Report Eighteen from Dallas 50th AASLD Meeting, Nov 5-9
Jules Levin, NATAP

Two Additional Amantadine Studies- this is NATAP's second report on amantadine as there were a number of studies reported at AASLD. Overall results are mixed and suggest no or yet uncharacterized benefir from amantadine in HCV. One study below suggests early viral clearance may improve by adding amantadine but longer term clinical benefit appeared to wane. 

INTERFERON a2B-RIBAVIRIN VS. INTERFERON a2B-AMANTADINE COMBINATION IN CHRONIC HEPATITIS C; ANALYSES OF A RANDOMIZED, DOUBLE-BLIND TRIAL- preliminary data in this study show no benefit to amantadine by end-of-treatment

Z M Younossi, K D Mullen, W Zakko, E Brandt, S Hodnick, D Barnes, W Carey, A McCullough, K Easley, L H Calabrese, Cleveland Clin Fdn, Cleveland

Optimum management of chronic hepatitis C (CH-C0 patients who have previously failed interferon (IFN) monotherapy is uncertain. AIM: To compare the efficacy of IFN-ribavirin to IFN+amantadine combination in patients who are non-responders to previous IFN monotherapy (NR). Design: 1. Patients with CH-C who previously failed interferon monotherapy [elevated ALT and HCV RNA (+) by PCR after at least 3 months of 3MU thrice weekly of IRN monotherapy] were enrolled in the study. 2. Patients were started on interferon a2b at a dose of 3 MU TIW and randomized (in a double-blind fashion) to receive ribavirin 800 mg/d or amantadine 200mg/d. 3. Biochemical (ALT), virologic (HCV RNA by PCR, Superquant‘, National Genetic Institute), histologic (modified Histologic Activity Index) and health-related quality of life (Chronic Liver Disease Questionnaire and Short Form-36) endpoints were monitored periodically.

 Results: 118 patients were randomized equally6 to each arm of the study. Demographic and clinical data reveal that 63% were male, median age was 44 years and 15% had cirrhosis. Baseline HCV RNA and ALT were similar in both groups (3.1 million vs 2.8 million copies/ml) and (108 vs. 99). HCV genotype breakdown reveal that 81% of patients were genotype 1, 6% were genotype 2, 8% genotype 3 and 5% were mixed. There were no differences in gender, age, route of transmission, genotype distribution, presence of cirrhosis and baseline HAI scores between the two groups. End of treatment viral eradication rates were 36% for IFN+ribavirin vs. 21% for IFN+amantadine combination (p-value=0.1). End of follow up data (24 weeks) and sustained virologic response rates are currently being collected.

Conclusions: 1. Treatment of IFN non-responders with either combination regimens provides an encouraging virologic ETR. 2. Although no clear effectiveness advantage of either regimen is apparent, based on viral ETR, there is trend favoring IFN+ribavirin combination. 3. Sustained response data are currently being assessed.

HEPATITIS C VIRAL DYNAMICS WITH TRIPLE VS. DOUBLE THERAPY IN NON-RESPONDER PATIENTS- this study showed a non-significant faster viral clearance at the beginning of therapy without effect on the number of HCV-RNA neg. patients on day 90

Elmar Jaeckel, JN Koerbel, A Kunka, A Schueler, S Heringlake, H Wedemeyer,  Trautwein, P Magerstedt, Medicine Hochschule Hannover, Hannover Germany; M Zankel, Essex-Pharma, Munich Germany; S Brinkmann, Merz+Co, Frankfurt Germany; MP Manns, Medicine Hochschule Hannover, Hannover German

An understanding of the viral kinetics in therapy of chronic hepatitis C virus (HCV) infection might optimize antiviral strategies and define early predictive parameters of treatment response. Due to the lack of effective  therapies for non-responder (NR) patients, only data for the short term  response in these patients is available. Furthermore, little is known about  the effect of amantadine-sulfate on viral kinetics in triple therapy. Aim: Viral kinetics were determined in 25 NR-patients being treated with a combination of (A; n=14) ribavirin (Riba), interferon-alfa-2b (IFN) and amantadine-sulfate or (B; n=11) Riba, IFN and placebo. IFN was given on a high daily induction dosing regimen: 2 weeks 10 Mio.U qd, 2 weeks 5 Mio.U qd, 8 weeks 3 Mio.U qd followed by 3 Mio.U every other day for another 9 months. 1000-1200 mg Riba and 200 mg amantadine/placebo were given orally qd. HCV-RNA was measured with Roche Amplicor II-test on day 0, 1, 2, 3, 7, 14, 30, 60, 90 and 120. To date, 14 and 11 patients completed month 3 of therapy in group A and B, respectively. Baseline characteristics at inclusion were evenly distributed in both groups: mean age 39 years, 84% genotype 1, 8% genotype 3, 8% genotype 4, viral load 1,28 Mio./ml. Results: There was a trend towards lower viral load in group A during early treatment phase (not significant, 10x=Ex). The decline of HCV-RNA was exponential. Three different phases of virus elimination with significant different decline slopes were identified (*p<0.05 vs. B).The viral half life during the initial 36 hours was 15.6 hours corresponding to a viral production of 1.6E10 virions per day without difference between group A and B. Patients becoming negative until day 90 of therapy showed a significant shorter viral half life (14.6 vs. 22.0 hours) and a steeper decline slope for day 14-90 (-0.056 vs. 0.003). Their viral load was significantly smaller starting from day 1 of therapy. Conclusions: 1) Loss of HCV-RNA can be achieved in a substantial number of IFN-Non-responders with high daily doses of IFN in combination with Riba and amantadine or placebo. 2) Amantadine causes a faster viral clearance at the beginning of therapy without effect on the number of HCV-RNA neg. patients on day 90. 3) Measurement of viral half life and kinetics might help to identify non-responders likely to clear the virus. Patients are currently being followed-up and sustained response rates have to be awaited.