Triple Therapy With Amantadine in Treatment–Naive Patients With Chronic Hepatitis C: A Placebo–Controlled Trial

Abstract

The antiviral efficacy of amantadine in patients with chronic hepatitis C is controversial. In this randomized, prospective, placebo-controlled, multicenter trial, triple therapy with interferon alfa (IFN-␣)-2a plus ribavirin and amantadine (amantadine group) was compared with combination therapy IFN-␣ plus ribavirin (control group). Four hundred previously untreated patients with histologically proven chronic hepatitis C were randomly allocated to treatment with amantadine sulphate (100 mg twice daily orally) or a matched placebo together with IFN-␣ induction plus ribavirin (1,000-1,200 mg/day orally) for 48 weeks. The primary end point was sustained virologic response (SVR) defined as undetectable serum hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment. SVR was observed in 52% of the amantadine group and in 43.5% of the control group (P ‫؍‬ .11). Among patients with HCV genotype 1 infection, the corresponding SVR rates were 39% and 31%, respectively. The virologic on-treatment response rate in week 24 was significantly higher in the amantadine group as compared with the control group (70% vs. 59%, respectively, P ‫؍‬ .016). This beneficial effect was mainly related to HCV type 1-infected patients (63% vs. 47%, respectively, P ‫؍‬ .012). Independent factors associated with SVR, according to multiple logistic regression analysis, were amantadine treatment, low baseline HCV RNA, platelet counts (>250/nL), pretreatment ALT quotient >3, and GGT level (<28 U/L) as well as HCV genotypes other than 1. In conclusion, although we could not demonstrate a significant advantage of the triple regimen in univariate analysis, multivariate analysis offers arguments that amantadine should be considered as a potential anti-HCV drug in future studies. (HEPATOLOGY 2003;37:1359-1367

Viral Kinetics During Antiviral Therapy in Patients With Chronic Hepatitis C and Persistently Normal Alt Levels

“…In agreement with previous studies, 22 we observed a correlation between the GGT level and the necroinflammation score and fibrosis. GGT elevations caused by toxic injury and obesity are unlikely due to strict inclusion criteria in the present study and a lack of correlation with body mass index.…”

“…21,22 Although baseline GGT levels and ALT levels are correlated, the effects on viral kinetic parameters were different in the present study. While patients with persistently normal ALT levels tended to a lower efficacy of blocking virus production and reduced infected cell loss, a lower efficacy of blocking virus production ⑀, a lower infected cell loss ␦, and a lower infected cell loss during treatment m␦ was observed in patients with elevated baseline GGT levels compared with patients with normal baseline GGT levels.…”

“…21,22 Baseline ALT levels 3 times the ULN were present in 9 (47%) of 19 patients with chronic hepatitis C and elevated ALT levels. Normal GGT levels were observed in 15 (75%) of 20 patients with persistently normal ALT levels and in 7 (37%) of 19 patients with elevated ALT levels.…”

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

“…14,23,24 By antiviral triple therapy containing amantadine, PEG IFN-␣ and ribavirin sustained virological response rates of 25% to 60% were achieved compared with 28% to 44% observed in patients receiving dual combination with PEG IFN-␣ and ribavirin. 11,25,26 A meta-analysis comprising 3257 treatmentnaïve patients enrolled in 17 controlled clinical trials showed that amantadine augments the response to interferon alfa in treatment-naïve patients, albeit to a lesser extent than most clinical trials assumed for sample size calculation. 15 In the largest randomized, placebo-controlled trial, 400 treatment-naïve patients with chronic hepatitis C were enrolled.…”

“…[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.…”