Report Twelve from Dallas Liver Meeting

Report Twelve from Dallas Liver Meeting , 50th AASLD, Nov 5-9

Amantadine
Jules Levin, NATAP

Several studies presented in Dallas showed mixed results on whether or not amantadine can be effective in treating HCV. This study had negative preliminary results. Several studies are reported below.

1. Preliminary Study Data Suggesting Amantadine Not Effective

COMPARISON OF HIGH DOSE ALPHA IFN INDUCTION TREATMENT COMBINED WITH AMANTADINE HCL VS. INDUCTION MONOTHERAPY IN PATIENTS WITH CHRONIC HEPATITIS C.

Jorge A Findor, Hospital de Clinicas Univ de Buenos Aires, Buenos Aires Argentina; Hugo Tanno, Hospital Centenario, Rosario Argentina; Estela Bruch Igartua, Hospital Aleman, Buenos Aires Argentina; Leonardo Pinchuk, IMOS, Buenos Aires Argentina; Juan A Sorda, Hospital de Clinicas Univ de Buenos Aires, Buenos Aires Argentina; Jose Curciarello, Hospital Rossi, La Plata Argentina; Andres J Findor, Hospital de Clinicas Univ de Buenos Aires, Buenos Aires Argentina; Rogelio Islas, Hospital Israel, Buenos Aires Argentina; Estela F Manero, Graciela Bianchi, Daniel Poncino, Hospital de Clinicas Univ de Buenos Aires, Buenos Aires Argentina; Jorge R Daruich, Hospital de linicas Univ de Buenos Aires, Buenos Aires Argentina

Background. The response rate in recombinant interferon alpha (IFNa) treated patients with chronic hepatitis C with 3 MU, TIW, 6 months is insufficient. Other therapeutic options like induction therapy with high doses of IFN and/or combination treatment with other antiviral drugs are currently under evaluation. Objective: To evaluate the effectiveness of combination treatment with Amantadine HCl (AHCl) associated with induction treatment in naive patients using high daily doses of IFNa and compare the results with a group of patients with the same scheme of IFNa but without AHCl. Material and method: This is preliminary communication from an ongoing study planned to last for 12 months of treatment with 6 months of follow up. The results presented here include patients who have completed at least 1 month of therapy. Initial viral load was performed by Amplicor Monitor (Roche) and controls of viremia at 4 and 24 weeks by RT-nPCR. HCV genotyping (Gt) was performed by INNO LiPA II (Innogenetic). Histology was evaluated by the modified Knodell score, separating necroinflammatory component from fibrosis. For statistical analysis, the Kruskall-Wallis and the Wicoxon Signed Ranks tests were used. Results: Group A (GA) included 48 patients (25 males) with an age of 46.4 years (±12.7), who received 200 mg daily of AHCl during 12 months plus 6 MU of rIFN a 2a, daily, during 4 weeks, TIW during the following 2 months and thereafter, 3 MU, TIW 9 months. Gt 1 was found in 29/48 patients (60.4%). Liver biopsy showed an inflammatory score of 6.5 (±3.1) and fibrosis of 1.33 (±1.18). Cirrhosis was present in 4 and severe fibrosis in 3. Initial viral load was 5.09 log copies/ml (±1.18) and ALT level was 3 (±2.5) times over the maximal normal level (xNL). Group B (GB) comprised 42 patients (29 males) with an age of 46.5 (±12) treated with the same scheme of rIFN a2a but without AHCl. Gt 1 was present in 24/42 (57.1%) and histology showed an inflammatory score of 6.9 (±2.5) and fibrosis of 1.59 (±1.23). 3 patients had cirrhosis and 6 severe fibrosis. Initial viral load was 5.36 copies/ml (±0.68) and ALT was 4 (SD ±2.6) times xNL. None of the variables between both groups were significant. In GA 10 patients were non responders (NR), 2 dropped out because of side effects and 4 presented a breakthrough phenomena after an initial response to treatment. In GB, 3 were NR, 2 stopped because of adverse effects and 5 presented breakthrough. At week 4, in 33/48 (68.8%) in GA and in 28/36 (77.7%) in GB, HCV RNA became undetectable (p=NS). At week 24, in GA, 24/40 (60%) and 17/27 (63%) in GB, HCV RNA continued negative. No difference was observed between both groups. Conclusions: No significant difference between naive patients treated with induction therapy with IFN alone or associated with ACHl could be demonstrated until 6 months. Breakthroughs were similar in both groups. Induction was associated with high viral clearance already at week 4 and reaches more than 60% at month 6, independently from the association with AHCl.

2. This study concludes amantadine did not improve interferon efftiveness on HCV.

COMBINATION OF INTERFERON ALFA-2A AND AMANTADINE DOES NOT IMPROVE THE EFFICACY OF INTERFERON THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C

Sien-Sing Yang, Tien-Chien Tu, Chi-Hwa Wu, Cathay Gen Hospital, Taipei Taiwan Roc; Ding-Shinn Chen, National Taiwan Univ Hospital, Taipei Taiwan Roc

We prospectively studied 30 patients having chronic HCV infection, who were naive without prior interferon and anti-viral therapy for the role of amantadine to improve the efficiency of interferon in the treatment of chronic HCV infection. Patients were assigned into two groups at a double blind and randomized controlled basis. Group 1 patients received 4.5 mu of interferon alfa-2a thrice weekly for 24 weeks. Group 2 patients received a combination of interferon and 200 mg amantadine daily for 24 weeks. Patients were observed and tested for blood chemistries every week for the initial 4 weeks and every 2 weeks thereafter during the treatment until 24 weeks. After the end of treatment, patients were followed up at 4-week intervals for 12 months. One patient lost to follow-up at 2 months after treatment did not respond to combined interferon and amantadine therapy with persistent abnormal serum ALT levels during and after therapy. Five (33.3%) patients responded to a combination of interferon and amantadine, and 7 (46.7%) patients responded to interferon therapy alone at the end of treatment. Three (21.4%) patients had a sustained complete response to a combination of interferon and amantadine, and 3 (20.0%) patients had a sustained complete response to interferon alone until 12 months after treatment. The response rates to combined therapy were not different from those with interferon therapy alone. We conclude that amantadine does not increase the efficacy of interferon in the treatment of chronic HCV infection.

3. The results of this study suggest ineffectiveness of amantadine.

PILOT STUDY OF INTERFERON-ALFA (IFNA) HIGH-DOSE INDUCTION THERAPY IN COMBINATION WITH RIBAVIRIN PLUS AMANTADINE FOR NONRESPONDER PATIENTS WITH CHRONIC HEPATITIS C

Thomas Berg, Uwe Hopf, Uta Naumann, Eckart Schott, Bertram Wiedenmann, Charite, Campus Virchow-Klinikum, Berlin Germany

Ribavirin/IFNa combination has led to a marked advance in the treatment of IFNa-naive or relapser patients with chronic hepatitis C but was shown to be only marginally effective in IFNa-nonresponders (with initial virological response rates of about 30% and sustained response rates of less than 10%). We therefore conducted a pilot study to see whether an intensified treatment protocol, combining high-dose IFNa-induction therapy with ribavirin plus amantadine might be more effective in inducing a virological response in patients who had not responded virologically to previous IFNa monotherapy.

Methods: 14 patients (mean age 51 years [32-69]; 9 males, 5 females, all but one infected with HCV genotype 1) with histologically proven chronic hepatitis C (8 patients with fibrosis stage 3, and one with stage 4) were included in the study. All patients were virological nonresponders concerning IFNa and had previously received at least 3 MU tiw for 12 weeks without normalization of ALT levels and still detectable HCV RNA by PCR (mean total IFNa dose 320 MU for a mean duration of 5 months). Patients received 9 MU IFNa-2a daily subcutaneously for 7 days followed by 9 MU IFN-2a every second day for 5 weeks. Afterwards (week 7-12) patients were treated with 6 MU IFN-2a tiw followed by 3 MU IFNa tiw (week 13-48). Ribavirn (1000-1200 mg/day) and amantadine sulphate (100 mg tid) was given orally for 48 weeks. Treatment was discontinued after 24 weeks in patients with still detectable HCV RNA by PCR.

Results: One patient discontinued therapy after first IFNa injection and one other patient after 10 weeks of therapy because of side effects. The remaining 12 patients completed treatment according to the protocol at least for 24 weeks (dose reduction of IFNa and ribavirin was required in one and three patients, respectively). Of these 12 patients, only two (17%) became HCV RNA undetectable at week 20 (and both patients had still HCV RNA detectable at week 12). In contrast, a decline in hepatitis C viremia was observed in all 13 patients after 4 weeks of therapy and 9 of them had a decline of 1 log (mean bDNA levels at baseline were 15.3 ± 2.97 MEq/mL and at week-4 1.6 ± 0.68 MEq/mL; p<0.0001). However, after this initial decline viremia stabilized in most patients (mean level at week-12: 1.4 ± 0.49 MEq/mL). ALT levels normalized in 6 patients by week 12.

Conclusions: Even triple therapy with high-dose IFNa plus ribavirin and amantadine fails to improve significantly the response rates in IFNa-nonresponders. The observed initial response rate of less than 20% is not superior to previous results in nonresponder patients receiving standard combination treatment with ribavirin plus IFNa.

4. This study does not find amantadine effective.

RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF INTERFERON-ALFA WITH AND WITHOUT AMANTADINE AS INITIAL TREATMENT FOR CHRONIC HEPATITIS C

Stefan Zeuzem, Gerlinde Teuber, Univ Hospital, Frankfurt a.M. Germany; Uta Naumann, Thomas Berg, Univ Hospital Charite, Berlin Germany; Jochen Raedle, Univ Hospital, Frankfurt a.M. Germany; Susanne Hartmann, Merz+Co, Frankfurt a.M. Germany; Uwe Hopf, Univ Hospital Charite, Berlin Germany

Amantadine (1-adamantanamine sulphate) is a chiral tricyclic amine that has been demonstrated to specifically inhibit the replication of the influenza A virus. Although the antiviral effects of amantadine have not been characterized for the hepatitisC virus (HCV), previous pilot studies suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the safety and efficacy of interferon-a2a alone or in combination with oral amantadine in previously untreated patients. 119 patients with histologically proven chronic hepatitis C received interferon-a2a at a dose of 6 MU tiw subcutaneously for 24 weeks, followed by 3 MU tiw for additional 24 weeks. Amantadine sulphate or a matched placebo was given orally 100 mg tid for 48 weeks. The baseline characteristics of the study group were: age 42 ± 12 yrs. (73 male, 46 female), ALT 59 ± 37 U/L, median pretreatment HCV RNA 0.49´106 copies/mL, HCV genotype 1 (69%), 2(5%), 3 (23%), 4 (2%), unknown (1%). According to the protocol, treatment was prematurely discontinued in 48/119 patients with detectable HCV RNA by reverse transcription-polymerase chain reaction (sensitivity 1000 copies/mL) 24 weeks after initiation of therapy. In 9 patients treatment was discontinued because of adverse events and in 9 patients due to non-compliance. WBC, hemoglobin and platelets decreased from baseline to week 4 from 6.4 ± 2.0/nL to 4.5 ± 1.2/nL, from 14.5 ± 1.3 g/dL to 14.1 ± 1.4 g/dL, and from 211 ± 60/nL to 161 ± 44/nL, respectively. Based on intent-to-treat analysis, serum ALT normalized by the end of treatment (week 48) and the end of the 24-weeks follow-up period in 43 and 24 patients, respectively. HCV RNA was undetectable in week 12, 24, and 48 of treatment in 57 (48%), 59 (50%), and 40 (34%), respectively. A sustained virological response as the primary endpoint of the study was achieved in 19 (16%) patients. The results remain tentative until unblinding of treatment groups in August 1999. In summary, the unblinded data suggest that sustained virological response rates of the combination interferon-a plus amantadine are not superior to combination treatment with interferon-a and ribavirin. Disclosure: This study was supported by Merz + Co, Frankfurt a.M. and Hoffmann-La Roche, Grenzach, Germany.

INTERFERON ALFA-2A IN COMBINATION WITH RIBAVIRIN AND AMANTADINE (TRIPLE THERAPY) IN HEPATITIS C PATIENTS WITH PREVIOUS NON-RESPONSE OR RELAPSE TO INTERFERON ALFA AND RIBAVIRIN COMBINATION THERAPY

Olle Reichard, Karolinska Inst, Stockholm Sweden; Karin Lindahl, Robert Schvarcz, Huddinge Hospital, Huddinge Sweden; Ingrid Uhnoo, Uppsala Univ, Uppsala Sweden; Steven Shev, Varberg Hospital, Varberg Sweden; Tony Carlsson, Karolinska Inst, Stockholm Sweden; Rune Wejstal, Gothenburg Univ, Gothenburg Sweden

Background: Interferon alfa (IFN) in combination with ribavirin (RIB) is today standard therapy for most patients with chronic hepatitis C virus (HCV) infection. However, many patients do not respond with a sustained HCV RNA clearance to this therapy. Recent preliminarey results have indicated that the antiviral drug amantadine (AMA) in combination with IFN is effective in non-responders to IFN monotherapy. Aim: To evaluate the efficacy and tolerability of IFN/RIB/AMA triple therapy in non-responders (NR) or response/relapsers (RR) to IFN/RIB combination therapy. Methods: In an open label pilot study, 23 patients, 13 NR and 10 RR to previous IFN/RIB therapy, were treated with subcutaneous IFN at a dose of 3 MU thrice weekly in combination with oral RIB 1000 mg/day, and oral AMA 200 mg/day for 24 weeks, with a 24 week follow-up period after end-of-treatment. Mean age was 45 years, 20 were males, and 5 had compensated cirrhosis. Mode of transmissions were posttransfusion in 5, intravenous drug use in 12, and unknown in 6. Genotype 1 was present in 7 out of 15 patients (47%) genotyped so far. Results: As yet, 19 patients (9 RR; 10 NR) have completed 24 weeks of IFN/RIB/AMA therapy. At end-of-treatment, 7/19 (37%)patients were HCV RNA negative. Six of these end-of-treatment responders were RR to previous IFN/RIB therapy. Thus, so far, only 1 NR to IFN/RIB has responded virologically to IFN/RIB/AMA therapy. Two patients discontinued treatment prematurely, at week 4 and 12, respectively, due to sleeping disturbances in one and alcohol abuse in the other. Otherwise, IFN/RIB/AMA therapy was generally well tolerated. Conclusions: Preliminary data from this open label pilot study does not seem to justify treatment with IFN/RIB/AMA in patients with a previous NR to IFN/RIB combination therapy. As for patients with a previous RR to combination therapy, sustained virological results to the triple therapy are still awaited. These results together with quantitative virological measurements will be presented.

AMANTADINE HCL + IFN IMPROVES RESPONSE IN NAIVE PTS: INTERIM EVALUATION OF A CONTROLLED STUDY.

A Mangia, I Cascavilla, M R Villani, A Andriulli, Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo

Background. Only 15-20% of naive pts with chronic hepatitis C achieve a sustained virological response with interferon monotherapy. Recently, it has been suggested that association of amantadine-HCI with IFN can improve the response rate of IFN monotherapy. Aim of this study was to compare efficacy and safety of IFN a2a alone or in combination with amantadine HCI for the treatment of HCV chronic hepatitis.

Patients and methods: 180 previously untreated pts with chronic HCV infection were randomly allocated to one of the two regimens 6 MU a2a three times weekly (Group 1) alone or in combination with amantadine HCI 100 mg twice daily (Group 2) for 12 mo. Biochemical response at 12 and 24 wks on Tx has been evaluated; virological at 12 wks. Preliminary 12 week, 24 week, and 1 year data are below.

Results: A limited number of patients are evaluable at 1 year (I think 50 of 90 in each treatment arm). Preliminary 3 and 6 month percent rate of either ALT normalization and HCVRNA negativity are shown in the table. Two and three pts in Group 1 and 2, respectively, discontinuated Tx for adverse effects. Pretreatment viremia levels (< or >200.000 Eq/ml) did not affect the response rate in each of the 2 groups. While in pts with genotype 2 the response was comparable in Group 1 (53%) and in Group 2 (59%), in pts with genotype 1 it was higher in group 2 (52%) than in Group 1 (18%) (p=0.01).

Conclusion: At 3rd and 6th mo of Tx, pts treated with IFN and amantadine show a significantly higher biochemical response than pts treated with IFN alone. This effect is particularly evident in pts with genotype.

At the end of 1 year of therapy, 38.2% of patients on the interferon plus amantadine group tested negative for HCV-RNA compared to 22.8% in the interferon only group. When broken down by genotype, the percentages of genotype 1 patients testing negative for HCV-RNA at the end of treatment was 35% for the interferon plus amantadine group compared to 8% for the interferon only group. For genotype 2, the results were 60% and 32%, respectively. These promising results are preliminary and in contrast to several studies finding amantadine not to be effective. Its my experience that if a treatment works in HIV this stark contrast of difference between studies would not occur.