IFN, ribavirin, and amantadine showed improved sustained virologic response rates in patients who were previously nonresponders but showed no significant benefit in naïve patients or relapsers in comparison with standard combination therapy (7,13,22,34,82,143). Additional studies with PEG-IFN, ribavirin, and higher doses of amantadine to verify a potential antiviral effect of amantadine in patients with chronic hepatitis C virus genotype 1 infection are under way.…”

Section: Mechanisms Of Resistance To Amantadinementioning

confidence: 99%

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

2007

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SUMMARY Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

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“…[6][7][8] Over more than 10 years, the antiviral efficacy of amantadine in combination with interferon alfa alone or interferon alfa and ribavirin has been evaluated in numerous yet underpowered clinical trials. [9][10][11][12][13][14] Randomized placebo-controlled multicenter clinical trials revealed controversial results for treatment-naïve patients, and meta-analyses suggested a slight improvement of sustained virological response rates for interferon-based treatment with amantadine. 15 In addition to results from clinical trials, in vitro examinations suggested inhibition of the HCV p7-protein by amantadine and an association of specific amino acid variations in the p7-protein with virological response to amantadine in combination with PEG IFN-␣ and ribavirin.…”

mentioning

confidence: 99%

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

Wagner¹,

Hofmann²,

Teuber³

et al. 2008

Hepatology

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The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 ؎ 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n ‫؍‬ 352) or (B) placebo (n ‫؍‬ 352), both in combination with 180 g peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P ‫؍‬ 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection. (HEPATOLOGY 2008;

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Randomized, controlled trial with IFN-α combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C

Cited by 36 publications

References 29 publications

A randomized trial of pegylated‐interferon‐α2a plus ribavirin with or without amantadine in the re‐treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin

A randomized trial of pegylated‐interferon‐α2a plus ribavirin with or without amantadine in the re‐treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection

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