Pegylated Interferon

A controlled, randomized, multicenter, ascending dose phase II trial of Pegylated interferon alfa-2a (PEG) vs standard interferon alfa-2a (IFN) for treatment of chronic hepatitis C
     Mitchell Shiffman, Med Coll of Virginia Commonwealth Univ, Richmond, VA; Paul J Pockros, Scripps Clin and Res Instute, La Jolla, CA; Rajender K Reddy, Univ of Miami, Miami, FL; Teresa L Wright, Veterans Affairs Med Ctr, San Francisco, CA; Robert Reindollar, Charlotte Clin, Charlotte, ND; Michael W Fried, Univ of North Carolina, Chapel Hill, NC; Preston P Purdum III, Charlotte Clin, Charlotte, NC; Gregory Everson, Univ of Colorado, Denver, CO; Simon Pedder, F. Hoffman-La Roche, Ltd., Nutley, NJ; PEG-IFN alfa-2a Clinical Study Group

IFN therapy has limited efficacy for treatment of chronic HCV. This may result from its limited half-life (4-6 hrs). In contrast, PEG has a serum half-life of >90 hrs, allowing this agent to be dosed once weekly (QW). The objectives of this study were to evaluate the safety and efficacy of PEG relative to standard IFN. Methods: 155 pts ages 18-57 yrs with anti-HCV (+), HCV-RNA (+), serum ALT > 1.5 ULN and no cirrhosis were enrolled. Pts received either IFN 3 mU TIW or one of four doses of PEG (45, 90, 180, 270 mg) SQ QW. Pts were treated for 48 wks followed by a 24 wk observation period and repeat LBX. HCV-RNA titer was assessed by Amplicor with lower limit of 2000 copies/mL. Results: TABLE illustrates % of pts HCV-RNA (-) at various times. Sustained response (SR) for 270 mg will be available in Feb '99. SR increased stepwise with increasing PEG dose to an efficacy plateau at 180 mg. Adverse events were similar to IFN. PEG resulted in a dose-dependent decline in PMN, but no pt required discontinuation of tx due to this effect. Conclusions: PEG is a more effective and convenient tx for chronic HCV than IFN. The optimal dose of PEG appears to be 180 mg QW which produces similar SR as that reported for IFN/ribavirin therapy.

The pharmacokinetics of pegylated-40K interferon alfa-2a (PEG-IFN) in chronic hepatitis C (CHC) patients with cirrhosis
     Elizabeth Jenny Heathcote, The Toronto Hosp, Toronto Canada; Paul J Pockros, Scripps Clin and Res Instute, La Jolla, CA; Michael W Fried, Univ of North Carolina, Chapel Hill, NC; M A Bain, Univ of Alberta, Alberta Canada; J DePamphilis, Marlene Modi, F. Hoffman-La Roche Ltd., Nutley, NJ; PEG-IFN alfa-2a Clinical Study Group

The cirrhotic CHC pt is the most difficult to treat. Even if the pt is not successfully treated for hepatitis C, treatment with interferon alfa may decrease the risk of progression to hepatocellular carcinoma. PEG-IFN is a modified form of recombinant interferon a-2a by covalent attachment of a branched methoxy polyethylene glycol moiety. Pegylation results in reduced renal clearance of the molecule as a mass of 40-60 kDa is required to retard glomerular filtration. The objective of this study was to examine the pharmacokinetics of PEG-IFN in CHC pts with cirrhosis participating in a phase II parallel dose study evaluating the safety and efficacy of PEG-IFN.

Methods: 40 pts ages > 18 yrs with anti-HCV (+), HCV-RNA (+), serum ALT > 1.3 ULN, and compensated cirrhosis or transition to cirrhosis were evaluated. Pts received either 90 or 180 mg PEG-IFN SQ QW for 48 wks followed by a 24 wk observation period. Serial blood samples were collected after the first PEG-IFN dose and after the dose at 48 weeks of treatment, and trough samples were collected monthly.

Results: Dose proportional increases in peak PEG-IFN serum concentrations occurred at about 80 hours after the first dose (Cmax: 4.9±2.5 and 7.8±0.7 ng/mL, 90 and 180 mg doses, respectively). PEG-IFN was slowly cleared as seen by sustained levels over the first week of dosing. The terminal half-life was approximately 70 to 90 hrs. Steady-state trough concentrations were proportional to dose and predictable from single dose data (trough concentrations: 6.1±3.6 and 12.3±3.6 ng/mL, 90 and 180 mg doses, respectively).

Conclusions: PEG-IFN kinetics in CHC pts with cirrhosis are similar to those reported in healthy volunteers and CHC patients without cirrhosis. Therefore, once weekly dosing of PEG-IFN is feasible in cirrhotic pts.

Relapsers May Benefit From Induction

A randomized trial of daily INF vs TIW for 1 month followed by TIW INF combined with ribavirin for a total of one year.
     Robert G. Gish, Francis Yao, Fred Poordad, Linda Brooks, Geraldine Cain-Shulze, RIBA-HEP Study Group, CA Pacific Med Ctr, San Francisco, CA

Background: The optimal dose, frequency and duration of interferon (IFN) (Intron-A")/ribavirin (Rbv) (Rebetol") combination {Rebetron"} for the treatment of hepatitis C (HCV) has yet to be defined. Preliminary studies have suggested that daily IFN is better than three times per week. Patients who have failed IFN therapy (nonresponders and relapse) may benefit from a second treatment course.

Methods: Patients were randomized to either daily or TIW interferon at 3MU for the first month. All patients are being treated with IFN TIW dosing thereafter for a total of one year. Ribavirin dosing was 1 gm per day for the treatment interval. Patients were defined as treatment failures if the patient was HCV RNA+ or ALT abnormal during or after treatment with any type of interferon. Relapse patients had a normal ALT or negative RNA on treatment. Inclusion required a minimal treatment during the first course of interferon of 3MU TIW for 3 months, maximal treatment of 1.2 billion units of interferon. This data analyzed whether there is difference at 3 mo. in nonresponder and relapse patients.

Results: 426 patients were randomized for therapy. HCV RNA data is available at 3 months on 232 patients. 86 patients (37%) are HCV RNA negative at 3 months. Of the 165 nonresponder patients, 50 (30%) have cleared HCV RNA during the second course of treatment, 42% in the daily treatment gp, and 58% in the TIW gp. Of the relapsers, 36 (53.7%) cleared RNA, 58.3% in the daily gp, and 41.6% in the TIW gp.

Conclusion: There appears to be an encouraging initial response rate for combination therapy in the patients who have failed interferon therapy. Further data will need to be collected to determine efficacy at the end of treatment and differences in durable response. Supported by a grant from Schering-Plough.

Amantadine and Rebetron' exert a synergistic antiviral effect on HCV replication in Interferon-a non-responders with chronic hepatitis C.
     Stefano Brillanti, Fabio Levantesi, Mauro Foli, Maddalena Di Tomaso, Luigi Bolondi, PoliClin S. Orsola Malpighi, Bologna Italy

Interferon-a plus ribavirin (Rebetron') is the treatment of choice for chronic hepatitis C, but it is of limited value in IFN non-responders. Amantadine may have a possible role in hepatitis C therapy, but no real efficacy has been proven. AIMS: We performed a study to assess whether amantadine exerts a synergistic antiviral effect in combination with Rebetron in patients who failed previous interferon-a therapy.

METHODS: Sixty consecutive interferon-a non-responders (with compensated liver cirrhosis in 25%, and HCV genotype 1 in 65%) were randomized (1:2) to receive either interferon-a (5 MU tiw) + ribavirin (0.8-1.0 gm/day) (20 pts) or the same therapy + amantadine (200 mg/day) (40 pts) for 12 months. ALT, qualitative HCV RNA (Roche HCV Amplicor), and quantitative HCV RNA (Roche HCV Monitor 2.0) were assessed throughout treatment period.

RESULTS: A biochemical & virological end-of-therapy response (ETR) was observed in 23/40 pts (57.5%) treated with triple therapy. Median ALT values significantly decreased from 124.5 (42-502) to 30 (8-77) U/L (p<0.0001). HCV RNA geometric mean titer significantly decreased from 5.46 to 3.74 (p=0.0014) during the first 2 months of therapy. This decrease was maintained during therapy and was observed both in patients with ETR (from 5.20 to 1.53, p<0.001) and in those without ETR (from 5.64 to 5.29, p=0.033). On the contrary, in patients treated with double combination therapy, biochemical ETR was observed in 4/20 (20%) and no significant decrease in HCV RNA geometric mean titer occurred.

CONCLUSIONS: Amantadine, in combination with Rebetron, exerts a significant synergistic antiviral effect on HCV replication in IFN non-responders with chronic hepatitis C.

Biochemical Responders with HCV Viremia Have a Reduced Risk of HCC
     Haruhiko Yoshida, Univ of Tokyo, Tokyo Japan; Y Arakawa, Nihon Univ, Tokyo Japan; Osamu Yokosuka, Chiba Univ, Chiba Japan; T Kuroki, Osaka City Univ Med Sch, Osaka Japan; Michio Sata, Kurume Univ, Fukuoka Japan; Shigetoshi Fujiyama, Kumamoto Univ, Kumamoto Japan; Michitami Yano, Nagasaki Chuo Hosp, Nagasaki Japan; Gotaro Yamada, Kawasaki Medical Sch, Okayama Japan; Masao Omata, Univ of Tokyo, Tokyo Japan

Aims:The IHIT (Inhibition of Hepatocarcinogenesis by Interferon Therapy) cohort study started in 1994 to evaluate the effects of IFN on the prevention of HCC. One tenth of IFN treated patients achieved sustained ALT normalization in spite of persistent HCV viremia (HCV+ve BR). They were compared with virological sustained responders with normalization of ALT (HCV-ve BR).

Methods:Among 2,358 hepatitis C patients treated with IFN, 789 (33.5%) achieved HCV-ve BR and 260 (11.0%) achieved HCV+ve BR. Predictive factors for each response were analyzed with multivariate logistic regression. The relative risk of HCC (87 events among 2,333 during 1,631 days' observation) was evaluated with a Cox proportional hazard model.

Results: Odds ratios of HCV-ve BR; age (by 1 yr): 0.985 (0.975-0.995), male: 1.584 (1.239-2.026), fibrosis F4 (vs. F0/F1): 0.471 (0.273-0.714), high HCV load: 0.214 (0.134-0.342), HCV serotype 1 (vs.2): 0.196 (0.155-0.247), high IFN dose: 0.725 (0.575-0.914). Odds ratios of HCV+ve BR; F2: 0.511 (0.349-0.747), F3: 0.340 (0.212-0.545), F4: 0.178 (0.082-0.388), serotype 1: 0.411 (0.283-0.598), high IFN dose: 0.610 (0.436-0.852), cf. HCV load: 0.766 (0.494-1.188). Relative risks of HCC; age: 1.072 (1.043-1.101), male: 2.227 (1.390-3.567), F2: 5.405 (1.246-23.44), F3: 14.58 (3.496-60.78), F4: 27.96 (6.648-117.6), HCV-ve BR: 0.273 (0.141-0.532, P=0.0001), HCV+ve BR: 0.295 (0.092-0.939, P=0.0388).

Conclusions: Predictive factors for HCV-ve and +ve BR were similar except that HCV+ve BR was more strongly associated with the stage of fibrosis and not with HCV load. The risk of HCC was reduced among subjects with HCV+ve BR as well as among those with HCV-ve BR.

Induction Therapy With Interferon Alone

Daily Dose Induction With Interferon-Alpha 2B (IFN) Results in High Early Remission Rate in Naive Subjects With Chronic Hepatitis C
     Michael F Lyons II, C M Varon, A K Coddou, P A Taylor, J G Carrougher, G E Schlepp, R D Baerg, W M Priebe, S A Streett, Tacoma Digest Disease Ctr, Tacoma, WA

Recent results of the Hepatitis Interventional Therapy Group (NEJM 1998;339:1485-92) demonstrated an end of treatment response of 24% for 48 weeks of three times weekly IFN and 50% for 48 weeks of three times weekly IFN + ribavirin in subjects with chronic hepatitis C (HCV). The purpose of this study was to see if higher remission rates could be achieved by daily dose induction therapy with IFN alone for three months followed by 3 million units three times weekly.

METHODS: Naive subjects with chronic HCV were randomized to either 3 million or 5 million units subcutaneous IFN daily for three months. If they were HCV RNA polymerase chain reaction (PCR) negative at 3 months, the dose was then reduced to three times weekly injections of 3 million units for 48 weeks total therapy. If the PCR was positive at three months they were considered treatment failures. The National Genetics Institute PCR assay was used. This study was approved by the Western Institution Review Board.

RESULTS: 52 subjects were enrolled. 13 individuals dropped out of the study prior to the first 3 month evaluation period due to side effects. Of the remaining 39, 25 (64%) were PCR negative and 14 (36%) were PCR positive at 3 months. 8/14 (57%) of non-responding individuals had a 4 logarithm reduction in PCR. Only 2 subjects did not have any response to daily therapy. There was no difference in response between the 3M and 5M dose groups. 58% of the PCR negative cohort was genotype 1a or 1b. 64% of the PCR positive group had genotype 1. Of the evaluable subjects 6 months into treatment, 70% have remained in remission.

CONCLUSIONS: 1) High rates of remission can achieved with daily dose IFN, even among genotype 1 subjects. 2) 3 million units of IFN seem to be as effective as 5 million units to achieve remission. This research was supported in part through an unrestricted grant provided by Schering-Plough Corporation.

Do Antioxidants Ameliorate Ribavirin Related Anemia in HCV Patients
     Clifford A Brass, Schering Lab, Oncology Biotech, Kenilworth, NJ; E Piken, South Bay Gastroenterology, Torrance, CA

Based on a large increase in efficacy, combination therapy with inteferon a-2b plus ribavirin has become the standard of care for the treatment of chronic HCV. However, this therapy causes ribavirin induced hemolysis, which leads to a 3 gm drop in hemoglobin necessitating dose reductions in about 15% of patients. Although the exact mechanism of this hemolysis has not been defined, a leading hypothesis is that the accumulation of ribavirin in the red cell leads to an overwhelming oxidative stress. Aim: Therefore, we conducted a pilot study to see if the concurrent use of over the counter antioxidants would ameliorate the anemia seen with interferon/ribavirin therapy.

Methods: Twelve consecutive treatment naive patients with chronic HCV were treated with 1,200 mg of ribavirin in 2 divided doses each day (1,000 mg if BW<75 kg) plus 3 MU interferon a-2b SQ TiW. These patients were also given over the counter preparations of vitamin C (1,000 mg) and vitamin E (800 IU) daily (AO). Controls (C) consited of 14 matched relapse patients from the same clinic who received 1,000 mg of ribavirin daily plus 3 MU interferon a-2b SQ TiW. Hemoglobin was measured pre-therapy, and at weeks, 2 4, 8, and 12.

Results: Patient demographics were similar in the two groups (M/F: 9/3 in AO, 11/3 C; race C/A/H/AA= 8/2/2/0 and 11/0/2/AA). Two patients in the AO group were cirrhotic vs 1 pt in the C group. There were fewer genotype 1 patients (44%) in the AO group than the C group (77%). Hemoglobin values are shown in the table: By week 4 all the C patients had a >1 gm drop in HgB with 9/13 patients experiencing a >2 gm drop in HbB. In contrast, 7/12 and 4/12 patients in the AO group had 1 or 2 gm drops in HgB at that time. Of note, 3 patients in the control group required DR of ribavirin, but no one in the AO required DR in the 1st 4 months of therapy.

Conclusions: The concomitant use of antioxidants appears to markedly delay the severity of anemia during the 1st several weeks of ribavirin/interferon a-2b therapy, when compared to both historical controls, and relapse patients within the same clinic. This effect is almost lost by week 12 of therapy. This pilot data suggests that alternative antioxidant regimens should be studied for their potential benefit in limiting ribavirin related anemia during ribavirin/interferon a-2b therapy in HCV patients.

HIGH Dose Interferon

Effect Of Initial Interferon Dosing And Dose On Response To Combination Therapy With Ribavirin In Chronic Hepatitis C.
     Peter Ferenci, Univ of Vienna, Vienna Austria; Harald Brunner, KH Lainz, Vienna Austria; Wolfgang Vogel, Univ of Innsbruck, Innsbruck Austria; Michael Gschwantler, KH Rudolfstiftung, Vienna Austria; Christian Datz, LKH Salzburg, Salzburg Austria; Petra Steindl-Munda, Univ of Vienna, Vienna Austria; Austrian Hepatitis Study Group

     Patients with chronic hepatitis C (CHC) becoming HCV-RNA negative within the first weeks of therapy are likely long-term responders. The initial dose and dosing regime of interferon (IFN)-alfa have an impact on early response rates, but the role of IFN-induction therapy in combination with ribavirin is unknown. Therefore the efficacy of various initial IFN-dosing regimens in combination with ribavirin on response rates was studied after 14 and 38 weeks (end of treatment = ETR) of therapy.

Study protocol: Patients with CHC were randomized to three different dosing regimes with IFN-alfa2b (IntronA®, Schering-Plough) for 14 weeks (group A:10 MU/d for 2 weeks, then 10 MU/2d; B: 5 MU/d; C: 5 MU/2d/). Thereafter all patients received 5 MU/2d for another 24 weeks. Throughout the whole study ribavirin (1 to 1.2 g/d) was given. Complete response was defined by neg. serum HCV-RNA after 14 and 38 weeks. Sofar, 338 patients (237 male/101 female, median age: 41.4 years, >70% subtypes 1a or 1b) were randomized, 229 and 95 completed 14 and 38 weeks of therapy, respectively.

Results (see table below): Conclusion: A high initial IFN has an impact on the early response and ETR to IFN-ribavirin therapy in CHC. No data on sustained response are available at present.

Folic Acid Supplementation Does Not Prevent Ribavirin Induced Anemia
     Henry Gonzalez, Maria E Rios, Esther A Torres, Humberto Munoz, Javier Arroyo, Fernando J Castro, Univ of Puerto Rico Sch of Medicine, San Juan, PR

Background:Therapy with interferon(IFN) and ribavirin has proven effective for hepatitis C. 14-21% of patients on ribavirin have a drop in hemoglobin (Hgb)of 4gm ascribed to hemolysis. Folic acid(FA) has been used in chronic hemolysis. Aims:Evaluate the effectiveness of FA supplementation in preventing ribavirin-induced anemia.

Methods:Patients enrolled in treatment protocols with INF and ribavirin were randomized to receive FA 1mg daily or no supplementation (control(C)). Ribavirin dose was 1,000 mg for weight <70kg and 1,200 mg for >70 kg. Hgb, reticulocyte count, LDH, haptoglobin and bilirubin were measured at baseline,2,4,6,8,12,16,20 and 24 weeks. Ribavirin was reduced to 600mg for Hgb<10 and discontinued for Hgb<8mg. Haptoglobin and serum folate were measured at baseline and 24 weeks in 24 patients (FA:9,C:15). Data was analyzed using ANOVA for normally distributed variables and Wilcoxon's Rank-Sum test for non distributed variables.

Results:21 patients received folic acid and 22 did not. Groups were similar in age, gender and ribavirin dose. Mean base Hgb was 15.1±1.0 for treated and 14.6±1.5 for controls(p>0.5). Mean drop in Hgb was 3.6±1.3 for treated and 2.6±1.2 for controls(p=0.004). There was no difference between groups (treament vs controls respectively) in relation to increase in reticulocytes(4.4% vs 4.4%),increase in LDH(71±89 vs 63±113),increase in bilirubin(0.5±0.3 vs 0.5±0.8)and decrease in haptoglobin(43.0 vs 21.0),p>0.05. Five patients required ribavirin reduction, 4 females and 1 male, all from the treatment group. Four patients had a decrease in reticulocytes and 12 patients(6FA) had an increase in haptoglobin during ribavirin treatment. Conclusions: Treatment with FA 1mg daily does not prevent ribavirin-induced anemia. A larger number of patients is needed to confirm this finding.

HCV HVR Diversity and Efficacy of Interferon Treatment
     T Yamanaka, Yamanashi Med Univ, Saku-city Japan; Y Hirose, Y Tawa, Dept. of Med. Yamanashi Med Univ, Yamanashi Japan; Masayuki A Fujino, First Dept of Medicine,Yamanashi Med Univ, Yamanashi Japan; S Nisida, Otsuka Pharm Co., Ltd., Shizuoka Japan; T Nomoto, Div of vilology Otsuka Assay Lab., Tokushima Japan; M Kinosita, Divisoin of vilology Otsuka Assay Lab., Tokushima Japan

HCV has much diversity, especially hyper variable regions (HVR) are known as that immuno-escaping mutations frequently occur. We performed randomized study to confirmed relationships between HCV HVR diversity and efficacy of IFN treatments against chronic hepatitis C.

Methods and Materials: we prepared serum samples obtained from Randomized 43 chronic hepatitis C patients before IFN treatments. Adding ordinarily analysis (HCV-RNA amounts and genotype), we analyzed HCV-HVR 1(NS2) diversity using FSSA (Fluorescence Single strand conformation polymorphism and Sequence Analysis). FSSA is similar to SSCP, HVR1 RT-PCR products applied to acrylamide gel and analyzed by Pharmacia DNA fragment manager V1.1. FSSA can check up HCV clones more than 100 copies/ml.

Results: Average of number of clones between 14 cases IFN complete responders (CR group) and 29 cases IFN non-responders (NR group) showed statistically difference (3.71±2.05 vs 5.4±2.05 P=0.013). Between 19 HCV-RNA over 106 cases and 24 less 106 cases, number of clones showed no statistically difference (4.21±2.12 vs 5.42±2.13 P=0.072). Between 27 genotype 1b cases and 16 other genotypes cases, number of clones showed statistically difference (5.59±1.91 vs 3.69±2.15 P=0.004).

Conclusions: The number of clones in HCV-RNA HVR-1 was dependent on genotypes, not RNA amounts. FSSA of HCV HVR diversity is not so available for a prospect of IFN efficacy. Our result shows that HCV genotype 1b has more HCV HVR diversity in spite of virus amounts. RNA polymerase sequence of HCV is different between genotypes, this difference between genotype 1b and other genotypes suggests RNA polymerase activity difference. HCV HVR diversity is influenced by RNA polymerase activity. Not only replication speed, but also RNA miss- replication must be discussed in future.

High Dose Consensus Interferon In The Treatment Of Naive Chronic Hepatitis C- A Preliminary Report
     Carl R Jones, Allegheny Gen Hosp, Pittsburgh, PA; Nicholas A Tibaldi, Rad Agrawal, Gary Ciambotti, Michael Babich, Ricardo Mitre, Same; George J Brodmerkel Jr

Chronic hepatitis C (CHC) patients treated with a-interferon therapy achieve a sustained biochemical response rate of 20-25%. The sustained virologic response (SR) in patients with gentoype 1 has been reported to range from 5%-10%. A study by Heathcote et al. reported that retreatment with 15 mg of consensus interferon (Infergen", Amgen Inc.) TIW for 48 weeks achieved a virologic SR of 58% for all relapsers and 36% in relapsers with genotype 1. The aim of this open label study is to see if dosing 5 times per week is more efficaious than TIW dosing with high dose, 15 mg, consensus interferon. Naive patients with biochemical and histological diagnosis of CHC were entered into the study. Patients are randomized to consensus interferon 15 mg once a day for five days a week or 15 mg TIW. Week 12 data are presented in the table below: The mean pretreatment HCV RNA level was 3.3 million copies/mL. Genotype 1 represented 80% of the patients. Five of 25 patients in the 5 times a week treatment group and 1/25 patients in the TIW group required a dose reduction. Dose reductions in the 5 times a week arm were due to hematologic effects (3 patients) and flu-like symptoms (2 patients). To date, 6/50 patients have dropped out of the study, all in the TIW group. The data suggest that patients treated with consensus interferon 15mg, 5 times a week have improved virologic clearance over the TIW therapy group, at week 12. Treatment was tolerated by both groups.

Histological Improvement of Fibrosis in Hepatitis C Patients with Sustained Response (SR) to Interferon (IFN) Therapy -Long-Term Follow-Up Study Using Paired Biopsy Samples
     Yasushi Shiratori, F Imazeki, M Moriyama, M Yano, Y Arakawa, O Yokosuka, T Kuroki, M Sata, G Yamada, S Fujiyama, H Yoshida, M Omata, Univ of Tokyo, Tokyo Japan

(Background/Aims) The aim of the present study was to assess liver fibrosis progression/regression rates in patients with chronic hepatitis C after IFN therapy using paired liver biopsy samples. (Method) 593 patients with chronic hepatitis C from 8 institutes who underwent a paired liver biopsy during 1987-1997 were analyzed. 487 patients received a 2- to 6-month course of IFN therapy within 6 months after initial liver biopsy, and the remaining 106 patients were untreated. Of these patients, virological SR and non-SR was demonstrated in 183 and 304 cases, respectively. Paired biopsy samples were obtained at an interval of 3.7 years (range; 1-10 years). Fibrosis and inflammatory activity of the liver biopsy samples were assessed respectively by the criteria of Desmet from stage F0 (no fibrosis) to F4 (cirrhosis) and from grade A0 (no activity) to A3 (severe activity). The fibrosis stages and activity grades of the paired liver biopsy samples were compared, and fibrosis progression/regression rate per year was calculated.

(Results) Although activity grade was unchanged in most of the untreated patients, it was improved in patients with virological sustained response (SR) shortly after IFN therapy and persisted thereafter. On the other hand, liver fibrosis progressed in untreated patients, and fibrosis progression rate was 0.095 unit/year. In contrast, fibrosis staging was gradually improved in patients with virological SR after IFN therapy, and it regressed at a ratio of -0.282 fibrosis unit/year. In patients with virological non-SR, the fibrosis progression rate was reduced (0.024 unit/year) compared with untreated patients. When the progression/regression of fibrosis was analyzed in relation to the initial staging score (F1-F4), the fibrosis progression rate in the untreated patients ranged from 0.048-0.367 unit/year for F0-F3. In contrast, the fibrosis regression rate in patients with virological SR for F1-F3 ranged from -0.374 to -0.157 unit/year, in contrast to 0.014-0.083 unit/year progression in patients with virological non-SR. Fibrosis progression rate in the F4-stage patients with virological SR and non-SR was -0.283 and -0.163 unit/year, respectively (Statistical values;0.0001 for F1-F3, 0.093 for F4).

(Conclusion) Virological SR by IFN therapy induces gradual regression of liver fibrosis and may eventually lead to resolution of early cirrhosis.

Histology Of Chronic HCV Based On Genotype
     Tarek Hassanein, Univ of CA, San Diego, San Diego, CA; C Behling, P Monson, E Chatfield, H Taha, S Mohanty, N Aronson, W G Hardison, Univ of CA and VA Med Ctr, San Diego, CA

Characteristic liver histology of HCV genotypes is controversial. Some authors have correlated the severity of necro-inflammatory changes and degress of fibrosis with HCV genotype, while others have found no relationship. Improved response to therapy in patients with chronic HCV has been related to genotypes 2 and 3 in chronic hepatitis C. We hypothesized that this may be a result of less histologic activity. We compared histology of genotypes I with genotypes 2 and 3. Liver biopsy was performed prior to treatment. Each biopsy was graded, using a modified Knodell histologic activity index (HAI) and fibrosis score, by one pathologist who was blinded to HCV genotype. Patients were divided into two groups based on HCV genotype (1, or 2 and 3). History of alcohol consumption and estimated duration of infection were recorded for all patients. Twenty-four patients with genotype 1 (Mean age 44 ± 5, 18M, 6F) and 14 patients with genotype 2 or 3 (Mean age 43 ± 8, 11M, 3F) were included in the study. Results are as follows. No significant differences were noted in the histologic activity, fibrosis score, duration of infection, or alcohol history between the two groups.

Conclusions: 1) there was no difference in histologybased on HCV genotype in our patient population, 2) histology does not explain the improved response to treatment in HCV genotypes 2 and 3.

How Long Will the Virological Sustained Responders to IFN Remain at Risk of Developing Hepatocellular Carcinoma?
     Haruhiko Yoshida, Univ of Tokyo, Tokyo Japan; Y Arakawa, Nihon Univ, Tokyo Japan; Osamu Yokosuka, Chiba Univ, Chiba Japan; T Kuroki, Osaka City Univ Med Sch, Osaka Japan; Michio Sata, Kurume Univ, Fukuoka Japan; Shigetoshi Fujiyama, Kumamoto Univ, Kumamoto Japan; Michitami Yano, Nagasaki Chuo Hosp, Nagasaki Japan; Gotaro Yamada, Kawasaki Medical Sch, Okayama Japan; Masao Omata, Univ of Tokyo, Tokyo Japan

Background: The IHIT (Inhibition of Hepatocarcinogenesis by Interferon Therapy) Study Group started a multicenter cohort study with support from the Japanese Government in 1994 to evaluate the effects of IFN on the prevention of HCC. Patients and Methods: A total of 2,896 consecutive hepatitis C patients who underwent liver biopsy from 1986 to 1994 were enrolled. Development of HCC was surveyed by ultrasonography at least every six months and other modalities when needed. During the observation for an average of 1,631 days, HCC developed in 59/495 IFN-untreated subjects, in 10/785 IFN-treated subjects who achieved virological sustained response (SR), and in 80/1,616 IFN-treated subjects without SR.

Results: By multivariate analysis with Cox proportional hazard model, both the IFN therapy as a whole (RR: 0.539, 95%CI: 0.374-0.779, P=0.001) and the virological SR in particular (RR: 0.203, 95%CI: 0.101-0.405, P=0.0001) were associated with a reduced risk of HCC, along with sex (female<male), age (young<old), and the stage of liver fibrosis (F0/F1<F2<F3<F4). Hazard function of HCC incidence increased with time after IFN therapy in the untreated and non-SR subjects. On the other hand, 9 of 10 HCC cases among subjects with SR were detected within four years of IFN therapy: the only exception was an F4 (cirrhotic) patient who developed HCC 6.9 years after IFN.

Conclusions: The risk of HCC decreased with time in subjects with virological SR but increased in non-SR and untreated subjects. No development of HCC was found from five years after IFN therapy among non-cirrhotic subjects with virological SR.

In HCV Naive Patients: Combination Therapy Improves Viral Clearance When Compared To Induction Therapy
     Tarek Hassanein, Univ of CA, San Diego, San Diego, CA; P Monson, C Behling, E Chatfield, H Taha, S Mohanty, N Aronson, K Medley, W G Hardison, Univ of CA and VA Med Ctr, San Diego, CA

Recommended treatment for HCV naive patients is IFN + ribavirin therapy. The efficacy of an initial induction course of IFN prior to the start of combination therapy has not been determined. Twenty-four naive patients were assigned to either an induction + combination, or a combination therapy protocol. During induction + combination, patients received 5 MU IFN a2b/day for 1 month, 3 MU IFN a2b/day for 1 month, then 5 MU IFN a2b TIW + ribavirin 800 mg/day for 10 months. In the combination group, patients received 5 MU IFN a2b TIW + ribavirin 800 mg/day for 12 months Eight patients were included in the induction group (Mean age 42 ± 9,3M,5F) and sixteen patients were included in the combination group (Mean age 43 ± 6, 12M, 4F).

Results are as follows:

Conclusions: In HCV naive patients: 1) combination of IFN + ribavirin from the start of therapy was significantly more effective in achieving viral clearance when compared to induction therapy, 2) ALT normalization was not significantly different in the combination group, compared to the induction qroup, and 3) treatment discontinuation was more common in the induction group, compared to the combination group.

Induction Interferon Treatment of African-Americans With Chronic Hepatitis C Results in an Enhanced Response Comparable to Caucasians Given Standard Interferon Therapy.
     Firdous Siddiqui, P H Naylor, M N Ehrinpreis, R Peleman, J L Kinzie, M G Mutchnick, Wayne State Univ, Detroit, MI

African-Americans constitute the majority of patients treated for chronic hepatitis C at our institution. African-Americans respond to interferon at a much lower rate than Caucasians using the standard dose of 3MU thrice weekly. The aim of this study was to determine if an induction treatment with interferon enhanced the response rate in African-Americans. Methods: forty three interferon-naive African-American patients were treated with 5 MU of IFN alfa -2b daily for 4 weeks followed by 3 MU three times a week for 8 weeks. Ten patients withdrew from treatment prior to the 12 week interval. Serum hepatitis C viral (HCV) RNA was determined at 12 weeks. If serum HCV RNA was detected at 12 weeks, treatment was discontinued. Patients with non detectable HCV RNA at 12 weeks were continued on treatment for a total of 48 weeks. Results: Eleven of the thirty three (33%) African-Americans had non-detectable HCV RNA at 12 weeks compared to a 5/55 (9%) response rate in African-Americans treated with standard 3 MU of IFN three times a week at our institution. The response observed with induction therapy in African-Americans compared favorably to the 14/40 (28%) response rate seen in our Caucasian population treated with 3 MU of interferon three times a week. The withdrawal rate in patients treated with induction interferon was 10/43 (23%) compared to 15/141(10%) in a cohort of patients treated with standard 3 MU interferon three times a week.

Conclusions: The poor response to interferon treatment of African-American patients with chronic hepatitis C can be overcome by a more intensive regimen of interferon but the withdrawal rate increases with this approach.

Induction Interferon a2b 5 MU Daily for 4 Weeks Followed by Combination Interferon-Ribavirin Versus Interferon-Ribavirin Without Induction for Previously Untreated Chronic Hepatitis C: Interim Results of Viral Non-Detectability at 3 Months
     Edward Lebovics, Unnithan V. Raghuraman, Kenny Hui, Anna Casellas, Carol McFarlane, New York Med Coll, Valhalla, NY; S P. Esposito, New York Hosp-Queens, Queens, NY; Hillel Tobias, New York Univ Med Ctr, New York, NY; J Geders, Methodist Hosp, Brooklyn, NY; Ira Jacobson, New York Hosp, New York, NY; F Klion, Mount Sinai Med Ctr, New York, NY; David C Wolf, Brad M Dworkin, New York Med Coll, Valhalla, NY

Combination interferon a2b (I) 3 MU TIW plus ribavirin (R)1000-1200 mg per day for 1 year results in sustained virologic response in 38% of previosly untreated chronic hepatitis C (CHC) patients (NEngJMed 1998;339:1485). Viral kinetic studies suggest that daily I would more effectively clear virus. We aimed to determine if I induction improves response.

Methods: Adult patients with CHC, HCV RNA PCR +, compensated liver disease and no other cause of liver injury were randomized to induction of I 5 MU daily for 4 weeks followed by I 3 MU TIW plus R 1000-1200 mg per day (I/R)for 44 weeks versus I/R for 48 weeks. This interim report addresses the endpoint of HCV RNA non-detectability at 3 months from the onset of anti-viral therapy.

Results: 112 patients are randomized, of which 72 have 3 month data completed. The groups were well-matched for baseline ALT, viral load and genotype (GT). Results are shown in table. None of the differences between the groups reached statistical significance. ALT normalized at 3 months in 25 (74%) of induction patients and 32 (84%) of non-induction patients.

Conclusions: Induction therapy does not improve interim virologic response. This may relate to shorter duration on I/R in the induction group. There is a trend to improved viral clearance with induction for GT 1B. Sustained response data is in progress.

Interferon Therapy of HCV Cirrhosis Reduces the Incidence of HCC, and Decompensation, and Significantly Improves Survival: a 5 year Comparative Trial
     Daniela Mura, Roberta Deliperi, Laura Fastame, Luigi Cugia, Piera A Cossu, Gavino Pisanu, Univ of Medicine of Sassari, Sassari Italy; Maria P Dore, VA Med Ctr and Baylor Coll of Medicine, Houston, TX; Giuseppe Realdi, Univ of Medicine of Sassari, Sassari Italy

Background: Therapy of patients with HCV cirrhosis is both unsatisfactory and controversial. Recent studies suggest that IFN therapy may significantly decrease the incidence of hepatocellular carcinoma (HCC), although these results are restricted to patients responding to treatment. Few long-term observations are available on the effects of therapy on decompensation and survival with respect to IFN therapy. We conducted a randomized control study with IFN vs no therapy in patients with well compensated cirrhosis.

Aim: To investigate the incidence of HCC, decompensation (jaundice, ascites, encephalopathy, bleeding and hepatorenal-syndrome) and survival after follow-up of at least 6 yrs. Methods: 57 patients enrolled had a histologically confirmed compensated cirrhosis (class A of Child), with abnormal ALT and HCV-RNA positive serum. 28 received IFN (3 MU three times a week for 12-18 months); 29 controls did not receive IFN therapy. Baseline characteristics were similar including age, sex, HCV-RNA, genotypes, liver function tests, and platelet counts. No patient had severe side effects requiring withdrawal of treatment.

Results: A significantly higher number of events were observed in the control group compared to IFN treated patients. At last observation (mean follow-up 76 months), development of HCC (5/29 vs 0/28, respectively; p=0.009) and decompensation (13/29 vs 2/28, respectively; p=0.001) were significantly more frequent in controls. Survival in controls (p=0,02; 95% CI 40-67%) was significantly worse vs patients treated with IFN. Conclusions: Long term follow-up showed that a standard regimen of IFN in patients with compensated HCV-RNA positive cirrhosis was associated with a significant reduction of HCC, decompensation, and a significant improvement in survival.

Iron Reduction Prior to and During Interferon Therapy of Chronic Hepatitis C: Initial Results of a Multicenter, Randomized, Controlled Trial in Previously Untreated Patients
     Herbert L Bonkovsky, Univ of MA Memorial Health Care-Univ Campus, Worcester, MA; J Israel, Univ of Conn; Robert Fontana, Univ of Michigan; N Grace, Tufts Univ; R Levine, SUNY at Stony Brook; P LeClair, Univ of MA; M Thiim, G Fiarman, Lahey Clin; A Tavill, CWRU

Patients with chronic hepatitis C (CHC) often have high normal or elevated serum ferritins and transferrin saturations, although normal hepatic irons. Those with lower levels of serum ferritin or hepatic iron are more likely to respond to interferon (IFN) therapy, and iron removal alone usually leads to a decrease in serum ALT, although it does not affect HCV RNA levels in serum (for review see Hepatology 1997;25:759). Iron reduction does not improve responsiveness to IFN in patients who previously had not responded to IFN alone but, in some small studies, it has improved responses in previously untreated patients. The aim of our study was to determine whether iron reduction by phlebotomy prior to and during therapy with IFNa-2b (3mu tiw x 24 wks) improves the rate of complete biochemical or virological responses in previously untreated non-cirrhotic patients with CHC.

Methods: We enrolled 81 patients (48 men; 33 women) with baseline serum ALT's >1.3xULN and HCV RNA detectable in serum by PCR (NGI SuperQuant). 42 were randomized to IFN alone (GpA) and 39 to iron reduction, followed by IFN (GpB). Initial iron reduction, accomplished by weekly phlebotomies of 1 pint of blood was continued until Hct <35% and serum ferritin <11 ng/mL or Tf satn <11%. The average volumes of blood removed to achieve iron depletion were 4.3L for 23 men and 2.9L for 16 women. In GpB patients during IFN therapy, Hct, Ferritin, and Tf satn were checked monthly and additional units of blood were removed whenever Hct >35% and ferritin >15ng/mL or Tf satn > 15%. During IFN therapy, the average volumes of additional blood removed were 0.8L (men) and 0.6L (women). During IFN therapy serum ALT's and HCV RNA's were measured at weeks 4 and 12. Results were compared by chi square likelihood ratios (SPSS).

Results: Patients in the two groups were well-matched for demographic and laboratory features at baseline. The decreases in both serum ALT and HCV RNA levels were significantly greater for GpB patients (iron reduced) at weeks 4 and 12 of therapy (Table). More patients in GpB had a complete biochemical response (ALT<ULN, 69% vs. 48%, p<0.05) and a complete virological response (HCV RNA<100cc/mL, 43% vs. 18%, p<0.02). Among those achieving complete responses during therapy, no patients in GpB vs. 27% in GpA had biochemical breakthroughs (p=0.008), whereas 1 in each group showed virological breakthroughs. Treatment continues in 7 patients. Adverse events (AE's) occurred in 2 patients in each group; no AE's were attributable to phlebotomies.

We conclude that iron reduction is well-tolerated in CHC before and during IFN therapy and improves the initial biochemical and virological responses to IFN therapy.

Pretreatment Histology Activity Index (HAI) Is An Indicator Of Early HCV Viral Clearance With IFN Therapy
     Brian P Mika, Nancy P Lam, Monica E McCarthy, Thomas J Layden, Thelma E Wiley, Univ of Illinois at Chicago, Chicago, IL

Background. Following IFN therapy, serum HCV RNA decline is biphasic with a rapid initial phase (24-48 hrs). The 2nd phase is slower but is the best viral kinetic predictor of early viral clearance at 3 mos (Science.1998;282:103). Patients with a faster 2nd phase slope had higher ALT's, suggesting a greater degree of histological activity. Aim. We determined whether a correlation existed between the HAI score and HCV clearance at 3 mos, 1st and 2nd phase viral decline and other viral kinetic parameters.

Methods. Hepatic biopsies of 23 genotype 1a or 1b pts, treated with daily IFNa-2b (5, 10, or 15 mIU for 2 wks, followed by 5 mIU for 10 wks), were rated for HAI using the Knodell score. HAI, excluding the fibrosis component, and individual components (i.e. intralobular necrosis, portal inflammation, and piecemeal±bridging necrosis) were correlated with various viral kinetic parameters and viral clearance at 3 mos.

Results. The 7 pts who cleared the virus had both significantly higher mean HAI scores (8.0±2.3(SD) vs. 4.8±2.9; p<.02) and piecemeal necrosis ratings (3.9±1.6 vs. 1.6±1.7; p<.01) compared to pts who did not clear the virus. Additionally, both HAI and piecemeal necrosis ratings positively correlated to the 2nd phase viral decline slope (p<.01). No correlation existed between the other components of HAI and early viral clearance at 3 ms or 2nd phase viral decline. Neither HAI nor any of the individual components significantly correlated to 1st phase viral decline, virion production rate or virion clearance rate.

Summary. Histological activity, in particular piecemeal necrosis, is a significant indicator of 2nd phase viral decline and early viral clearance, suggesting that a pre-existing immune response to HCV infected hepatocytes is an important component of early viral clearance.

Ribavirin Dose Reduction Does Not Affect Week 12 HCV RNA Levels During Interferon/Ribavirin Therapy.
     Terry D Box, Jane E Christiansen, Kate Rose, Mount West Gastroenterology, Salt Lake City, UT; Robert G Gish, Linda Brooks, Gerry Schulze, CA Pacific Med Ctr, San Francisco, CA; Mark E Boschert, I Raymond Thomason, William R Hutson, John H Bowers, Mount West Gastroenterology, Salt Lake City, UT

Hemolysis is a known adverse effect of oral ribavirin therapy. In combination interferon/ribavirin treatment of chronic hepatitis C (HCV), significant hemolysis has been addressed by reducing the daily dose of ribavirin. The impact of such dose reduction on treatment week 12 HCV RNA levels is evaluated. Three hundred three (303) of 384 patients enrolled in the multicenter North American RIBAHEP Study Group have completed at least 12 weeks of interferon/ribavirin therapy for HCV. Two hundred sixty-six (266) males and 118 females were randomized to recieve 1000 mgm of ribavirin daily with either 3 million units (MU) Intron A" TIW for 48 weeks or 3 MU Intron A" daily for 28 days followed by Intron A" 3 MU TIW for 44 additional weeks. When necessary for hemolysis, ribavirin dose was reduced to 600 mg daily. All patients enrolled are nonresponders or relapsers after a minimum of 12 weeks of interferon monotherapy for chronic HCV. Treatment week 12 HCV RNA levels (by RT-PCR, National Genetics Institute) document 41% of the entire study group with RNA level < 100 copies/ml. For ribavirin dose reduced patients, 40% (33 of 81) had week 12 HCV RNA < 100 copies/ml. For patients who remained on full dose ribavirin throughout treatment, 41% (92 of 222) had week 12 RNA < 100 copies/ml. Week 12 virologic responders and nonresponders were equally matched regarding sex and interferon treatment scheme.

Conclusion: The twelve week response rates between treatment groups are equal. If this continues to be the case with sustained response rates, re-evaluation of the recommended ribavirin dose in combination interferon/ribavirin therapy would be in order.

Sustained Responders to Retreatment with Consensus Interferon (CIFN) have Similar Patterns of HCV RNA Decrease Regardless of Genotype
     H Fromm, George Washington Univ Med Ctr, Washington, DC; Emmet Keeffe, Stanford Univ Med Ctr, Palo Alto, CA; Elizabeth J. Heathcote, The Toronto Hosp, Toronto Canada; Samuel Lee, Health Sci Ctr, Calgary Canada; and the CIFN Study Group

Genotype is a key factor affecting response rates to interferon among patients with chronic HCV infection. Recently, Keeffe et al demonstrated that among patients with a viral sustained response (SR) there was no difference in the time course of viral response to initial CIFN treatment based on genotype. However, among nonresponders (NR) there were significant differences by genotype, with genotype 1 patients having several logs less of a decrease in serum HCV RNA compared to patients with genotype 2 or 3. The aim of this analysis was to determine if there were differences in the pattern of HCV RNA response to CIFN retreatment based on genotype. Patients who did not respond or relapsed after initial interferon therapy (6 months of 9 mcg CIFN or 3 MU IFN alfa-2b TIW) were retreated with 15 mcg CIFN for 12 months. Patients with a SR to CIFN retreatment had undetectable median serum HCV RNA values by week 8 of retreatment, regardless of genotype with 83-100% clearing virus by this time. In contrast, patients who were NR to retreatment showed clear differences in the pattern of response based on genotype. The log decreases in viral concentration during retreatment of NR with genotypes 1, 2, and 3 were 1.6, 3.8, and 2.8. Fifty percent of NR with genotype 2 had a transient viral response to CIFN retreatment, while only 22% of NR with genotype 3 and 19% of NR with genotype 1 had transient viral responses during retreatment. The overall viral SR to CIFN retreatment for genotypes 1, 2, and 3 were 12%, 25%, and 25% for prior viral nonresponders and 44%, 50%, and 88% for prior viral relapsers. In summary, genotype affects not only the response rate but also the pattern of HCV RNA decrease during CIFN retreatment. This research was funded by Amgen Inc.

Sustained Responders (SR) with High HCV Viral Concentrations Clear Virus More Slowly than Patients with Lower Baseline Viral Concentrations
     F. Blaine Hollinger, Baylor Coll of Medicine, Houston, TX; Paul G. Killenberg, Duke Univ Med Ctr, Durham, NC; Saya V. Feinman, Univ of Toronto, Toronto Canada; and the CIFN Study Group

Patients with chronic HCV who were viral SR to IFN therapy were assessed for the pattern of viral clearance based on their baseline viral concentration. Previous studies show that SR clear virus very early and have median HCV RNA values of <100 copies/mL by week 2 of consensus interferon (CIFN, Interferon alfacon-1) treatment and that 96% of SR have responded by week 12. The aim of this analysis was to determine if the time to viral clearance was affected by the baseline viral concentration. 232 patients from a multicenter trial were randomized to receive 9 mcg CIFN TIW for 6 months. Patients were divided into quartiles [(Q1: <1.2x106)(Q2:1.2-3.0x106)(Q3:3.0-4.8x106)(Q4:>4.8x106)] based on baseline viral HCV RNA concentration. The percent of all patients who responded by week 12 in each quartile was 71%, 53%, 34% and 34% in Q1 through Q4, respectively. A greater percentage of patients with lower baseline viral concentrations responded early compared with higher baseline viral concentrations. SR in the lower 3 quartiles had median undetectable HCV RNA values by week 2-4 of CIFN treatment, while SR in the highest quartile did not have median undetectable HCV RNA values until week 12. Another observation was that the posttreatment increase in HCV RNA among patients who initially responded to CIFN but then relapsed during posttreatment seemed to correlate with baseline viral concentration. Also, 56% and 41% of nonresponders in Q1 and Q2 respectively had a virologic response during treatment suggesting that more aggressive therapy may benefit these patients.

In summary, the baseline viral concentration in patients with chronic HCV affects the pattern of viral decrease among SR and the pattern of posttreatment viral increase among relapsers. This research was funded by Amgen Inc.