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High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon
LIVER,PANCREAS,AND BILIARYTRACT
DIGEST LIVER DIS 2000;32:703-7
High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon G. G. M. A.
Bresci Parisi Bertoni Capria
: Dr. G. Bresci, vie Alefsandro delle
MuLrrrBw
Spina 1 I, 56125 Piss, Italy. Fax: +39-
Background. Recently, the combination treatment of recombinant alpha-interferon plus ribavirin has been proposed for chronic hepatitis C patients unresponsive to previous therapy with recombinant alpha-interferon alone. Aim. To determine the effectiveness of the combination therapy for the re-treatment of chronic hepatitis C patients unresponsive to previous interferon therapy Immediate and long-term follow-up data are reported. Patients and Methods. A series of 100 patients with chronic hepatitis C not responding to recombinant alpha-interferon 3 MU tiw, were randomly assigned to two groups of 50 patients each: Group A, treated with recombinant alpha-interferon therapy for an additional six months but at a double dosage (6 MU tiw] in association with ribavirin. Group 8, same treatment as group A but without ribavirin. All patients responsive to therapy were then followed-up for at least 12 months. At the end of the treatment and at the end of the follow-up period, we distinguished between complete responses [return to normal of alanine aminotransferase with undetectable serum HCV-RNA] and biochemical responses [return to normal of alanine aminotransferase still with detectable viraemia]. Results. Side-effects were observed only in patients treated with recombinant alpha-interferon plus ribavirin: 12% discontinued the therapy due to haemolytic anaemia. In group A, the percentages of end-of-treatment complete response, end-of-treatment biochemical response, sustained complete response, and sustained biochemical response, were 38%, 20%, 8%, and 14%, respectively, whilst in group 8, these percentages were 12%, 16%, 6%, and 16%, respectively Conclusion. The results indicate that in patients with chronic hepatitis C unresponsive to previous recombinant alpha-interferon therapy, re-treatment with higher recombinant alpha-interferon doses, either alone or in combination with ribavirin, lead to mild long-term benefit. However the satisfactory end of treatment complete response in group A suggests that a significant percentage of patients are sensitive to the combination therapy; and that a more aggressive the lrapeutic protocol in this selected subset of patients could r--’ ’ a larger number EWIL.‘& In of long-lasting responses __ leading, in turn, to a more favourable cost-effect ratio.
Key words:
chronic
hepatitis
C; interferon
plus
Ribavirin;
interferon
therapy;
non-responders
703
Therapy in non-responders
to r-IFN-w
Introduction Hepatitis C virus (HCV) has been identified as one of the major agents of acute hepatitis, which becomes chronic in more than 50% of cases. Between 20-30% of chronic hepatitis cases evolve towards cirrhosis and the related complications, including the development of hepatocarcinoma l-3. In an attempt to arrest the progression of this form of hepatitis, corticosteroids, immunosuppresants, and antiviral agents have been used without any apparent positive results 4-7. Only interferon (IFN) has resulted in a biochemical and virological response. With IFN treatment, serum aminotransferase levels may return to normal, hepatic histology improves and disappearance of serum HCV-RNA is achieved, even though more than 50% of the patients do not respond to the first course of treatment with IFN-a or relapse after a transient response 8-‘5. A persistent return to normal of transaminases and elimination of HCV-RNA with IFN-a therapy has been reported in only lo-20% of cases, and data emerging from personal experience, since 1989 16-18,is in keeping with most reports in the literature. In the attempt to reduce the number of non-responders to courses of IFN-a, treatment, research workers are attempting to understand how an increase in IFN-a dosage and duration of treatment or new antiviral drug associations could improve the results. Re-treatment with a double dose of IFN may be useful in non-responders or patients that relapse after a first course of treatment with IFN-a, even if this attempt has not led to a significant therapeutic advantage, especially in non-responders. Better results have been achieved in patients who relapse, who generally respond to a second course of IFN-a therapy if the first had been successful in exerting a response, even temporary, of HCV viraemia 19-26.This fact has resulted in the need to achieve longer lasting results with new therapeutic approaches for non-responders. Recently, the combination treatment of IFN-a plus ribavirin has been proposed for patients in whom transaminase levels failed to return to normal after therapy with IFN alone l9 27-31. The results of these studies are not clear since some support this combination while others are less enthusiastic. Moreover, it is hard to compare the results of these trials as they often include not only non-responders to IFN-a treatment but also patients that relapse. Furthermore, no long-term follow-ups were performed in these trials, even though this information is fundamental to understanding the efficiency of the therapeutic protocol in terms of sustained response. Finally, some trials adopted, in the combination therapy group, the usual dosage of IFN-a (3 MU tiw), and compared this combination to higher doses of IFN-a alone, thus making it difficult to evaluate the re-
al efficiency of ribavirin with respect to IFN-a alone unless the same doses of EN-a are used in both cases. Thus, to determine the actual efficiency of the combination therapy in patients unresponsive to previous IFN-a courses, we compared the re-treatment with IFN-a alone versus the association with ribavirin, using higher IFN-a doses in both groups and evaluating also the long-term behaviour of the disease.
Patients and Methods A series of 100 patients with chronic hepatitis C unresponsive to previous therapy with r-EN-a (a2b, 3 Million Units three times a week for 4 months) were included in our trial. The diagnosis of chronic hepatitis C was based, prior to the initial treatment, upon clinical, serological and histological data in all patients 3233.Results showed serum alanine aminotransferase (ALT) levels at least twice the upper normal value (40 U/l), measured 3 times during the 6 months preceding their enrolment. Serum HCV-RNA was assessed by the nested reverse transcription polymerase chain reaction (RT-PCR) using primers covering the conserved 5’-untranslated region of the viral genome 34, with a cut-off of lo3 gen/ml. HCV genotypes were determined by a reverse-hybridisation line probe assay 35. Liver biopsies were collected in all patients before starting treatment and were analysed by a single pathologist: the Knodell histological activity index was used to score the tissue samples 36. None of the enrolled patients had alcohol consumption ~40 g/day, drug-induced liver disease, presence of HBV, HDV or HIV infections, autoimmune factors (positivity of anti-nuclear, antismooth muscle and/or anti-mitochondrial antibodies), metabolic disorders (haemochromatosis, Wilson’s disease, alpha- 1-antitrypsin deficiency), pre-existing anaemia, or thyroid dysfunction. Other exclusion criteria were: concomitant liver diseases, histological diagnosis of liver cirrhosis, and recent antiviral treatments (less than six months before the study). After obtaining written consent, patients were randomly assigned to one of the two groups of fifty patients each: Group A treated with the same type of r-IFNa for an additional six months but at a doubled dosage (6 MU tiw) with respect to the first therapy, in association with ribavirin ( 1000 or 1200 mg/day given orally at two different doses to patients weighing, respectively, less than or more than 75 kg). Group B treated with the same therapy, dose and duration of r-IFNa as group A, but without ribavirin. Randomization was done using the Random Numbers Table. Main characteristics of the patients enrolled in each group are summarized in Table I. l
l
C. Brssci et al.
zdl.
Demographic and clinical data of hepatitis C patients en-
A Patients MaladFemalas Age (~1 Imaan f SD1 Duration d dieaee Lyrsl [mean f SD1 Basal AU tlJ/Il Imaan f SD1 HCV Genotype 1 Knodell histalogical activity index Mean fibrosis score
EK?;! 52Lk9 7t9 149&8 78% 10.3zk3.1 2.0*1
II
In group B, an ETCR was obtained in 6 (12%) patients, and an ETBR in 8 (16%). At the end of the follow-up, a SCR was observed in 3 natients (6%). and a SBR in A 8 (16%) (Table II).
&4 48&l 1 6i7 15Ok52
IWe II. Results of combined [Group Al and IFN [Group 8) trsatment in chronic hepatitis C patients unresponsive to a previous course of rlfN.
Et2.5 2:2&.8
Grolpr
A
ETCR ETBR SC8 SER
19 (38%) IO [2lJ%I 4 (8%) 7 [14%1
The same physician, using the same laboratory equipment, performed clinical and laboratory evaluations at monthly intervals. An end-of-treatment complete response (ETCR) was defined as return to normal of ALT with disappearance of serum HCV-RNA just after stopping therapy, while an end-of-treatment biochemical response (ETBR), as a return to normal of serum ALT levels with still detectable viraemia. All the patients with ETCR or ETBR were followed-up for at least 12 months, and monthly clinical and laboratory tests were also performed in this period. At the end of the follow-ups, a sustained complete response (SCR) was defined as the persistence of normal ALT and undetectable viraemia, while a sustained biochemical response (SBR) as persistence of normal ALT with still detectable serum HCV-RNA. A statistical analysis was made to evaluate the homogeneity of the groups with respect to age, sex, presumed duration of disease, genotype, histological activity and ALT levels. The X2-test, Wilcoxon tests for independent and related samples, and Fisher’s exact test were used when appropriate.
Results The two groups were homogeneous as far as concerns age, sex, and duration of the disease, genotype, histological diagnosis and ALT levels (Table I). Side-effects were observed only in the group of patients treated with r-IFN-a plus ribavirin. In fact, in this group, 12 (24%) patients developed haemolytic anaemia, though only 6 had to withdraw from treatment due to the entity of the anaemia - all these patients made a prompt recovery after withdrawal. The other 6 patients continued the therapy after a dose reduction of ribavirin. In group A, an ETCR was seen in 19 (38%) patients, and an ETBR in 10 (20%). At the end of the treatment free follow-up period, a SCR was observed in 4 (8%) patients, and a SBC in 7 (14%).
p
Statistical analysis of our data showed that the r-IFN-a plus ribavirin combination was significantly (p
Discussion Data from the literature demonstrate that the percentage of patients obtaining a short-term response to a second course of treatment with IFN-a differ considerably between non-responders and relapsing patients. Indeed, most studies upon re-treatment of non-responders to IFN-a monotherapy report percentages of an early return to normal of ALT levels varying from 516%, while in the case of relapsing patients, the use of IFN-a alone leads to short-term normalization in 70% of cases 23-31. Therefore, the results of re-treatment with IFN-a alone in non-responders to a first therapy of IFN-a are unsatisfactory I5. The limited efficiency of re-treatment with IFN-a in monotherapy in these patients has led to an investigation to seek an alternative approach, including the combined therapy with IFN-a plus ribavirin. Some preliminary trials I9527-31,37 have shown this combination to be of greater efficiency than IFN-a alone. Unfortunately, as previously mentioned, most of the trials adopted standard doses of r-IFN-a (3 MU tiw) in
105
Therapy in non-responders
to r-IFN-tx
the combination protocol then compared such a combination protocol with a re-treatment of higher doses of r-IFN-a alone. Hence, data from these studies do not demonstrate the actual effectiveness of ribavirin - also since different doses of IFN-a were adopted. On the contrary, in our study, we adopted the same IFN-a treatment (6 MU tiw for 6 months) in both groups. As the efficiency of antiviral treatment can only be evaluated several months after the end of the therapy, we completed follow-ups to responder patients for at least one year after termination of therapy. We preferred to enrol only non-responders to an initial therapy of r-IFN-a, excluding those who relapsed in order, to obtain a more homogeneous group in terms of expected response. Moreover, to make our data as reliable as possible, we excluded from our study, subjects with other concomitant liver diseases, which might have affected our results. Furthermore, we also excluded patients with a histological diagnosis of cirrhosis since, at present, it is widely accepted that IFN therapy, in these subjects, is poorly, or not effective, at all 38-4o. The homogeneity of the two groups with respect to age, sex, duration of the disease, genotype, histological diagnosis and ALT levels was checked to reduce any possible influence on the results. None of the treated patients showed any side-effects serious enough to require withdrawal from r-IFN-a therapy; probably, this is due to our inclusion criteria, as all enrolled patients had already completed a course of IFN-a. Ribavirin was also well tolerated, even if 12% of the patients developed significant haemolytic anaemia (with complete recovery after interruption) that induced withdrawal from treatment. Our data demonstrate that high-dose r-IFN-a plus ribavirin produces better results, in the short-term, than rIFN-a alone. This positive effect is transient and lasts only as long as the combined treatment is administered. In fact, at the end of the follow-up period, there was no statistically significant difference between the two treatment regimens. Our data disagree with those obtained in some other studies 3041but, confirm the results of recent trials 42-44which showed that there is no indication for IFN-a plus ribavirin in chronic hepatitis C resistant to a previous IFN treatment. Results in different groups were not influenced by viral genotype, even if, in the literature, genotype 1 represents a factor of reduced response compared to non1 genotypes. This finding could be due to the fact that in the patients enrolled the disease was unresponsive to a previous IFN-a therapy, independent of their genotype. On the basis of these findings, in our opinion, both the combination therapy and the re-treatment with solely IFN-a, even if with higher doses, are unable to lead to long-term benefits. However, the satisfactory early re706
sults in group A (more than one third of complete responses at the end of the combination therapy) should make us reflect upon possible modifications of this type of treatment in order to maintain similar results also in the long-term. It is reasonable to hypothesize that a larger cohort of patients could obtain a sustained response to the re-treatment through a modification of the ongoing schedule: for example, by prolonging the re-treatment therapy with the same drug scheme or with different doses or, finally, with the addition of other agents. Nevertheless, taking into account the costs and the possible side-effects of such drugs, we need to select those patients who would most benefit from more aggressive treatments. This cohort of patients could easily be identified by frequent biochemical and virological assays, and, therefore, our data could represent a stimulus for future trials aimed at modifying the ongoing therapy in accordance with the viraemic suppression, i.e., to tailor treatment to the single patient in order to obtain a more favourable cost-effect ratio.
References ’ Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic nonA, non-B hepatitis. N Engl J Med 1989;321:1494-500. Z Hasan F, Jeffers LJ, De Medina M, Reddy KR, Parker T, Schiff ER, et al. Hepatitis C-associated hepatocellular carcinoma. Hepatology 1990;12:589-91. 3 Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S, et al. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Nat1 Acad Sci USA 1990;87:6547-9. 4 Hoofnagle JH. Chronic hepatitis: The role of corticosteroids. In: Szmuness W, Alter HJ, Maynard JE, editors. Viral hepatitis. International Symposium. Philadelphia: Franklin Institute Press; 1981. p. 573-83. 5 Pappas SC, Hoofnagle JH, Young N, Straus SE. Treatment of non-A, non-B hepatitis with acyclovir: a pilot study. J Med Virol 198.5;15:1-9. 6 Stokes P, Lopez WC, Balart LA. Effects of short-term corticosteroids therapy in patients with chronic non-A, non-B hepatitis (NANB). Gastroenterology (Abstract) 1987;92:1783. ’ Perrillo RP. Antiviral therapy of chronic viral hepatitis. Current opinion on gastroenterology. London: Gower Academic Journal 1988;4:420-7. ’ Marcellin P, Benhamou JP. Treatment of chronic viral hepatitis. Baillieres Clin Gastroenterol 1994;8:233-53. 9 Tine F, Magrin S, Craxi A, Pagliaro L. Alpha-IFN in non-A, nonB chronic hepatitis: a meta-analysis of randomized clinical trials. J Hepatol 1991;13:192-9. ‘” Malaguamera M, Restuccia S, Trovato G, Sicilian0 R, Motta M, Trovato BA. IFN-a treatment in patients with chronic hepatitis C: a meta analytic evaluation. Clin Drug Invest 199.5;9: 141-9. I’ Ryff JC. Usefulness of IFN for treatment of hepatitis C. J Hepato1 1995;22:101-9. I’ Poynard T, Leroy V, Marielle C, Leroy V, Cohard M, Thevenot T,
6. Bresci et al.
et al. Meta-analysis of IFN randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996;24:778-9. I3 Hoofnagle J. The treatment of chronic viral hepatitis. N Engl J Med 1997;5:336-56. I4 Camma C, Giunta M, Linea C, Pagliaro L. The effect of IFN on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis. J Hepatol 1997;26: 1187-99. I5 Rizzetto M. Therapy of chronic viral hepatitis: a critical view. Ital J Gastroenterol Hepatol 1999;31:781-93. I6 Bresci G, Parisi G, Banti S, Bertoni M. Therapy of active chronic hepatitis with recombinant o2b-IFN: an 18 month follow-up. EJM 1993;6:349-52. ” Bresci G, Del Corso L, Giuliano G. The use of recombinant IFN alfa-2b in elderly patients with anti-HCV positive chronic active hepatitis. J Am Geriatr Sot 1993;41:857-62. I8 Bresci G, Gambardella L, Parisi G, Banti S, Scatana F, Capria A. Sustained remission and viremia in chronic hepatitis C treated with recombinant a-IFN. Int J Clin Pharm Res 1995;5:175-9. I9 Schalm SW, Brouwer JT. Antiviral therapy of hepatitis C. Stand J Gastroenterol 1997;223:46-9. ?” Toyoda H, Nakano S, Takeda I, Kumada T, Sugiyama K, Osada T, et al. Retreatment of chronic hepatitis C with IFN. Am J Gastroenterol 1994;89: 1453-7. ?’ Hagiwara H, Hayashi N, Kasahara A, Oshita M, Katayama K, Naito M, et al. Long-term biochemical and virological response to natural interferon-alpha in patients with chronic hepatitis C. Dig Dis Sci 1996;41:1001-7. ?? Arase Y, Kumada H, Chayama K, Tsubota A, Koida I, Ikeda K, et al. Interferon retreatment of nonresponders with HCV-RNA-positive chronic hepatitis C. J Gastroenterol 1994;29:299-304. ?? Marcellin P, Boyer N, Pouteau M, Benhamou JP, Erlinger S. Retreatment with IFN alpha of chronic hepatitis C virus infection. Lancet 1994;344:690- 1. 211Bresci G, Parisi G, Banti S, Capria A. Re-treatment of IFNresistant patients with chronic hepatitis C with IFN-a. J Viral Hepat 1995;2: 155-8. 25 Gerken G, Teuber G, Goergen B, Meyer zum Buschenfelde KH. IFN alpha retreatment in chronic hepatitis. J Hepatol 1995;22:118-21. x Bresci G, Parisi G, Banti S, Scatena F, Bretoni M, Capria A. Chronic hepatitis C: what treatment for non-responders to recombinant-IFN-a? Clin Drug Invest 1996;11:224-8. ?’ Brillanti S, Garson J, Foli M, Whitby K, Deaville R, Masci C, et al. A pilot study of combination therapy with ribavirin plus IFN alfa for IFN alfa resistant chronic hepatitis C. Gastroenterology 1994;107:812-7. zx Schvarcz R, Ando Y, Sonnerborg A, Weiland 0. Combination treatment with IFN alfa-2b and ribavirin for chronic hepatits C in patients who have failed to achieve sustained response to IFN alone: Swedish experience. J Hepatol 1995;23:17-21. ?y Scotto G, Fazio V, Tantimonaco G. Pilot study of a short course of ribavirin and alpha IFN in the treatment of chronic active he-
patitis C not responding to alpha-IFN alone. Ital J Gastroenterol 1996;28:505-11. 3oBellobuono A, Mondazzi L, Tempini S, Silini E, Vicari F, Ideo G. Ribavirin and IFN-alpha combination therapy vs IFN-alpha alone in the treatment of chronic hepatitis C: a randomized clinical trial. J Viral Hepat 1997;4:185-91. 31 Schvarcz R, Ando Y, Sonnerborg A, Weiland 0. Ribavirin enhances the efficacy but not the adverse effects of IFN in chronic hepatitis C. Meta-analysis of individual patients data from European centers. J Hepatol 1997;26:961-6. 32 Boyer JL. Chronic hepatitis. In: Schiff L, Schiff ER, editors. Disease of the liver. 7th edition. Philadelphia: JB Lippincott Company. 1993. p. 586-637. 13 Scheuer P. Liver biopsy interpretation (third edition). London: Bailliere Tindall; 1980. p. 102-32. 34 Imberti L, Cariani E, Bettinardi A, Zonaro A, Albertini A, Primi D. An immunoassay for specific amplified HCV sequences. J Virol Methods 1991;36:233-43. x Lee JH, Roth WK, Zeuzem S. Evaluation and comparison of different hepatitis C virus genotyping and serotyping assays. J Hepatol 1997;26:1001-9. 36 Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-5. 37 Schalm SW, Brouwer JT, Chemello L, Alberti A, Bellobuono A, Ideo G, et al. IFN-ribavirin combination therapy for chronic hepatitis C. Dig Dis Sci 1999;41:131-4. 38 Camps J, Crisostomo S, Garcia-Granero M, Riezu-Boj JI, Civeira MP, Prieto J. Prediction of response of chronic hepatits C to IFN alfa: a statistical analysis of pretreatment variables. Gut 1993;34:1714-7. 39Jouet P, Roudot-Thoraval F, Dhumeaux D, Metreau JM. Comparative efficacy of IFN alfa in cirrhotic and non cirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 1994;106:686-90. 4o Pagliaro L, Craxi A, Camma C, Tine F, Di Marco V, Lo Iacono 0, et al. IFN-alfa for chronic hepatitis C: an analysis of pretreatment clinical predictors of response. Hepatology 1994;19:820-8. 4’ Milella M, Santantonio T, Pietromatera G, Maselli R, Casalino C, Mariano N, et al. Retreatment of non-responders or relapser chronic hepatitis C patients with IFN plus ribavirin vs IFN alone. Ital J Gastroenterol Hepatol 1999;31:21 l-5. 42 Andreone P, Gramenzi A, Cursaro C, Sbolli G, Fiorino S, Di Giammarino L, et al. IFN-alpha plus ribavirin in chronic hepatitis C resistant to previous IFN-alpha course: results of a randomized multicenter trial. J Hepatol 1999;30:788-93. 43 Spadaro A, Freni MA, Ajello A, Alessi N, Barbaro E, Resta ML, et al. Interferon retreatment of patients with chronic hepatitis C. A long-term follow-up. Hepatogastroenterology 1999;46:3229-33. 44 Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, Pellicelli A, Grisorio B, et al. Intravenous recombinant interferon-beta versus interferon-alpha-2b and ribavirin in combination for short-term treatment of chronic hepatitis C patients not responding to interferon-alpha. Stand J Gastroenterol 1999;9:928-32.
DIGEST LIVER DIS 2000;32:703-7
High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon G. G. M. A.
Bresci Parisi Bertoni Capria
: Dr. G. Bresci, vie Alefsandro delle
MuLrrrBw
Spina 1 I, 56125 Piss, Italy. Fax: +39-
Background. Recently, the combination treatment of recombinant alpha-interferon plus ribavirin has been proposed for chronic hepatitis C patients unresponsive to previous therapy with recombinant alpha-interferon alone. Aim. To determine the effectiveness of the combination therapy for the re-treatment of chronic hepatitis C patients unresponsive to previous interferon therapy Immediate and long-term follow-up data are reported. Patients and Methods. A series of 100 patients with chronic hepatitis C not responding to recombinant alpha-interferon 3 MU tiw, were randomly assigned to two groups of 50 patients each: Group A, treated with recombinant alpha-interferon therapy for an additional six months but at a double dosage (6 MU tiw] in association with ribavirin. Group 8, same treatment as group A but without ribavirin. All patients responsive to therapy were then followed-up for at least 12 months. At the end of the treatment and at the end of the follow-up period, we distinguished between complete responses [return to normal of alanine aminotransferase with undetectable serum HCV-RNA] and biochemical responses [return to normal of alanine aminotransferase still with detectable viraemia]. Results. Side-effects were observed only in patients treated with recombinant alpha-interferon plus ribavirin: 12% discontinued the therapy due to haemolytic anaemia. In group A, the percentages of end-of-treatment complete response, end-of-treatment biochemical response, sustained complete response, and sustained biochemical response, were 38%, 20%, 8%, and 14%, respectively, whilst in group 8, these percentages were 12%, 16%, 6%, and 16%, respectively Conclusion. The results indicate that in patients with chronic hepatitis C unresponsive to previous recombinant alpha-interferon therapy, re-treatment with higher recombinant alpha-interferon doses, either alone or in combination with ribavirin, lead to mild long-term benefit. However the satisfactory end of treatment complete response in group A suggests that a significant percentage of patients are sensitive to the combination therapy; and that a more aggressive the lrapeutic protocol in this selected subset of patients could r--’ ’ a larger number EWIL.‘& In of long-lasting responses __ leading, in turn, to a more favourable cost-effect ratio.
Key words:
chronic
hepatitis
C; interferon
plus
Ribavirin;
interferon
therapy;
non-responders
703
Therapy in non-responders
to r-IFN-w
Introduction Hepatitis C virus (HCV) has been identified as one of the major agents of acute hepatitis, which becomes chronic in more than 50% of cases. Between 20-30% of chronic hepatitis cases evolve towards cirrhosis and the related complications, including the development of hepatocarcinoma l-3. In an attempt to arrest the progression of this form of hepatitis, corticosteroids, immunosuppresants, and antiviral agents have been used without any apparent positive results 4-7. Only interferon (IFN) has resulted in a biochemical and virological response. With IFN treatment, serum aminotransferase levels may return to normal, hepatic histology improves and disappearance of serum HCV-RNA is achieved, even though more than 50% of the patients do not respond to the first course of treatment with IFN-a or relapse after a transient response 8-‘5. A persistent return to normal of transaminases and elimination of HCV-RNA with IFN-a therapy has been reported in only lo-20% of cases, and data emerging from personal experience, since 1989 16-18,is in keeping with most reports in the literature. In the attempt to reduce the number of non-responders to courses of IFN-a, treatment, research workers are attempting to understand how an increase in IFN-a dosage and duration of treatment or new antiviral drug associations could improve the results. Re-treatment with a double dose of IFN may be useful in non-responders or patients that relapse after a first course of treatment with IFN-a, even if this attempt has not led to a significant therapeutic advantage, especially in non-responders. Better results have been achieved in patients who relapse, who generally respond to a second course of IFN-a therapy if the first had been successful in exerting a response, even temporary, of HCV viraemia 19-26.This fact has resulted in the need to achieve longer lasting results with new therapeutic approaches for non-responders. Recently, the combination treatment of IFN-a plus ribavirin has been proposed for patients in whom transaminase levels failed to return to normal after therapy with IFN alone l9 27-31. The results of these studies are not clear since some support this combination while others are less enthusiastic. Moreover, it is hard to compare the results of these trials as they often include not only non-responders to IFN-a treatment but also patients that relapse. Furthermore, no long-term follow-ups were performed in these trials, even though this information is fundamental to understanding the efficiency of the therapeutic protocol in terms of sustained response. Finally, some trials adopted, in the combination therapy group, the usual dosage of IFN-a (3 MU tiw), and compared this combination to higher doses of IFN-a alone, thus making it difficult to evaluate the re-
al efficiency of ribavirin with respect to IFN-a alone unless the same doses of EN-a are used in both cases. Thus, to determine the actual efficiency of the combination therapy in patients unresponsive to previous IFN-a courses, we compared the re-treatment with IFN-a alone versus the association with ribavirin, using higher IFN-a doses in both groups and evaluating also the long-term behaviour of the disease.
Patients and Methods A series of 100 patients with chronic hepatitis C unresponsive to previous therapy with r-EN-a (a2b, 3 Million Units three times a week for 4 months) were included in our trial. The diagnosis of chronic hepatitis C was based, prior to the initial treatment, upon clinical, serological and histological data in all patients 3233.Results showed serum alanine aminotransferase (ALT) levels at least twice the upper normal value (40 U/l), measured 3 times during the 6 months preceding their enrolment. Serum HCV-RNA was assessed by the nested reverse transcription polymerase chain reaction (RT-PCR) using primers covering the conserved 5’-untranslated region of the viral genome 34, with a cut-off of lo3 gen/ml. HCV genotypes were determined by a reverse-hybridisation line probe assay 35. Liver biopsies were collected in all patients before starting treatment and were analysed by a single pathologist: the Knodell histological activity index was used to score the tissue samples 36. None of the enrolled patients had alcohol consumption ~40 g/day, drug-induced liver disease, presence of HBV, HDV or HIV infections, autoimmune factors (positivity of anti-nuclear, antismooth muscle and/or anti-mitochondrial antibodies), metabolic disorders (haemochromatosis, Wilson’s disease, alpha- 1-antitrypsin deficiency), pre-existing anaemia, or thyroid dysfunction. Other exclusion criteria were: concomitant liver diseases, histological diagnosis of liver cirrhosis, and recent antiviral treatments (less than six months before the study). After obtaining written consent, patients were randomly assigned to one of the two groups of fifty patients each: Group A treated with the same type of r-IFNa for an additional six months but at a doubled dosage (6 MU tiw) with respect to the first therapy, in association with ribavirin ( 1000 or 1200 mg/day given orally at two different doses to patients weighing, respectively, less than or more than 75 kg). Group B treated with the same therapy, dose and duration of r-IFNa as group A, but without ribavirin. Randomization was done using the Random Numbers Table. Main characteristics of the patients enrolled in each group are summarized in Table I. l
l
C. Brssci et al.
zdl.
Demographic and clinical data of hepatitis C patients en-
A Patients MaladFemalas Age (~1 Imaan f SD1 Duration d dieaee Lyrsl [mean f SD1 Basal AU tlJ/Il Imaan f SD1 HCV Genotype 1 Knodell histalogical activity index Mean fibrosis score
EK?;! 52Lk9 7t9 149&8 78% 10.3zk3.1 2.0*1
II
In group B, an ETCR was obtained in 6 (12%) patients, and an ETBR in 8 (16%). At the end of the follow-up, a SCR was observed in 3 natients (6%). and a SBR in A 8 (16%) (Table II).
&4 48&l 1 6i7 15Ok52
IWe II. Results of combined [Group Al and IFN [Group 8) trsatment in chronic hepatitis C patients unresponsive to a previous course of rlfN.
Et2.5 2:2&.8
Grolpr
A
ETCR ETBR SC8 SER
19 (38%) IO [2lJ%I 4 (8%) 7 [14%1
The same physician, using the same laboratory equipment, performed clinical and laboratory evaluations at monthly intervals. An end-of-treatment complete response (ETCR) was defined as return to normal of ALT with disappearance of serum HCV-RNA just after stopping therapy, while an end-of-treatment biochemical response (ETBR), as a return to normal of serum ALT levels with still detectable viraemia. All the patients with ETCR or ETBR were followed-up for at least 12 months, and monthly clinical and laboratory tests were also performed in this period. At the end of the follow-ups, a sustained complete response (SCR) was defined as the persistence of normal ALT and undetectable viraemia, while a sustained biochemical response (SBR) as persistence of normal ALT with still detectable serum HCV-RNA. A statistical analysis was made to evaluate the homogeneity of the groups with respect to age, sex, presumed duration of disease, genotype, histological activity and ALT levels. The X2-test, Wilcoxon tests for independent and related samples, and Fisher’s exact test were used when appropriate.
Results The two groups were homogeneous as far as concerns age, sex, and duration of the disease, genotype, histological diagnosis and ALT levels (Table I). Side-effects were observed only in the group of patients treated with r-IFN-a plus ribavirin. In fact, in this group, 12 (24%) patients developed haemolytic anaemia, though only 6 had to withdraw from treatment due to the entity of the anaemia - all these patients made a prompt recovery after withdrawal. The other 6 patients continued the therapy after a dose reduction of ribavirin. In group A, an ETCR was seen in 19 (38%) patients, and an ETBR in 10 (20%). At the end of the treatment free follow-up period, a SCR was observed in 4 (8%) patients, and a SBC in 7 (14%).
p
Statistical analysis of our data showed that the r-IFN-a plus ribavirin combination was significantly (p
Discussion Data from the literature demonstrate that the percentage of patients obtaining a short-term response to a second course of treatment with IFN-a differ considerably between non-responders and relapsing patients. Indeed, most studies upon re-treatment of non-responders to IFN-a monotherapy report percentages of an early return to normal of ALT levels varying from 516%, while in the case of relapsing patients, the use of IFN-a alone leads to short-term normalization in 70% of cases 23-31. Therefore, the results of re-treatment with IFN-a alone in non-responders to a first therapy of IFN-a are unsatisfactory I5. The limited efficiency of re-treatment with IFN-a in monotherapy in these patients has led to an investigation to seek an alternative approach, including the combined therapy with IFN-a plus ribavirin. Some preliminary trials I9527-31,37 have shown this combination to be of greater efficiency than IFN-a alone. Unfortunately, as previously mentioned, most of the trials adopted standard doses of r-IFN-a (3 MU tiw) in
105
Therapy in non-responders
to r-IFN-tx
the combination protocol then compared such a combination protocol with a re-treatment of higher doses of r-IFN-a alone. Hence, data from these studies do not demonstrate the actual effectiveness of ribavirin - also since different doses of IFN-a were adopted. On the contrary, in our study, we adopted the same IFN-a treatment (6 MU tiw for 6 months) in both groups. As the efficiency of antiviral treatment can only be evaluated several months after the end of the therapy, we completed follow-ups to responder patients for at least one year after termination of therapy. We preferred to enrol only non-responders to an initial therapy of r-IFN-a, excluding those who relapsed in order, to obtain a more homogeneous group in terms of expected response. Moreover, to make our data as reliable as possible, we excluded from our study, subjects with other concomitant liver diseases, which might have affected our results. Furthermore, we also excluded patients with a histological diagnosis of cirrhosis since, at present, it is widely accepted that IFN therapy, in these subjects, is poorly, or not effective, at all 38-4o. The homogeneity of the two groups with respect to age, sex, duration of the disease, genotype, histological diagnosis and ALT levels was checked to reduce any possible influence on the results. None of the treated patients showed any side-effects serious enough to require withdrawal from r-IFN-a therapy; probably, this is due to our inclusion criteria, as all enrolled patients had already completed a course of IFN-a. Ribavirin was also well tolerated, even if 12% of the patients developed significant haemolytic anaemia (with complete recovery after interruption) that induced withdrawal from treatment. Our data demonstrate that high-dose r-IFN-a plus ribavirin produces better results, in the short-term, than rIFN-a alone. This positive effect is transient and lasts only as long as the combined treatment is administered. In fact, at the end of the follow-up period, there was no statistically significant difference between the two treatment regimens. Our data disagree with those obtained in some other studies 3041but, confirm the results of recent trials 42-44which showed that there is no indication for IFN-a plus ribavirin in chronic hepatitis C resistant to a previous IFN treatment. Results in different groups were not influenced by viral genotype, even if, in the literature, genotype 1 represents a factor of reduced response compared to non1 genotypes. This finding could be due to the fact that in the patients enrolled the disease was unresponsive to a previous IFN-a therapy, independent of their genotype. On the basis of these findings, in our opinion, both the combination therapy and the re-treatment with solely IFN-a, even if with higher doses, are unable to lead to long-term benefits. However, the satisfactory early re706
sults in group A (more than one third of complete responses at the end of the combination therapy) should make us reflect upon possible modifications of this type of treatment in order to maintain similar results also in the long-term. It is reasonable to hypothesize that a larger cohort of patients could obtain a sustained response to the re-treatment through a modification of the ongoing schedule: for example, by prolonging the re-treatment therapy with the same drug scheme or with different doses or, finally, with the addition of other agents. Nevertheless, taking into account the costs and the possible side-effects of such drugs, we need to select those patients who would most benefit from more aggressive treatments. This cohort of patients could easily be identified by frequent biochemical and virological assays, and, therefore, our data could represent a stimulus for future trials aimed at modifying the ongoing therapy in accordance with the viraemic suppression, i.e., to tailor treatment to the single patient in order to obtain a more favourable cost-effect ratio.
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