Serial analysis of serum metalloproteinase-2 and-9 in human chronic liver diseases

AASLDA1459

April 2000

detect early emotional distress . In depre ssed patients, IFN therapy may be completed with concomitant SSRI medic ation. Depression Scores (HAOS) durtng IFN alpha

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6613 HIGH DAILY DOSING INTERFERON-ALPHA IN MONOTHERAPY, DOUBLE AND TRIPLE THERAPY OF HEPATITIS C NONRESPONSER PATIENT. Ulrike Kullig, Heiner Porst, Manfred Wie se, Andreas Herrmann, U. Sundermann, U. Oesen, R. Behrens , Dept Internal Medicine, Dresden , Germany ; St George's Hosp, Leipzig , Germany; Univ, Jena, Germany ; Hosp, Erfurt, Germany; Hosp, Chemnitz , Germany ; Pract, Halle, Germany . No effective treatment of interferon-nonresponders have been recommended . Hence, we investigated if the effect of high-dose IFN-induction therapy can be enhanced by addition of ribavirin, or ribavirin and amantadine. Methods: A total of 64 patients with histologically proven hepatit is C (grading 1-3, staging 1-4),46 years old (median), 48% males, genotype I in 94%, baseline virus load of > I million copieslml in 77%, were included. Therapy regime: groupA : IFN-alpha-2 a: week 1-4: 9MU daily, week 5-24: 6MU every other day, week 25-72 : 3MU every other day; groupB : additionall200mg ribavirin daily (week 1-24), groupC: additional 1200mg ribavirin and 200mg amantadine daily (week 1-24). Patient s with < 100 copies/ml were defined responder s. Results: of treatment 45 weeks meen duration: Conclusions : Retreatment of nonresponders with high-dose IFN plus ribavirin is much more effective than with high-dose IFN alone, however the addition of amantadine does not improve the results of the double therapy. group A (IFN.monotherapy) B(IFN, ribavirin) C(IFN, ribavirin, amantadine)

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6614 COMBINATION THERAPY WITH INTERFERONA AND rINCREASES HOST IMMUNE RESPONSE IN PATIENTS WITH CHRONIC HEPATITIS C. Ryukichi Kumashiro , Tatsuya Ide, Masaru Sasaki, Shiro Murashima, Hiroshi Suzuki, Hiroshi Yoshida , Toshih iko Kawahara, Kazuhisa Gondo, Naoto Maruyama , Shotaro Sakisaka , Kyuichi Tanikawa, Michio Sata, Kurume Univ Sch of Medicine, Kurume , Fukuoka, Japan; Yame Public Gen Hosp, Yame, Fukuoka , Japan; Asakura Hosp, Amagi,Fukuoka, Japan ; Yanagawa Hosp, Yanagawa, Fukuoka, Japan ; Maruyama Hosp, Dazaifu, Fukuoka, Japan; Inti Institute for Liver Research , Kururne, Fukuoka, Japan . Purpose: The aim of this study is to evaluate the efficacy of combination therapy with interferon aand yas retreatment of chronic hepatitis C as well as the patient responses to this combinat ion therapy . Patients and methods: 19 patients with chronic hepatiti s C with genotype Ib who were non responders or relapseres in their previous therapy using IFNEaandior IFNJ3. They received natural IFNa5MU daily for 2 consecutive weeks and 3 times a week for the next 22 weeks followed by natural IFN)'IMU daily for 2 consecutive weeks . Biological and virological response were monitored and followed up until 24 weeks after the treatment. Parameters of host immune reponses and cytokines related to Th I and Th 2 were also evaluated during the combination therapy. Results: Four of 17 patients (23.5%) who completed the treatment regimen were biologically complete responderes, I (5.9%) was partially responded and the rest of 12 (70.6%) were non-responders as evaluated by serum alanine aminotransferase. In three of these 4 complete responders (75.0%), HCV RNA was not detected at the end of observation period and they were classified as virological responders. Serum levels of beta 2 microglobuli n (BMG), neopterin, soluble (s) Fas, sILl2, CD8 and IFN)'Were significantly increased at the end of the combination therapy. Ratios of BMG 1 sILl O, sFas 1 sILl 0, sILl 2 1 sILl 0, neopterinlsIL6 and neopterin 1 sILl 0 significantly incereased. Production of If'Nyand TNFaby peripher al monocytes showed significant augmentati on. Ratios of cytokine producti on according to Th 11 Th 2 showed a significant increase in IFN)'I IL 4 , IFN)'I IL 10 and in TNFal IL 5 . No serious adverse reaction s were observed . Conclusion: Combination

therapy with interferon aand yas retreatment for chronic hepatitis C suppresses HCV in a small subset of patients who had been non-resp onder s to their previous therap y with interferon. And it also augment s host immune responses related to Th I cells which are necessary to eradicate HCV and to stop hepatocellular carcinoma from developing.

6615 SERIAL ANALYSIS OF SERUM METALLOPROTEINASE·2 AND-9 IN HUMAN CHRONIC LIVER DISEASES. Wu-Hsien Kuo, Hsio-Chin Lu, Fen-Pi Chou, Yih-Shou Hsieh, Div of Gastroenterology, Armed Forces Taichun g Gen Hospi, Taichun g County, Taiwan, ROC ; Dept of Lab Medicine, Armed Forces Taichun g Gen H, Taichung County, Taiwan , ROC; Institute of Biochemistry, Taichun g City, Taiwan, ROC; Chung-Shan Medical and Dental Coli , Taichun g City, Taiwan, ROC. Background : A mjor pathological change during the progre ssion of liver disease is the quantity of extracellular matrix protein . Deregulation of matrix metalloproteinases (MMPs) activity is accused being one of the factors responsibe for the alternation of the extracellular matrix in Liver disease. Change in the expre sion of matrix metalloproteinase during the hepatocyte injury may result in fibrosis. In this study we investigate the role of matrix metalloproteinases in the fibrogenesis and as a marker for hepatocellular carcinoma in human chronic liver disease. Methods: Serum from 667 patients with different stage of chronic liver disease (healthy control, patients diagonsed with carrier that were positive for HBsAg, both HBsAg and HBeAg, or HCV Ab, chronic hepatitis B or chronic hepatitis c.liver cirrhosis, and hepatocelluar carcinoma) were collected to measure MMPs activity by gelatin zymography. Results : All of the viral liver disease patients have significantly lower level of MMP-9 and higher levels of MMP-2 than normal control(P
6616 ALPHA-INTERFERON WITH RIBAVIRIN FOR THE TREAT· MENT OF CHRONIC HEPATITIS C IN TREATMENT NAIVE PATIENTS. Paul Y. Kwo, Sheryl Fields, Naga Chalasani, Won Cho, David W. Crabb , Oscar W. Cummings , Th omas Imperiale , James M. McGill , Reid Ness, David Pound, Robert Pintozzi, Charles Lansford, Indiana Univ Med Ctr, Indianapolis" NB; Indiana Univ Med Ctr, Indianapolis, IN. Combination therapy with ribavirin plus interferon is more beneficial than interferon (IFN) alone for treatment of naive patients and in retreatment of interferon relapsers and non-responders with chronic hepatitis C. Our Aim was to determine the efficacy of combination therapy with alpha-interferon 3 MU Trw and oral ribavirin 1000 mg daily for 48 weeks with the primary endpo int of sustained virologic response (SVR) at week 72. Methods: Subjects received IFN 3 MU TIW and ribavirin 1000 mg daily for 48 weeks. HCV RNA by RT-PCR was obtained at 0, 12,48, and 72 weeks; ALT was assayed at baseline and at 4 week intervals , liver biopsy was obtained within 2 years of entry. Results : 108 subjects (7 1M, 37F) were enrolled with a mean age of 45 ± I years. 77% of subjects had HCV genotype la or lb. By liver biopsy, 22/94 (23%) subjects have cirrhosis thus far. Mean (± SEM) baseline values were as follows: ALT: 103± 8 IU/mL ; HCV RNA by RT-PCR : 3.0 x 106 ± 0.2 x10 6 copies/mL; Hgb: 14.9 ± 0.1 g1dL. 22 patients withdrew due to side effects, 15 withdrew due to lack of response (week 24), and 3 were lost to follow-up . The virologic response rates at weeks 12 and 48 were 40% (43/108) and 31% (31/ 10I) respectively thus far. The SVR at week 72 is 25% (24/96) thus far. There were no statistically significant difference s in SVR for genotype 1 vs other (2 1% vs 35%) and for cirrhotic vs non-cirrhotic disease (16% vs 29%). As compared to previously published US data with 48 weeks of interferon and ribavirin (NEJM;339:1485), SVR was lower (25% vs 38% (87/228); P=0.02) by intention to treat analysis. In a per protocol analysis the SVR was not statistically different from the US trial (31% (23n 5) vs 38% (87/228); p=0.24). Compared to this US trial, there was a higher proportion of cirrhotic patients (23% vs 7%; p