Amantadine and interferon in the combined treatment of hepatitis C virus in elderly patients
Introduction
The risk of developing chronic liver disease and/or hepatocellular carcinoma [1], [2] represents the rationale for treating hepatitis C virus (HCV) infection, and both α-interferon (α-IFN) and α-IFN plus Ribavirin are well accepted treatments [3], [4], [5]. In older patients with long-standing infection and chronic active liver disease, the need to treat has to be balanced against the risk of side effects from both drugs [4], [5], [6].
Preliminary data indicate a beneficial effect of amantadine hydrochloride (AH) on serum transaminases in chronic hepatitis C probably reducing the rate of reinfection of the liver cells by HCV [7], [8], [9]. The mechanism of action appears to be rather aspecific, the molecule interacts in different ways with the cell membrane reducing both internalization and denudation of the virus [10] and has no effect in vitro on protease, helicase, ATPase, polymerase of HCV and has a non-specific translation inhibition [11]. AH is currently used in the prevention of influenza A2 infection [12] and its use, on a large scale, in the elderly has shown AH to be particularly safe in terms of side effects [13], [14], [15].
The aim of this study was to investigate the effect of AH in combination with α-IFN in patients over 65 years of age in whom a previous cycle of treatment had failed to eradicate HCV and in whom, however, there is a specific indication to treat the infection due to the high risk of hepatocellular carcinoma. A second group of patients received AH alone and a third underwent a second course of α-IFN, one of the approved drugs for retreatment of relapsing and non-responding patients in Italy being α-IFNn3.
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Patients and methods
The trial was designed with the intention to eradicate HCV infection and a population size of 165 participants was foreseen in order to compare the three treatment schedules and allow a 15% drop-out in 2 years. The trial was approved by the Council of the Department of Clinical Sciences; the use of AH, marketed in Italy for the treatment of Parkinson's disease and influenza, was approved by the Ethics Committee at the University. Patients over 65 years of age (females n=86; males n=79) were
Group A
After enrollment and randomization, two patients refused treatment since AH was experimental, three because the trial did not include IFN and eight patients because of fear of side effects.
Thus 42 patients aged 68±3 years, (F/M:24/18), were then treated with AH 100 mg twice per day for 12 months. Serum ALT and HCV-RNA throughout the study are summarized in Table 2.
At entrance HCV-RNA was 482±227×103 copies per ml in 41/42 patients, in one, although the qualitative PCR was positive, the count of
Discussion
The end point of the present trial of AH, IFNα-n3 and AH plus IFNα-n3 treatment was the eradication of HCV infection and the parameters to establish the result was the number of HCV-RNA copies as shown by the quantitative PCR reaction and number of patients free of HCV at the end of an adequate follow up. From this point of view, the overall success of treatment was 14.4% of patients eradicated out of the 165 individuals enrolled, the overall response at the end of treatment being approximately
Acknowledgements
Work was supported by grants 0280.05.15.01.36 from MURST (Italy) and RC1/98 from St.I.F. Authors are grateful to F. Anzini who managed all outpatient attendances and to Dr C. Berardo, Dr R. Gerardi and Dr R. MA Marinelli who filled in records of majority of patients and to Marian Shields and to Mosha Patsouri for reviewing manuscript.
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Cited by (23)
Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting
2010, Digestive and Liver DiseaseLiver disorders in the elderly
2009, Best Practice and Research: Clinical GastroenterologyCitation Excerpt :The AISF (Italian Association for the Study of Liver Disease) guidelines recommend that treatment is indicated in elderly patients (subjects aged 65 or more) who have increased risk of developing severe liver disease (2009 Annual Meeting, unpublished data). Table 2 shows the SVR rate observed in elderly patients with different genotypes in published studies [28–34]. In general, the SVR rates are lower than in adult patients, as demonstrated by a case-control study 45% vs. 69.7%, (p < 0.02)[33].
Aging Liver and Hepatitis
2007, Clinics in Geriatric MedicineCitation Excerpt :Studies on treatment of HCV infection in older patients are few, and early ones did not assess the rate of sustained virologic response [46,47]. Later studies, although assessing sustained virologic response, used treatments such as IFN monotherapy or IFN with amantadine [48–50], which are now considered obsolete. However, in these studies the rate of sustained virologic response for patients older than 60 years (mean age, 64 years) was similar to that for younger patients (mean age, 48 years; 18% [9/50] versus 20% [21/104]) [49].
Differential effects of a novel IFN-ζ/limitin and IFN-α on signals for Daxx induction and Crk phosphorylation that couple with growth control of megakaryocytes
2005, Experimental HematologyCitation Excerpt :IFN-α and IFN-β are widely utilized for the treatment of patients with virus infection, autoimmune diseases, and malignant diseases [24]. Recent advances for IFN therapy are a combined therapy with ribavirin as well as an appearance of a pegylated IFN and a consensus IFN [25–27]. Although these new therapeutic strategies are more efficient than IFN monotherapy, adverse effects of IFNs are still severe problems.
Evaluation of amantadine in chronic hepatitis C: A meta-analysis
2004, Journal of HepatologyA new interferon, limitin, displays equivalent immunomodulatory and antitumor activities without myelosuppressive properties as compared with interferon-α
2004, Experimental HematologyCitation Excerpt :However, patients on chronic treatment with IFNs sometimes experience fatigue, anorexia, depression, and myelosuppression, and these adverse effects can require dose reduction or discontinuation of treatment [8]. Recent advances for IFN therapy are a combined therapy with ribavirin or amantadine as well as an appearance of a pegylated IFN and a consensus IFN [3,22–24]. In the treatment of malignant disease, IFN combined therapies with other cytokines or chemotherapeutic agents have been addressed [6].