A randomized trial of consensus interferon in combination with ribavirin as initial treatment for chronic hepatitis C q

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1 Journal of Hepatology 39 (2003) A randomized trial of consensus interferon in combination with ribavirin as initial treatment for chronic hepatitis C q Giovanna Fattovich 1, *, Irene Zagni 1, Eliseo Minola 2, Martina Felder 3, Pierangelo Rovere 4, Antonio Carlotto 5, Sergio Suppressa 6, Anna Miracolo 7, Claudio Paternoster 8, Caterina Rizzo 9, Angelo Rossini 10, Paolo Benedetti 11, Marco Capanni 12, Chiara Ferrara 13, Paolo Costa 14, Tosca Bertin 15, Maurizio Pantalena 16, Lorenzo Lomonaco 1, Chiara Scattolini 1, Giuseppe Mazzella 7, Massimo Giusti 6, Sergio Boccia 9, Stefano Milani 12, Renato Marin 13, Maria Lisa Ribero 17, Alessandro Tagger 17 1 Servizio Autonomo Clinicizzato di Gastroenterologia, Università di Verona, Piazzale La Scuro 10, Verona, Italy 2 Divisione di Malattie Infettive, Ospedali Riuniti, Bergamo, Italy 3 Divisione di Gastroenterologia, Ospedale Regionale, Bolzano, Italy 4 Divisione Malattie Infettive, Ospedale Civile, Legnago, Italy 5 Divisione Malattie Infettive, Ospedale Civile, Schio, Italy 6 Divisione di Medicina, Azienda USL 3, Pistoia, Italy 7 Dipartimento di Gastroenterologia, Università di Bologna, Bologna, Italy 8 Divisione Malattie Infettive, Presidio Ospedaliero Villa Igea, Trento, Italy 9 Divisione di Gastroenterologia, Ospedale S. Anna, Ferrara, Italy 10 Divisione di Medicina, Spedali Civili, Brescia, Italy 11 Divisione di Malattie Infettive, Ospedale S. Bortolo, Vicenza, Italy 12 Unità di Gastroenterologia, Università di Firenze, Firenze, Italy 13 Divisione di Medicina, Presidio Ospedaliero, Dolo, Italy 14 Divisione Malattie Infettive, Ospedale Carlo Poma, Mantova, Italy 15 Divisione di Gastroenterologia, Ospedale S. Bortolo, Vicenza, Italy 16 Dipartimento di Medicina, Ospedale di Arzignano, Arzignano, Italy 17 Istituto di Virologia, Università di Milano, Milano, Italy Background/Aims: The aim of the present, open-labeled, randomized study was to determine the efficacy and safety of different doses of consensus interferon plus ribavirin in the initial treatment of chronic hepatitis C. Methods: One hundred and one genotype 2/3 patients were randomized to receive 9 mcg (group A, n 5 48) or 18 mcg (group B, n 5 53) of consensus interferon thrice weekly plus ribavirin (1000/1200 mg/daily) for 24 weeks and 92 genotype 1 patients to receive 9 mcg (group C, n 5 47) or 18 mcg (group D, n 5 45) of consensus interferon plus ribavirin for 48 weeks. Results: In an intention-to-treat analysis, the sustained virologic response at 24-week follow-up was 69% and 66% for group A and B (P 5 0:77) and 40% and 36% for group C and D (P 5 0:63). The overall sustained response was 67% and 38% in patients with genotype 2/3 and 1, respectively. Among genotype 1 patients the sustained virologic response was 39% and 41% for high or low baseline viremia levels. Conclusions: Higher consensus interferon dose does not increase sustained virologic response. Naive genotype 1 patients may achieve significant response rate of approximately 40% if treated with 9 mcg of consensus interferon plus ribavirin for 48 weeks. q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Chronic hepatitis C; HCV genotype 1; Consensus interferon; Ribavirin; Initial therapy Received 16 February 2003; received in revised form 18 July 2003; accepted 22 July 2003 q The authors who have taken part in this study declare that they have no relationship with the manufacturers of the drug(s) involved either in the past or present and did not receive funding from the manufacturers to carry out their research. * Corresponding author. Tel.: þ ; fax: þ address: giovanna_fattovich@tin.it (G. Fattovich) /$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /s (03)00391-x

2 844 G. Fattovich et al. / Journal of Hepatology 39 (2003) Introduction Consensus interferon (IFN alfacon-1) is a synthetic molecule derived by assigning the most frequently observed amino acids of several natural IFN alpha subtypes to develop a novel type 1 IFN [1]. IFN alfacon-1 has been used in monotherapy for chronic hepatitis C and its efficacy has been demonstrated in clinical trials of patients who had not been treated previously with IFN alpha (naive) and retreatment of patients who had relapsed following initial response to IFN alpha [2 7]. One study compared the efficacy of the treatment regimen of IFN alfacon-1 at the dose of 9 mcg three times a week (TIW) with that of IFN alpha-2b at the dose of 3 million units (MU) TIW and similar sustained virologic response (SVR) rates in the overall groups of naive patients have been reported [2,3]. Additional data have indicated that IFN alfacon-1 may be an effective therapy for patients infected with HCV genotype 1 and for patients with high baseline viral load [2,3,6,7]. In one trial using high dose (15 mcg TIW) IFN alfacon-1 for 48 weeks in anti-hcv positive relapsed patients, SVR rates of 58% were reported [5], leading to the indication of high dose IFN alfacon-1 therapy in this clinical setting [8]. At the time of planning this study the gold standard for treating naïve patients with chronic hepatitis C was the combination with IFN alpha-2b at the dose of 3 MU TIW with ribavirin, however, this therapy provides approximately 40% of patients with a chance of SVR and the response rate is even lower in the subgroup of patients infected with genotype 1 [9,10]. Currently the therapeutic efficacy of IFN alfacon-1 in combination with ribavirin in chronic hepatitis C remains to be determined. On this background we conducted an open-labeled, randomized study to evaluate the efficacy and safety of different doses of IFN alfacon-1 plus ribavirin in previously untreated patients with chronic hepatitis C. 2. Materials and methods 2.1. Patient selection One hundred and ninety-three naive patients of both genders, aged years with chronic HCV infection were recruited for this study between June 2000 and June Patients were eligible for the study if they had elevated alanine aminotransferase (ALT) for at least 6 months, tested positive for hepatitis C virus (HCV)-RNA in serum and had liver biopsy taken within 12 months of enrollment into the study with a histopathological evaluation of chronic hepatitis. Criteria for exclusion were: patients who were pregnant or breast feeding, severe cytopenia (platelet, /cm 3 and/or white blood count,3.000/cm 3 and/or neutrophil count,1.500/cm 3 ), anemia (,12 g/dl in women and 13 g/dl in men), any other cause of liver disease including positivity for hepatitis B surface antigen and high alcohol intake (.20 g/day in females and.40 g/day in males), decompensated cirrhosis and any other concomitant serious medical disorder Study design This randomized, controlled trial was carried out in 15 hospitals in Italy and approved by the local ethics committees. All patients gave informed consent before enrollment in accordance with the Helsinki declaration. HCV genotype 2 or 3 patients were randomized to receive IFN alfacon-1 (Infergen, Yamanouchi Europe B.V., Leiderdorp, The Netherlands) subcutaneously at a dose of 9 mcg (group A) or 18 mcg (group B) TIW plus oral ribavirin (Meduna Arzneimittle GmbH, Isernhagen, Germany) for 24 weeks and HCV genotype 1 patients to receive 9 mcg (group C) or 18 mcg (group D) of IFN alfacon-1 TIW plus ribavirin for 48 weeks. In all patients ribavirin dose was adjusted according to body weight (1000 mg/day for weight 75 kg or less and 1200 mg/day for weight more than 75 kg). Eligible patients were randomly assigned to treatment in a 1:1 ratio (with a block size of four) by a centralized computer algorithm that stratified according to the presence or absence of cirrhosis. During treatment patients were evaluated for safety, tolerability and efficacy at weeks 2, 4, 6, 8 and subsequently every 4 weeks and at weeks 4, 12 and 24 after stopping therapy. HCV genotype was identified by commercially available probe-specific hybridization assay (Innolipa assay, Innogenetics, Gent, Belgium) at each center s laboratory. Serum HCV-RNA was measured by a in-house nested reverse-transcription-polymerase-chainreaction assay (RT-PCR) with a lower limit of detection of 100 copies/ml in a single laboratory [11]. HCV genotype 1 patients who tested positive for HCV-RNA at week 24 of combination therapy were considered as nonresponders and withdrawn from the study [12]. Liver biopsies were classified for hepatic inflammation and fibrosis according to Scheuer [13] Assessment of efficacy The primary efficacy end point was SVR defined as HCV-RNA in serum below detection limit (100 copies/ml) at the end of follow-up week 24. Data were also analyzed for virologic breakthrough, i.e. reappearance of HCV-RNA during therapy, relapse, i.e. reappearance of HCV-RNA at the end of follow-up week 24 after end of therapy virologic response (ETVR) had been achieved and sustained biochemical response, i.e. normal ALT at the end of follow-up week Adherence to therapy evaluation Patients were divided into two groups according to an adherence criterion previously adopted in the assessment of the efficacy of pharmaceutical agents [14,15]: (1) patients who received.80% of their total IFN alfacon-1 dose and.80% of the ribavirin dose and were treated for.80% of the expected duration of therapy (80/80/80 subgroup); (2) patients who received,80% of IFN alfacon-1 and/or ribavirin for.80% of the expected duration of therapy (,80/,80/.80 subgroup) Statistical analysis A sample size of 182 genotype 2 or 3 patients (91 in each treatment group A and B) was estimated on an a type error of 0.05 and a b error of 0.20, on the assumption of 60% SVR in group A and of 80% SVR in group B. A sample size of 206 genotype 1 patients (103 in each treatment group C and D) was estimated on an a type error of 0.05 and a b error of 0.20, on the assumption of 30% SVR in group C and of 50% SVR in group D. An interim analysis showing similar rates of SVR between group A and B and between group C and D, respectively, led to the decision to stop the enrollment of patients [16]. Efficacy measurements were done on an intention-to-treat method, i.e. included all 193 patients who were randomized and received at least one dose of study medication. Patients who stopped treatment prematurely and/or without end point data were considered as treatment failures. The chi-square test, Fisher s exact test (two-tailed), the Mann Whitney test or multiple logistic regression analysis were used, as appropriate. All data were analyzed using the SPSS for Windows version 10 software package (SPSS, Inc., North Chicago, IL, USA). 3. Results Overall 101 genotype 2 or 3 patients and 92 genotype 1 patients were randomized and underwent treatment (group A, n ¼ 48; group B, n ¼ 53; group C, n ¼ 47;

3 G. Fattovich et al. / Journal of Hepatology 39 (2003) Table 1 Baseline characteristics of patients HCV genotype 2/3 HCV genotype 1 Group A (n ¼ 48) Group B (n ¼ 53) Group C (n ¼ 47) Group D (n ¼ 45) Gender Male 27 (56) 39 (74) 31 (66) 31 (69) Female 21 (44) 14 (26) 16 (34) 14 (31) Age (years) #40 20 (42) 29 (55) 25 (53) 20 (44) (58) 24 (45) 22 (47) 25 (56) Weight (kg) #75 33 (69) 40 (75) 27 (57) 28 (62) (31) 13 (25) 20 (43) 17 (38) Source of infection Transfusion 4 (8) 5 (9) 4 (8) 3 (7) Injection drug use 19 (40) 27 (51) 11 (24) 13 (29) Sporadic/unknown 25 (52) 21 (40) 32 (68) 29 (64) Grading 1 2 (4) 8 (15) 6 (13) 6 (13) 2 38 (79) 34 (64) 35 (74) 34 (76) 3 5 (11) 11 (21) 6 (13) 5 (11) 4 3 (6) Staging (4) 3 (6) 5 (11) 1 19 (40) 22 (41) 20 (43) 12 (27) 2 22 (46) 21 (40) 17 (36) 21 (47) 3 3 (6) 3 (6) 3 (6) 3 (7) 4 4 (8) 5 (9) 4 (9) 4 (8) ALT #3 ULN 32 (67) 31 (58) 31 (66) 32 (71).3 ULN 16 (33) 22 (41) 16 (34) 13 (29) Serum HCV-RNA # copies/ml 19 (40) 28 (53) 13 (28) 9 (20) copies/ml 28 (58) 22 (41) 32 (68) 34 (76) missing 1 (2) 3 (6) 2 (4) 2 (4) group D ¼ 18 mg IFN alfacon-1, three times a week for 48 weeks in both groups; ALT, alanine aminotransferase; ULN, upper limit of normal. Values expressed as number of patients (percentage). group D, n ¼ 45). The pretreatment clinico-demographic characteristics were similar in the two treatment groups A and B, with the exception of a different distribution of severity of necroinflammation at histology (P ¼ 0:04); no difference in baseline features was observed between the two treatment groups C and D (Table 1). Of the 193 enrolled patients, 66 terminated therapy prematurely, namely 22 (11%) stopped treatment for severe adverse events, 18 (9%) for non-compliance or lost to follow-up and 26 (28%) patients infected with genotype 1 for insufficient response at week 24 of therapy with similar rates in groups C and D, respectively (Table 2). Table 2 Rates of discontinuation of treatment and dose modification during treatment HCV genotype 2 or 3 HCV genotype 1 Group A (n ¼ 48) Group B (n ¼ 53) Group C (n ¼ 47) Group D (n ¼ 45) Discontinuation of treatment for Severe adverse events 3 (6) 8 (15) (15) 4 (9) 0.37 Insufficient response 13 (28) 13 (29) 0.89 Non-compliance or lost to follow-up 4 (8) 4 (7) (4) 8 (18) 0.03 Dose reduction for a Any adverse events b 14 (29) 20 (38) (23) 22 (49) Anemia 10 (21) 10 (19) (21) 13 (29) 0.39 Neutropenia 2 (4) 4 (7) (11) Other adverse events 5 (10) 14 (26) (4) 15 (33) group D ¼ 18 mg IFN alfacon-1, three times a week for 48 weeks in both groups. Values expressed as number of patients (percentage). a Dose modification was defined as the reduction or omission of one or more doses. b Some patients who required dose modification had both anemia and other adverse events.

4 846 G. Fattovich et al. / Journal of Hepatology 39 (2003) Table 3 Proportion of patients with virologic and biochemical responses to interferon (IFN) alfacon-1 and ribavirin combination therapy HCV genotype 2/3 HCV genotype 1 Response Group A (n ¼ 48) Group B (n ¼ 53) Group C (n ¼ 47) Group D (n ¼ 45) Negative HCV-RNA End of therapy 37 (77) 38 (72) (47) 19 (42) 0.65 End of 24 week follow-up 33 (69) 35 (66) (40) 16 (36) 0.63 Normal ALT End of therapy 35 (73) 35 (66) (53) 20 (44) 0.40 End of 24 week follow-up 33 (69) 35 (66) (40) 15 (33) 0.48 group D ¼ 18 mg IFN alfacon-1, three times a week for 48 weeks in both groups; ALT, alanine aminotransferase. Values expressed as number of patients (percentage) Subgroups analysis according to treatment schedules Among genotype 2 or 3 patients, the rates of ETVR, SVR and sustained biochemical response were similar in the treatment group A and B (Table 3). None of the genotype 2 or 3 patients underwent virologic breakthrough, whereas virologic relapse was observed in four (8%) and three (6%) patients in group A and B, respectively (P ¼ 0:59). Among genotype 1 patients, the proportion of patients with ETVR, SVR and sustained biochemical response were comparable between the treatment group C and D (Table 3). Virologic breakthrough during therapy occurred in three (6%) and one (2%) patients in group C and D, respectively (P ¼ 0:61) and off therapy virologic relapse was observed in three (6%) and three (7%) patients in group C and D, respectively (P ¼ 0:9) Sustained virologic response according to baseline characteristics and treatment regimen As shown in Table 4 among genotype 2 or 3 patients or genotype 1 patients the rates of response to either treatment regimen was not influenced by sex, age, weight, source of infection, stage of fibrosis, pretreatment ALT levels or serum HCV-RNA levels. The following parameters were examined as potential prognostic factors for a SVR (yes ¼ 1, no ¼ 0) and were introduced as dichotomous variables into a logistic regression analysis: gender (female ¼ 1, male ¼ 0), age (#40 years ¼ 1,.40 years ¼ 0), stage of fibrosis (F0/F1/F2 ¼ 1, F3/F4 ¼ 0), HCV-RNA level (#2 million copies/ml ¼ 1,.2 million copies/ml ¼ 0), ALT quotient calculated as the average of the serum ALT values before treatment divided by the upper limit of normal Table 4 Rates of sustained virologic response according to baseline characteristics of patients and treatment group HCV genotype 2/3 HCV genotype 1 Group A (n ¼ 48) Group B (n ¼ 53) Group C (n ¼ 47) Group D (n ¼ 45) Gender Male 17/27 (63) 26/39 (67) /31 (42) 14/31 (45) 0.79 Female 16/21 (76) 9/14 (64) /16 (37) 2/14 (14) 0.22 Age (years) #40 16/20 (80) 18/29 (62) /25 (44) 10/20 (50) /28 (61) 17/24 (71) /22 (36) 6/25 (24) 0.35 Weight (kg) #75 21/33 (64) 24/40 (60) /27 (44) 8/28 (71) /15 (80) 11/13 (85) 1.0 7/20 (35) 8/17 (47) 0.45 Source of infection Transfusion 3/4 (75) 3/5 (60) 1.0 1/4 (25) 1/3 (33) 1.0 Injection drug use 13/19 (68) 17/27 (63) /11 (64) 6/13 (46) 0.44 Sporadic/unknown 17/25 (68) 15/21 (71) /32 (34) 9/29 (31) 0.78 Fibrosis stage F0/F1/F2 30/41 (73) 31/45 (69) /40 (40) 16/38 (42) 0.85 F3/F4 3/7 (43) 4/8 (50) /7 (43) 0/ ALT #3 ULN 24/32 (75) 21/31 (68) /31 (35) 11/32 (35) ULN 9/16 (56) 14/22 (64) /16 (50) 5/13 (39) 0.53 Serum HCV-RNA a # copies/ml 13/19 (68) 21/28 (75) /13 (46) 3/9 (33) copies/ml 19/28 (68) 13/22 (59) /32 (41) 13/34 (38) 0.84 group D ¼ 18 mg IFN alfacon-1, three times a week for 48 weeks in both groups; ALT, alanine aminotransferase; ULN, upper limit of normal. Values expressed as number/total number of patients (percentage). a 185 patients with available data.

5 G. Fattovich et al. / Journal of Hepatology 39 (2003) Table 5 Results of logistic regression analysis correlating pretreatment variables with a sustained virologic response B regression coefficient S.E. Odds ratio (95% CI) HCV genotype 2 or 3 Gender (female) ( ) 0.61 Age (,40 years) ( ) 0.75 Fibrosis stage (F0/F1/F2) ( ) 0.72 ALT (.3 ULN) ( ) 0.61 Serum HCV-RNA (, copies/ml) ( ) 0.30 Treatment with 18 mcg IFN alfacon ( ) 0.74 HCV genotype 1 Gender (female) ( ) 0.12 Age (,40 years) ( ) 0.09 Fibrosis stage (F0/F1/F2) ( ) 0.36 ALT (.3 ULN) ( ) 0.27 Serum HCV-RNA (, copies/ml) ( ) 0.92 Treatment with 18 mcg IFN alfacon ( ) 0.72 (. 3 ¼ 1, # 3 ¼ 0), and treatment assignment (18 mcg regimen ¼ 1, 9 mcg regimen ¼ 0). No prognostic factor for SVR was identified among genotype 2 or 3 patients as well as among genotype 1 patients (Table 5) Sustained virologic response according to adherence to therapy As summarized in Table 6 the proportion of genotype 2 or 3 patients with a SVR was similar to either treatment regimen with 9 or 18 mcg of IFN alfacon-1 among those who were most adherent to combination therapy (80/80/80 subgroup) (83% vs. 81% in group A and B, respectively; P ¼ 0:81); the corresponding figures for SVR among patients who had a substantial dose reduction (, 80/, 80/. 80 subgroup) were 67% and 100% in group A and B (P ¼ 0:12). Among genotype 1 patients, the rates of SVR were comparable to either treatment regimen among the 80/80/80 subgroup (47% vs. 50% in group C and D, respectively, P ¼ 0:92); the corresponding figures for SVR among the,80/,80/.80 subgroup were 67% and 47% in group C and D, respectively (P ¼ 1:0) Analysis for all patients Overall a SVR was observed in 53% (103 out of 193) patients and as expected the rate of SVR was greater in the genotype 2 or 3 patients than in those infected with the genotype 1, i.e. 67% (68 out of 101) and 38% (35 out of 92), respectively. Overall 98% (101 out of 103) of patients with a SVR had sustained biochemical response. In the genotype 2 or 3 group the overall rates of SVR were 72% (34 out of 47) and 64% (32 out of 50) according to low or high baseline levels of HCV-RNA, respectively (P ¼ 0:37), and 71% (61 out of 86) and 47% (7 out of 15) according to fibrosis stage F0/F1/F2 or F3/F4, respectively (P ¼ 0:06); the corresponding figures in the genotype 1 group were 41% (9 out of 22) and 39% (26 out of 66) for low or high baseline levels of HCV-RNA, respectively, (P ¼ 0:9), and 41% (32 out of 78) and 21% (3 out of 14) for fibrosis stage F0/F1/F2 or F3/F4, respectively (P ¼ 0:13) Safety The rate of discontinuation of therapy for adverse events was 11% (11 out of 101) among genotype 2 or 3 patients Table 6 Rates of sustained virologic response according to adherence to therapy HCV Genotype 2/3 HCV Genotype 1 Group A (n ¼ 48) Group B (n ¼ 53) Total (n ¼ 101) Group C (n ¼ 47) Group D (n ¼ 45) Total (n ¼ 92) 80/80/80 a 29/35 (83) 25/31 (81) /66 (82) 17/35 (47) 9/18 (50) /53 (49),80/,80/.80 b 4/6 (67) 10/10 (100) /16 (87) 2/3 (67) 7/15 (47) 1.0 9/18 (50) Excluded c group D ¼ 18 mg IFN alfacon-1, three times a week for 48 weeks in both groups. Values expressed as number/total number of patients (percentage). a Patients who received $80% IFN alfacon-1 plus $80% ribavirin for $80% of the expected duration of therapy. b Patients who received,80% IFN alfacon-1 and/or,80% ribavirin for $80% of the expected duration of therapy. c Indicates the number of patients excluded from the analysis because they received treatment for less than 80% of the expected treatment duration.

6 848 G. Fattovich et al. / Journal of Hepatology 39 (2003) Table 7 Frequency of adverse events Group A Group B Group C Group D Total (n ¼ 48) (n ¼ 53) (n ¼ 47) (n ¼ 45) (n ¼ 193) Influenza-like symptoms Fatigue Weight loss Gastrointestinal symptoms Psychiatric symptoms Depression Insomnia Irritability Dermatologic symptoms Thyroid dysfunction Values are expressed as percentages. Events that occurred in at least 5% of patients are reported in this table; patients may have had more than one adverse event. treated for 24 weeks and 12% (11 out of 92) among genotype 1 patients treated for 48 weeks and, as shown in Table 2, the number of patients undergoing premature termination of therapy because of side effects were not different between treatment groups A and B or C and D, respectively. The reason for discontinuation were depression (B, 4; C, 4; D, 1), hyperthyroidism (A, 1; C, 2; D, 1), dermatologic symptoms (A, 1; B, 1; C, 1; D, 1), severe fatigue (B, 1; D, 1), abnormal aminotransferase levels (A, 1) and severe anemia (B, 2). Dose reduction of IFN alfacon-1 (usually a 25 50% reduction in the assigned dose) and/or ribavirin (usually to 600 mg) because of adverse events other than anemia was more frequent in patients of group D receiving the dose of 18 mcg of IFN alfacon-1 in combination with ribavirin for 48 weeks than in those in group C (33% vs. 4%, P ¼ 0:000) (Table 2). The frequency of adverse events that occurred in at least 5% of patients enrolled in this study is shown in Table Discussion The results of the study indicate that the higher IFN alfacon-1 dose does not affect the final treatment outcome as compared to the lower dose. Similar rates of SVR at the end of follow-up week 24 were observed for patients treated with 9 or 18 mcg of IFN alfacon-1 both among genotype 2 or 3 patients (69% and 66%, respectively) and among genotype 1 patients (40% and 36%, respectively). Multivariate logistic regression analysis confirmed that higher IFN alfacon-1 regimen had no significant effect on SVR (Table 5). Moreover, the evaluation of adherence to treatment schedule showed similar SVR rates to either 9 or 18 mcg of IFN alfacon-1 among those patients who were most adherent and received. 80% of their total IFN alfacon-1 and ribavirin dose for more than 80% of the expected duration of therapy, further supporting the data that the higher dose of IFN alfacon-1 is no more effective (Table 6). In consideration of these results we have evaluated the combined data from the two schedules of combination therapy. The rate of sustained responses in genotype 1 patients was 38% as compared to a SVR ranging from 29 [17] to 33 [18] and 36% [19] reported with standard IFN alfa-2b (3 MU TIW) and ribavirin combination therapy in the same subgroup of patients. In addition in our study the rate of SVR in patients infected with genotype 1 and pretreatment high viral load was 39% as compared to 27% [17] and 33% [19] with standard combination therapy. Subsequent to the initiation of this trial the combination of peg IFN alfa-2b and ribavirin was approved as initial therapy for patients with chronic hepatitis C. Manns et al. [18] have reported that in genotype 1 patients the rate of SVR was 42%, a figure in keeping with our rate of 38%, and 32% by using a high or low dose of peg-ifn alpha-2b, respectively. In a recent study, Fried et al. [19] have reported a SVR of 46% by using a fixed dose of peg-ifn alpha-2a in genotype 1 patients; the same treatment schedule has achieved a SVR of 41% in genotype 1 patients with pretreatment high viral load, similar to our rate of 39%. Overall these findings suggest that the sustained response with IFN alfacon-1 and ribavirin combination therapy in this difficult to-treat group of patients surpasses that reported with standard combination therapy and approaches that achieved with peg-ifn alpha in combination with ribavirin. IFN alfacon-1 and ribavirin therapy maintained the safety of standard IFN alpha or peg-ifn alpha combination therapy. The rate of discontinuation for adverse events was 12% for 48 weeks therapy as compared with 13 21% with IFN alpha plus ribavirin [9,18] and with 10 14% with peg- IFN alpha and ribavirin [18,19] given for the same duration of 48 weeks. The evaluation of tolerability showed that the rate of dose reduction for any adverse event was 23% with 9 mcg of IFN alfacon-1 TIW plus ribavirin for 48 weeks as compared with 21 34% with standard combination therapy and with 22 42% with peg-ifn alpha and ribavirin

7 G. Fattovich et al. / Journal of Hepatology 39 (2003) [18 20]. It is of note that the frequency of dose modification for neutropenia was 4% and 0% with 9 mcg of IFN alfacon- 1 combination therapy given for 24 or 48 weeks, respectively (Table 2), and that none of the patients enrolled in this study required dose reduction because of thrombocytopenia. In addition the rates of the more frequent adverse events in patients treated with IFN alfacon-1 combination therapy were similar or lower than previously reported in trials using peg-ifn alpha and ribavirin [18 20]. Thus, influenza like symptoms (incidence of 45% with IFN alfacon-1 and 43 46% with peg-ifn) and depression (incidence of 20% with IFN alfacon-1 and 22% with peg- IFN alpha) appear to occur with similar frequency, whereas fatigue, weight loss, gastrointestinal disturbances (nausea, diarrhea), psychiatric symptoms (insomnia, irritability) and dermatologic symptoms were reported less frequently (by at least 5%) in our trial compared with published studies of peg-ifn alpha and ribavirin [18 20]. It should be pointed out that future studies will need to compare directly the combination of IFN alfacon-1 and ribavirin with the combination of peg-ifn and ribavirin in order to confirm these results regarding efficacy as well as safety and tolerability. In summary the use of higher IFN alfacon-1 dose of 18 mcg in combination with ribavirin does not increase SVR rates as compared to 9 mcg of IFN alfacon-1 plus ribavirin regimen. Previously untreated patients with genotype 1 chronic hepatitis may achieve significant response rate of approximately 40% if treated with 9 mg of IFN alfacon-1 TIW plus ribavirin for 48 weeks. The combination of IFN alfacon-1 and ribavirin could be considered as an alternative treatment for the difficult to-treat genotype 1 patients or in general for those patients discontinuing peg-ifn plus ribavirin because of severe side effects, such as reduction in neutrophil and/or platelet counts. It is pertinent that currently in Italy the wholesale weekly cost of 9 mcg doses of IFN alfacon-1 TIW is 78 Euros, whereas 80 mcg or 100 mcg weekly doses of peg-ifn alpha 2b cost 224 and 280 Euros, respectively, and 180 mcg weekly doses of peg-ifn alpha 2a cost 304 Euros. The lower cost of IFN alfacon-1 should be taken into account to consider this combination therapy, at least in the difficult totreat genotype 1 patients, especially in countries where the cost of peg-ifn alpha cannot be afforded. 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