120A AASLD A B S T R A C T S HEPATOLOGY October 1995

53 INTERFERON-alpha AND TAUROURSODEOXYCHOLIC ACID IN CHRONIC HEPATITIS C: A NOVEL THERAPEUTIC COMBINATION. M. Angelico, C. Gandin, C. Del Vecchio, C. Plat, A. aini, T~ La Rosa, E.Pescarmona, L.Ca~ocaccia. Dpt Publ Hlth, Tot Vergata Univ and 2nd GI Div, La Sapienza Univ,Rome, Italy,

Interferon-alpha (IFN-a) is of limited long-term value in chronic hepatis C and rarely eradicates the virus. Adjuvant drugs are under investigation, Two recent trials have shown that ursodeoxycholic acid (UDCA), given during and after IFN-a, delays the onset of relapse after IFN-a withdrawal. Tauroursodeoxycholic acid (TUDCA) might be a better choice, as, in experimental models, it is clearly more cytoprotective than UDCA. We thus compared the efficacy of two time-schedules of a combination of IFN-a (6 megaU t.i.w.) and TUDCA (250 mg b.i.d) on biochemical and histological features of chronic hepatitis C. Forty anti-HCV+ pts were randomized to receive: l ymphoblastoid IFN-a, from day 0 to 180, plus TUDCA, from day 61 to 240 (IFNa+TUDCA); or TUDCA, from day 0 to 180, p!ua IFN-a from day 61 to 240 (TUDCA+IFNa). All patients underwent liver biopsy before and 2 months after IFN-a cessation. Disease activity at entry was similar in the two groups. Treatment was completed by 18 and 19 patients respectively, who then underwent 12 months of follow-up, on average, TUDCA administration was followed by a 20% drop in ALT values, either when given alone or with IFN-a. Non responders during treatment were 5 of 18 in the IFNa+TUDCA and I0 of 19 in the TUDCA+IFNa group (p= 0.11). Long-term reaponders were 7 and 3, respectively (p=0.096). Comparison of paired biopsy specimens showed that the combined inflammatory histology scores decreased by 1.25~0.81 in the IFNa+TUDCA (p=0.154) and by 0.21+067 (n.s.) in the TUDCA+IFNa groups. The average length of normal ALT was 8.7~1.8 (s.e.m. l and 4.7~1.8 months, respectively (p= 0.067). We conclude that IFNa followed by TUDCA seems to be better than TUDCA followed by IFNa, although larger trials are needed to achieve statistical significance.

54 TAUROURSODEOXYCHOLIC ACID FOR THE TREATMENT OF CHRONIC HEPATITIS: A DOSE-RESPONSE STUDY M.Podda. A.Crosi~nani. PM.Battezzati. L.Buscarini. D.Conte. A.Notarbartolo. A.Floreani. R.Stabilini. Manehisi O,Q,. Departments of Internal Medicine and of Gastroenterology, University of Milan, Piacenza, Palermo, Padova, Monza, Castellana Grotte

Retention of detergent endogenous bile acids may aggravate hepatocellular damage in patients with necroinflammatory liver disease. Tauroursodeoxycholic acid (TUDCA), a highly hydrophilic bile acid, was shown to counteract the detrimental effects of endogenous bile acids in experimental models and, more recently, to have distinct metabolic properties compared with the unconjugated ursodeoxycholic acid. We designed a muhicenter randomized study aimed at assessing the optimal dose of TUDCA for patients with chronic hepatitis (CH). In 7 Italian centers 155 patients with histological diagnosis of CH were enrolled into the study. They were randomly assigned to receive a 6-mo. course of TUDCA at the daily doses of 250 mg, 500 mg, 1000 mg, or no treatment. Serum liver enzymes were measured at entry and after 1, 3 and 6 mos. The large majority of patients, i,e. 86%, had HCV-related liver disease. Twelve patients left the study before the first month of treatment and were excluded from the analysis. Only two patients were withdrawn for minor side effects (one for diarrhea and one for dyspepsia). AST, ALT and Gamma-GT decreased in patients administered TUDCA compared to patients receiving no treatment (p <0.001). After 6 mos. of treatment ALT decreased by 14%, 23% and 37% with 250, 500 and 1000 mg of TUDCA, respectively. In patients administered 1000 mg/day of TUDCA, the degree of improvement of serum liver enzymes was significantly higher compared with the group administered 250 mg (p <0.05). Interestingly, a significant time effect was found only for the two higher doses which showed a progressive linear improvement of ALT with time (p <0.05 for interaction between time and dose). In conclusion, TUDCA is safe and effective in improving serum liver enzyme levels in patients with CH. Further studies with clinically relevant end-points are warranted. According to our data, daily doses of about 15 mg per Kg b.w. are suggested.

55 LONG-TERM TREATMENT WITH DIFFERENT REGIMENS OF RECOMBINANT INTERFERON ALFA IN CHRONIC HEPATITIS C M.Podda, PM.Battezzati, M.Zuin, S.Bruno, "tP.Gallotti, ̂ M.Borzio. ^F. B0rzio, *F.Fornari. *A,Laazini. **A.Salmi, A.Russo Depts. of Internal Medicine, University of Milan and of *Brescia; ̂ Fatebenefratelli, Milan, tVigevano, )Piacenza, and **S.Orsola, Brescia Hospitals

Sustained response rates following treatment of chronic hepatitis C with standard interferon regimens are unsatisfactory. Extension of treatment duration has been suggested to improve response rate in spite of increased costs. We designed a multicenter study to evaluate cost- effectiveness of recombinant interferon alfa-2a (IFN) treatment for 18 mos. according to different schedules. Patients with chronic hepatitis C and ALT levels persistently >2 x N over the 12 mos. before admission, who were not drug addicts, or HIV positive, or alcohol abusers were enrolled. Patients showing ALT <1.5 x N after an initial 3-mo. course of treatment with 6 MU t.i.w. IFN were randomly assigned to regimen A (3 MU t.i.w, for an additional 15 mos.), or to regimen B (4.5 MU b.i.w, for 2 mos., followed by 4.5 MU once weekly for 13 mos.). Liver histology was assessed at baseline and after 24 mos. (6 mos. after discontinuation of IFN). Evaluation of virologic markers included HCV RNA genotyping and quantification. Of the 263 patients enrolled in the 6 participating centers, 167 (63%) had serum ALT <1.5 x N after the initial IFN course, and 160 accepted to continue IFN treatment according to regimen A (n.=86; mean age+SD, 50+13 yrs; 64% men; 24% with cirrhosis; baseline ALT, 4.2+_2.3 x N) or B (n.=74; mean age, 50-!-_13 yrs; 60% men; 26% with cirrhosis; baseline ALT, 3.6+2.3 x N). Normal ALT at 18 mos. was found in 49% of patients allocated to regimen A and in 45% of those allocated to regimen B; normal ALT was maintained between time of response and 18 mos. in 27% and in 19%, respectively; normal ALT was maintained up to 24 mos. by 21% and 16% of patients, respectively. No significant difference was found between the two regimens when the above outcomes, as well as the area under the ALT curve, were compared. Among the initial 263 patients, 11% maintained a response up to 24 mos. after the initial response. Lower IFN doses than those used in the standard regimen may be used in patients treated with an initial course of 6 MU t.i.w, for maintenance of response. However, even after 18 mos. of treatment sustained response rates are disappointingly low.

56 INTERFERON THERAPY INDUCES SUPEROXIDE=DISMUTASE ACTIVATION. C. Lo~uercio, F.Morisco, P. Piscopo, G. lasevoli, G, Sessa, C.Tucci l lo. Gastroenterologyj 2th Universi ty,Naples, I ta ly .

I t is known that in ter feron( IFN}generates superoxide an- ion and hydrogen peroxide in the hepatocytes of experimen- tal animals.Superoxide-dismutase(SOD}is the enzyme that c_aa talyzes the dismutation of superoxide to hydroperox ide; th is oxidant species may react with the cellular membranes indu- cincj l ipoperoxidat ion. ln this study we prel iminarly evaluate 10 patients with b iopsy-proven HCV-related chronic hepati- t is{8 men and 2 females,aged between 37 and 59 years,medi an 40)in basal conditions(El)and 1,2,3 and 4 weeks af ter the rapy with alpha-IFN(6MU three times a week).We determined plasma levels of aminotransferases and l ipoperoxides{LPO) and malonaldehyde(MDA}.ln addition we evaluate SOD act iv i - ty and LPO and MDA levels in the ery throcy tes . Results are reported in the Table{mean+ 5D}.

~3 I 2 3 4 LPLI 0.20+0.07 0.29+0.1 0.25+0.09 0.26+0.05 0.25+0.08 (nmlml] MDA 0.26+_0.03 0.27+0.04 0.25+_0.04 0.26+_0.03 0.26+-0.03 (nmlml) SOD 0.70+0.10 2.89+0.79* 0.71+0.10 1.10+0.90 0.82+0.10 (U/ml) *P<0.001 vs B

Similar results were obtained for plasma values. IFN induced a marked increase of SOD part icu lar ly in patients with per- sistent ly high levels of aminotransferases at 4 weeks.These data suggest that IFN induces free-radical production act iva t ing SOD in the c i rcu lat ion, that bloks the fu r ther progress- ion of l ipoperoxidat ive processes.