More on Amantadine in Combination with Interferon and Ribivarin

The data on amantadine has been very frustrating, with some studies showing it was effective in combination with interferon while other studies showing it didn't increase effectiveness. Some studies showed effectiveness in nonresponders but others showing it was not effective in nonresponders. Studies reported at AASLD November 2000 showed mixed results: Does Amantadine Help Response to HCV Therapy?

WHAT IS AMANTADINE? In previously untreated patients with chronic hepatitis C, the combination of interferon alfa and ribavirin achieves a sustained response in over 40% of patients. In addition, about 50% of patients who relapsed after response to interferon therapy may obtain a sustained response after re-treatment with the combination. During the past years, millions of patients with chronic hepatitis C were given interferon worldwide, but over 40% of them did not respond to this treatment. Unfortunately, in these patients re-treatment with the combination of interferon and ribavirin is much less satisfactory, obtaining a sustained response in 10% to 15% at best. This led to the recommendation of no re-treatment in interferon nonresponders.

In 1997, an intriguing article indicated amantadine hydrochloride as a possible option for interferon nonresponders, but further reports did not confirm the efficacy of amantadine in patients with chronic hepatitis C. The rational for using amantadine in patients with chronic hepatitis C is unclear. Amantadine is an antiviral agent active against influenza A with a specific mechanism of action able to block the viral membrane matrix protein, M2, which functions as an ion channel and is required for internalization of the virus by endocytosis.

However, the antiviral action of amantadine is probably not limited to influenza A virus. Evidence exists that this compound may inhibit the replication of other viruses. In addition, amantadine has been shown to interact with both interferon alfa and ribavirin, producing an additive or synergistic antiviral effect. Finally, a small pilot study from our group obtained a surprising sustained response in one third of interferon nonresponders after re-treatment with amantadine in combination with interferon and ribavirin.

The present study was aimed at testing the efficacy and safety of amantadine in combination with relatively high doses of interferon alfa (5 million U every other day) and with ribavirin for a treatment period of 12 months in interferon nonresponders in a randomized controlled trial. In addition, we evaluated the effects of the triple therapy on the circulating levels of HCV RNA.

Triple Antiviral Therapy as a New Option for Patients With Interferon Nonresponsive Chronic Hepatitis C
     Hepatology Sept 2000, Vol 32, Number 3; Brillanti et al.

This study showed patients who were previous nonresponders to interferon, responded better to triple therapy of IFN+RBV+Amantadine than to IFN+RBV: at the end of follow-up HCV RNA was undetectable in 48% (19/40) receiving triple therapy vs 5% (1/20).

The aim of the study was to evaluate the efficacy of triple antiviral therapy with interferon, ribavirin, and amantadine in comparison with interferon and ribavirin combination treatment in patients with interferon-nonresponsive chronic hepatitis C. We performed an open-label, prospective randomized controlled trial at a secondary referral center. We used a 2:1 ratio, patients received interferon, ribavirin, and amantadine, or interferon and ribavirin for 12 months, and were followed up for an additional 6 months. Ninety-four consecutive adult interferon nonresponders with chronic hepatitis C were screened. Sixty consecutive elected patients entered the study. No patients withdrew because of adverse effects. Forty patients received interferon alfa (5 megaunits on alternate days), ribavirin (800-1,000 mg daily), and amantadine (200 mg daily) for 12 months, and 20 patients received the same treatment without amantadine. At the end of follow-up, alanine transaminase (ALT) level normalization was maintained in 23 of 40 patients (57%) after triple therapy, but in 2 of 20 patients (10%) after double therapy (P < .001, RR = 2.11, 95% CI, 1.43-3.12), whereas disappearance of serum HCV RNA persisted in 19 of 40 patients (48%) and in 1 of 20 patients (5%), respectively (P < .001, RR = 1.81, 95% CI, 1.32-2.47). The safety profile was similar in the 2 groups. In conclusion, in patients with interferon-nonresponsive chronic hepatitis C, triple antiviral therapy for 1 year results in a high rate of sustained biochemical and virologic responses.

A Randomized Trial of Amantadine and Interferon Versus Interferon Alone as Initial Treatment for Chronic Hepatitis C
     Hepatology April 2001; 33:989-993

In this study IFN+Amantadine was more effective than IFN in treatment-naïve patients at 6 months posttreatment: 29.8% vs 16.8%.

The aim of this study was to compare, in an open-label study, the efficacy and safety of a combination of interferon (IFN) and amantadine (AMA) with that of IFN alone in previously untreated patients with chronic hepatitis C. A total of 200 patients were randomized to 6 MU of IFN-a2a 3 times per week, with 200 mg of AMA daily (n 5 99) or to an identical dose of interferon a2a (n 5 101). Patients were treated for 12 months and observed for 6 months' posttreatment. At the completion of treatment, 28.7% of patients in the monotherapy group and 45.5% in the combination group had a virologic response (P 5 .014). At 6 months' posttreatment, a sustained virologic response was observed in 16.8% (95% CI: 9-23) of patients with IFN alone versus 29.3% 95% CI: 19-37) of patients who were treated with combination therapy (P 5 .036). In each of the 2 treatments, genotype was the only predictive parameter for a sustained response. At the logistic regression analysis, therapy and genotype were the only 2 parameters with an independent predictive value. In the combination group, at examination of month 3, hepatitis C virus (HCV)-RNA status had a 97.6% (95% CI: 93-102) positive predictive value and a 50% (95% CI: 37-63) negative predictive value for a sustained virologic clearance. A substantial proportion of naive patients with chronic hepatitis C have an end-of-treatment and end-of-followup virologic and biochemical response to a combination of IFN and AMA. This new treatment appears safe and well tolerated. (HEPATOLOGY 2001;33:989-993.)

Monocyclic L-nucleosides with type 1 cytokine-inducing activity (ICN 17261).
     Journal of Medicinal Chemistry, 2000 Mar 9, 43(5):1019-28; Ramasamy, KS; Tam, RC; Bard, J; Averett, DR.

Abstract:
A series of 1,2,4-triazole L-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided co mpounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.