Liver, Pancreas and Biliary Tract
No beneficial effects of amantadine in treatment of chronic hepatitis C patients

https://doi.org/10.1016/j.dld.2009.10.006Get rights and content

Abstract

Background

Benefit of adding amantadine to antiviral therapy for hepatitis C is controversial.

Aims

We aimed to examine whether such policy enhances sustained viral response in treatment-naïve patients.

Methods

297 naïve hepatitis C patients were randomized for treatment with amantadine 200 mg or placebo, combined with weight-based ribavirin and 12-day high-dose interferon alpha-2b induction therapy, followed by PEG-interferon alpha-2b (1.5 μg/kg/week up to 26 weeks and thereafter, 1.0 μg/kg/week until week 52). Treatment was discontinued if hepatitis C virus (HCV) RNA was positive at week 24.

Results

49% of patients were (former) drug users. Genotype 1 occurred in 45%, high viral load in 70% and severe fibrosis/cirrhosis in 32%, without differences between amantadine or placebo groups. 90 patients prematurely discontinued treatment, mainly because of grade 3 or 4 toxicity. Intention-to-treat analysis revealed sustained viral response in 47% and 51% of amantadine and placebo groups (p = 0.49). Amantadine did not enhance sustained viral response in patients with genotype 1 or high viral load nor did it improve primary non-response, breakthrough or relapse rates. Genotype non-1 and lower pre-treatment γGT levels were independent predictors for sustained viral response.

Conclusion

Adding amantadine to antiviral therapy of previously untreated chronic hepatitis C patients has no beneficial effects.

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.

Section snippets

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

References (28)

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This investigator-driven study was supported by a grant by Schering-Plough BV, Maarssen, The Netherlands.

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