HEPATOLOOY Vol. 34, No. 4, Pt. 2, 2001 AASLD ABSTRACTS 579A

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][-IIGI-I DOSE CONSENSUS INTERFERON INDUCTION THERAPY TO- GETHER WITH RIBAVIRIN FOR NAIVE PATIENTS WITH CHRONIC I~IEPATITIS C. Michael Fuchs, Thomas Witth0ft, Diether Ludwig, Eduard F Stange, Division of Gastroenterology, Medical University of Luebeck, Luebeck Germany

Despite recent advances in antiviral therapy for chronic hepatitis C, sustained virological response rates of all patients are approximately 40%. Improved response rates may be obtained with consensus interferon, especially in diffi- c.ult-to-treat patients with genotype 1 or high viral load. In addition, pharma- codynamic and viral kinetic studies indicate that dose and application fre- quency during the first weeks of therapy may determine treatment response. We hypothesized that a daily high dose induction therapy with consensus interferon in combination with ribavirin may improve sustained virological response rates in naive patients with chronic hepatitis C. We therefore initiated a pilot study to investigate the efficacy and safety of a regimen where patients were treated with 18/zg consensus interferon daily for 8 weeks. Thereafter 18/zg consensus interferon was given TIW for up to 48 weeks. Ribavirin was administered at a dose of 800rag/day throughout. So far we enrolled 22 patients at age 32-+9 (6 female) with histologically proven chronic hepatitis C (grade 1-3, stage 1-3) and elevated ALT values, The mean baseline viral load was 0.92-+0.25x106 IU/ml in females and 0.55-+0.39x106 IU/ml in males, 15 pa- tients had genotype 1 (68%). Quantitative and qualitative HCV-RNA levels were determined frequently employing standardized RT-PCR with lower sen- sitivities of 600 and 50 IU/ml, respectively. To date, 14 and 9 patients have completed at least 12 and 24 weeks of therapy, respectively. Within 2 weeks after initiation of treatment, HCV RNA was undetectable in 11 patients (50%). Viral clearance was highest with 79% after 8 weeks of therapy and remained unchanged thereafter. In general, therapy was well tolerated, severe side effects did not occur. The maximum drop in WBC, neutrophils and hemoglobin occurred between 4 and 8 weeks of therapy but neither the consensus inter- feron nor the ribavirin dose had to be reduced or stopped. These results suggest that a high dose consensus interferon induction therapy together with ribavirin may improve the efficacy of antiviral treatment. Further follow-up of this study will show whether the high initial viral clearance will translate into sustained viral response rates.

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RANDOMIZED, CONTROLLED TRIAL WITH INTERFERON-ALFA PLUS RIBAVIRIN WITH AND WITHOUT AMANTADINE SULPHATE IN PA- TIENTS 'WITH CHRONIC HEPATITIS C RELAPSING AFTER PRIMARY SUCCESSFUL ANTIVIRAL TREATMENT. Gerlinde Teuber, Med Klinik II, Frankfurt Germany; Pascu Maria, Universit~tsklinikum CharitG Berfirl Ger- many; Michael Lafrenz, Klinik und Poliklinik fflr Innere Medizin, Rostock Germany; Hans Weidenbach, Medizinische Universitatsklinik, Ulm Germany; Juergen Schoelmerich~ Klinik und polikfinik Innere Medizin, Regensburg Ger- many; P Wietzke-Braun, Abteilung far Gastroenterologie un dEndokrinologie, G6ttingen Germany; R Arnold, Zentrnm f~r Innere Medizin, Marburg Ger- many; J Pausch, Medizinische Klinik I, St~idtisches Klinikum, Kasse Germany; G Lock, Klinik und Poliklinik Innere Medizin, Regensburg Germany; U Junge, Klinik f~r Inhere Medizin/Gastroenterologie, Klnikum Rosenh0he, Bielefeld Germany; Eugen Musch, Abteilung f~r Innere Medicine, Marienhospita!, Bot- trop Germany; Stefan Zeuzem, II Medizinische Klinik, Frankfurt Germany

Retreatment with standard regimens of interferon-alfa (IFN-alfa) and ribavirin in patients with chronic hepatitis C relapsing after a primary successful IFN- alfa treatment showed therapeutic efficacy with sustained virologic response rates of approximately 40-50%. The aims of the present trial were to evaluate efficacy and safety of IFN-alfWribavirin retreatment with and without amanta- dine sulphate in a cohort of 61 patients (35 males, 26 females, mean age 46.4 years) relapsing after primary successful antiviral treatment. Patients received IFN-alfa2b 5 MU daily for 4 weeks~ 5 MU tiw for 20 weeks~ followed by 3 MU tiw for additional 24 weeks in combination with ribavirin 1000-1200 mg/d (n=28) or with IFN-alfa2b/ribavirin plus amantadine sulphate 100 mg bid for 48 weeks (n=33). Treatment was discontinued in patients with detectable serum HCV-RNA after treatment week 24. An overall sustained virologic re- sponse was achieved in 42/61 (69%) patients. Slightly higher sustained viro- logic response rates were observed in patients receiving triple therapy com- pared with those retreated with interferon/ribavirin alone (73% vs. 64%). However, the observed difference between the two treatment arms was not statistically significant (p=n.s.). Irrespective of treatment, patients infected with HCV-genotype non-1 were more likely to respond to antiviral retreatment than patients infected with HCV-genotype i (88% vs. 56%). In conclusion, the addition of amantadine sulphate to interferon/ribavirin retreatment did not lead to a signifcant improvement of antiviral efficacy. The observed relatively high overall sustained virologic response rate may be related to intensified interferon retreatment in combination with ribavirin compared with standard regimens.

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TRIPLE THERAPY FOR INTRON/RIBAVIRIN FAILURE PATIENTS WITH HEPATITIS C. FREILICH, B., WESTON, A., DEGUZMAN, L. Bradley Freilich, Baptist Medical Ctr, Kansas City, MO; Allan Weston, V A Medical Center, Kansas City, MO; Lino De Guzman, Arrowhead Regional Medical Ctr, Colton, CA

Clinical trials have shown that PEG-interferon alpha-2b in combination with Ribavirin is significantly more effective than standard Inron-Ribavirin for naive patients. No significant data has been published looking at Combination PEG- Intron Ribavirin treatment for the population of Intron-Ribavirin failures or nonresponders. Limited data on Triple Therapy with Intron/Ribavirin and Amantadine has shown both improvement and no significant difference in response compared to standard Intron-Ribavirin. Aim: The objective of this treatment protocol is to determine the benefit of combination Pegylated inter- feron and ribavirin, with or without Amantadine, for patients who have previ- ously failed treatment with Rebetron. Method: 200 patients will be enrolled. To date 120 patients have been enrolled. These patients, who have either fated to respond to Rebetron or who have relapsed after treatment with Rebetron, were randomly assigned to one of two treatment groups: Patients in Group 1 (Triple Therapy)recieved Pegylated interferon (1.0ug/Kg q week) + ribavirin (1000 rag/d) + Amantadine (200 rag/d). Patients in Group 2 (Dual Therapy) recieved Pe~zlated interferon (1.0ug/Kg q week) + ribavirin (1000 rag/d). 48 weeks of treatment is planned. Conclusions: Interim end of treatment results reveal no significant difference between Dual vs. Triple Therapy. The trend is in favor of Dual[ Therapy as being superior. Sustained response data for this group of Rebetron failures will be available as the study matriculates.

Results: Triple Therajoy . . . . . . Dual Therapy

-~'~' RNA Undetectable @ 48 wk 6/25 (24%) 9/29 (31%) Genotype 1 3/2"~ (14%) 5/22 (23%) Nonl~sponders 1/15 (7%) 4/20 (20%) Relapsers 2/6 (33%) t/2 (50%) Nongenotype 1 3/4 (75%) 4/7 (57%) Nonresponders 0/1 (0%) 1/2 (50%)

_Rela0sers 3/3 (100%) 3/5(60%)

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HIGH DOSE INDUCTION THERAPY WITH IFNot-2B + RIBAVIRIN IS EFFECTIVE IN NON-RESPONDERS TO PREVIOUS IFN THERAPY. Shiro Iino, St-Marianna University School of Medicine, Kawasaki Japan; Kyuichi Tanikawa, International Institute for Liver Research, Kurume Japan; Hiroshi Suzuki, Yamanashi University School of Medicine, Yokohama Japan; Koichi Kanai, Toshiba Hospital, Tokyo Japan; Japan Ribavirin Study Group, Japan, Osaka Japan

Background: Among patients with chronic hepatitis C, non-responders to pre- vious treatment with IFN (HCV RNA clearance not observed at the end of treatment) along with patients with genotype lb and high viral titers are re- fractory to treatment. In particular, non-responders with genotype lb and high viral titers are the most difficult patients to treat. Di Bisceglie et al. conducted a study to compare one-year and 6-month treatment with 3 MIU of IFNcr-2b administered 3 times a week in combination with ribavirin. Regardless of the duration of treatment, the sustained viral response (SVR) rate was reported to be about 30%. Objective: Efficacy of 6-10 MIU of IFNa-2b + ribavirin combi- nation therapy was examined in patients determined to be non-responders to previous IFN therapy. Methods: 96 patients who were non-responders to pre- vious IFN therapy were pooled from the two multi-center double-blind studies conducted in Japan. The efficacy of high doses of IFNa-2b in combination with ribavirin was examined by comparison with IFNcr-2b monotherapy. SVR (HCV RNA negativity at 24 weeks after the end of treatment) was used for the evaluation of efficacy. Results: 52 patients received combination therapy and 44 received monotherapy. No difference between the groups was observed in gender, age, and viral load. HCV genotype lb accounted for 94% of patients in the combination therapy group and 90% in the monotherapy group. SVR was observed in 19% with combination therapy in contrast to 2% with mono- therapy, and the difference was statistically significant. SVR by patient back- ground factor in the combination therapy group was 17% (8/47) in genotype lb and 100% (1/1) in genotype 2a. SVR by viral load was 14% (5/37) with 500 Kcopies (RT-PCR) or more and 38% (5/13) with less than 500 Kcopies. Factors contributing to SVR were examined by logistic analysis, and treatment group (combination vs monotherapy) and pretreatment viral load were considered factors affecting response. Conclusions: IFNa-2b at the dose of 6 or 10 MIU in combination with ribavirin was administered for 6 months to CHC patients who were non-responders to previous IFN therapy. SVR rate in cases of geno- type lb and high viral titers was significantly higher at 19.3% (9.6-32.5%) with combination therapy than with monotherapy at 2% (0.1-12.0%), and efficacy also in non-responders to previous IFN therapy can be expected with the increase in IFN dose.