Liver, Pancreas and Biliary TractNo beneficial effects of amantadine in treatment of chronic hepatitis C patients☆
Introduction
Chronic hepatitis C virus (HCV) infection is a major health problem [1]. Current antiviral treatment with PEG-interferon and ribavirin achieves sustained virological response rates (SVR) of 55–64% in treatment-naïve patients [2], [3]. HCV genotype affects SVR rates strongly (approximately 45% SVR in genotype 1 and 80–90% in genotypes 2 and 3) [2], [3]. Amantadine enhances immune response to various viruses as influenza A, dengue and herpes zoster [4], [5], [6], [7] and is an effective prophylactic and therapeutic drug against influenza virus [4]. Also, beneficial effects of amantadine on HCV have been reported. In one study, amantadine monotherapy induced on-treatment decreases in serum amino-transferases, without effects on viral load [8]. Caronia et al. showed increased on-treatment virological responses after 3 months of interferon alpha/amantadine combination, without differences in SVR rates [9]. In contrast, a meta-analysis revealed significant increases in SVR with interferon alpha/amantadine compared to interferon monotherapy [10]. Also, in a small study in non-responders to interferon alpha monotherapy, Brillanti et al. found 0% SVR in patients treated with interferon alpha/ribavirin vs. 30% SVR for amantadine/interferon alpha/ribavirin triple therapy [11]. Another study reports SVR of 18% in interferon alpha non-responders when amantadine was used as monotherapy [12]. Berg et al. randomized 400 naïve patients to amantadine sulphate (100 mg twice daily) or placebo, in combination with interferon alpha-2a and ribavirin (1000–1200 mg daily). On-treatment viral response rates at week 24 were significantly higher (70% vs. 59%, p = 0.02) and SVR rates tended to be higher (53% vs. 43%, p = 0.11) in the amantadine group [13]. Nevertheless, there are also several negative studies on the effect of amantadine in HCV-infected patients [14], [15], [16]. In the current double-blind, placebo-controlled, multicentre, randomized trial in naïve HCV patients, we explored whether adding amantadine to PEG-interferon alpha and ribavirin could improve virologic outcome.
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Patient selection
Eligible subjects were previously untreated adult patients who tested positive for serum HCV-antibodies and HCV RNA, with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevated at least once within 6 months before inclusion and liver biopsy (performed within 1 year before entry) consistent with chronic viral hepatitis. Minimal baseline haematological values were: haemoglobin 6.5 mmol/L, white blood cells 2.5 × 109 L−1, neutrophils 1.5 × 109 L−1, platelets 70 × 109 L−1 and serum
Baseline patient characteristics
333 patients were considered for inclusion, and 321 patients were randomized for amantadine or placebo treatment (Fig. 1). 24 of these patients did not use any medication for various reasons, leaving 297 patients actually treated with PEG-interferon alpha 2b/ribavirin in combination with amantadine hydrochloride (N = 144) or placebo (N = 153). 18% of patients exhibited positive serum antinuclear antibodies, 26% positive anti-smooth muscle antibodies and 2% positive anti-mitochondrial antibodies.
Discussion
The major finding of the current study is that, in treatment-naïve HCV patients, adding amantadine to PEG-interferon alpha-2b and ribavirin does not enhance SVR rates. In line with our findings, amantadine affected neither RNA replication nor release or infectivity of HCV particles across a spectrum of HCV isolates and genotypes in recent in vitro studies [17]. Also, in that study, p7 ion channel activity was not affected by amantadine, indicating that amantadine is not an HCV-selective
Conflict of interest
None declared.
Acknowledgements
The authors thank Dr. J. van Hattum for the important contribution to this work. Contributions of Dr. P.D. Warners (Lorentz Ziekenhuis Zeist), Dr. L.P. Bos (Maasland Ziekenhuis Sittard), Dr. S.Y. de Boer (Slingeland Ziekenhuis Doetinchem), Dr. N. van Bentem (Medisch Spectrum Twente, Enschede), Dr. H.A.R.E. Tuynman (Medisch Centrum Alkmaar), Dr. R.S. de Jong (Martini Ziekenhuis Groningen), Dr. H. Faber (Wilhelmina Ziekenhuis Assen), Dr. M.J. Wagtmans (Flevoziekenhuis Almere), Dr. de Nie
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Meta-analysis: Amantadine may lower the efficacy of pegylated interferon plus ribavirin in treatment-naive hepatitis C genotype 1 patients
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This investigator-driven study was supported by a grant by Schering-Plough BV, Maarssen, The Netherlands.