Interferon and ursodeoxycholic acid combined therapy in chronic viral C hepatitis: controlled randomized trial in 203 patients

LIVER,PANCREAS,AND BILIARYTRACT

IllfiEST LIVER OIS 2000;32:29-33

Interferon and ursodeoxycholic acid combined therapy in chronic viral C hepatitis: controlled randomized trial in 203 patients E. Boucher D. Guyader S. Jacquelinet P. Andre’ M.H. Mendler B. Turlin* V. Canva3 Clinique des Maladies du Foie et INSERM lJ49; I Laboratoire de Virologie; 2 Service dAnatomie Pathologique 6, H&pita1 Pontcheillou, Rennes; 3 Centre Hospitelier Universitaire [CHUI, Hopital Claude Huriez9 Lille; 4 CHU, Hopital de la Cavale Blanche, Brest; 5 CHU, Hopital Saint Andre, Bordeaux; 6 Centre Hospitalier La Bauchee, St. Brieuc; 7 Centre Hospitalier de Metz Thionville. Me& e CHU, Caen; g CHU, Hopital Laennec, Nantes; 1o Centre Hospitalier, Duimper: l1 Centre Hospitalier, Vitre; I2 Centre Hospitalier Chubert, Vannes; 73 Canoe Hospitelier d’Avranches, Avranches; l4 Centre Hospitalier, Hennebont, France Addmss for mwmsptmknce: Dr. E. Boucher Clinique des Maladies du Foie, Hopital Pontchaillou, 35033 Rennes cedex, France. Fax: +33-299-284 I 12. E-mail: boucher@sunaimed. univ-rennes I. fr Authors et-e indebted to Laboratoires Houde and Produits Roche for financial support; and to 0. Le Quilleuc and J.-Y. Robert for excellent technical assistance.

J. Boutin” R Bergerault?* F. Joram13 F? Colmar14 M. Messner F! Brissot Y. Deugnier

Aims. This prospective randomized trial was carried out in order to determine whether the long-term administration of ursodeoxycholic acid after discontinuation of interferon had any beneficial effect on the clinical course of hepatitis C virus infection. Methods. Enrolled in the study were 203 patients with chronic active hepatitis C. They were all given: interferon a-2a (3 MU subcutaneously thrice a week] and ursodeoxycholic acid [IO mg/kg/day] for 9 months. At month 9, biochemical responders only were randomized into ursodeoxycholic acid treatment or placebo for 12 additional months (double blind study]. Results. At the end of interferon therapy, 71 patients [37%] were virological responders and 107 [56%] patients were biochemical responders and were randomized: 54 into the ursodeoxycholic acid group and 53 into the placebo group. Sustained response was evaluated 12 months after withdrawal of interferon. Sustained biochemical and virological responses were, respectively 30% and 22% in the ursodeoxycholic acid group and 46% and 32% in the placebo group, which did not significantly differ Histological evolution of fibrosis and necrotic inflammatory activity were similar in the two groups. Conclusion. Continuation of ursodeoxycholic acid therapy after withdrawal of interferon in patients with end-of-treatment response did not result in any significant improvement either in the maintenance of response to interferon or in liver histology

Digest

Submitted September 30, 1999. Accepted October 29$ 1999.

J.-B. Nousbaum4 P.-H. Bernard5 0. NoueF J.-J. Raabe7 T. Dao8 P. Gasserg F? VergerlO

Liver

Key words: acid

Dis 2000;32:29-33 chronic

hepatitis;

follow-up

study;

hepatitis

C; interferon-alpha;

ursodeoxycholic

29

UOCH acid therapy in chronic hepatitis C

Introduction Efficiency of recombinant alpha interferon (IFN) alone in chronic hepatitis C is inadequate l 2, up to 80% of patients being either non-responders or relapsers. Currently, the most efficient combined therapy is interferon plus ribavirin which results in almost 60% of sustained response 3. However, not all patients can be treated by ribavirin on account of adverse events, leading to discontinuation in approximately 20% of cases 3. Thus, there is a need to evaluate therapeutic protocols combining IFN with other putatively active drugs. In a previous non randomized open study 4, we demonstrated that: i) the combination of IFN and ursodeoxycholic acid (UDCA) slightly improves the end-of-treatment response (ETR) and that ii) the continuation of UDCA for three months after IFN therapy delays the biochemical relapse. We undertook the present prospective controlled randomized trial in order to determine whether long-term administration of UDCA after the discontinuation of IFN had any beneficial effect on the maintenance of the biochemical response and histological course of hepatitis C virus (HCV) infection, and whether UDCA could, therefore, be advocated as an adjunct to antiviral therapy.

Patients and methods A total of 203 patients were enrolled in the study from March 1993 to August 1994. Inclusion criteria were as follows: 1) age between 18 and 70 years; 2) rise in alanine transferase (ALT) 2 1.5 the upper limit of normal (ULN) for six months or more before enrolment in the study; 3) presence of serum antibody to hepatitis C virus (anti-HCV) assessed by a second generation enzyme immunoassay (ELISA - Ortho Diagnostic Systems, Rajitan, NJ, USA); 4) HCV viraemia positive by reverse transcription-polymerase chain reaction (RT-PCR) 5) liver biopsy, performed during the six months before randomization, showing histological features of chronic active hepatitis; 6) absence of any other cause of chronic active hepatitis: no HBs antigen and no HBV DNA in serum by radioimmunoassay and dot-blot hybridization; serum autoantibodies (anti-nuclear, antismooth muscle, antimitochondrial) s l/l 00; no history of chronic alcoholism or intake of hepatotoxic drugs; serum alpha- 1-antitrypsin and ceruloplasmin within normal levels; 7) white blood cell count >1500/mm3, and platelet count >50,000/mm3; 8) no previous corticosteroid or immunosuppressive treatment. Exclusion criteria 1) history of decompensated chronic liver disease, 2) marked abnormalities in liver func30

tion tests (serum bilirubin >70 pmol/l and/or serum albumin ~30 g/l and/or prothrombin time c50%), and 3) serum positivity for anti-human immunodeficiency virus antibody. Treatment regimen (Fig. 1) All the patients included in the study received the following treatment for 9 months: aIFN-2a (RoferonTM, Produits Roche. Neuilly sur Seine, France), 3 million units subcutaneously thrice a week (tiw), and UDCA (DelursanTM, HoudC Laboratories, Paris, La Defense, France), 10 mg/kg/day. Randomization Those who experienced a biochemical response at month 9 were randomized and assigned either to continue UDCA at the same dosage for 12 additional months or to receive a placebo. Randomization was made using a blocking method with a table of random permutations (blocks of six). Follow-up and laboratory testing Patients were followed-up for a 21-month period. Side effects were monitored every month. Serum ALT, bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT) and haematologic tests were measured at entry and every month throughout the following 21 months. HCV viraemia was screened in serum samples at entry and at months 9 and 21, detected by RT-PCR as previously reported 5. HCV-RNA was quantified in pre-treatment serum specimens only with a quantitative PCR method (MonitorTM, Roche diagnostic systems). Two liver biopsies were collected: at entry and at month 21. Histological activity and fibrosis were graded according to Knodell et al. 6 and to the METAVIR score ‘. Response to therapy Biochemical and virological responses were classified according to serum ALT level and HCV viraemia, respectively. ETR and sustained response (SR) were defined as normal ALT level (biochemical response) and negative serum HCV RNA (virological response) at month 9. The corresponding sustained responses were evaluated at the end of UDCA or placebo therapy 12 months after IFN-UDCA withdrawal. Liver biopsies obtained before and 12 months

after treatment were analysed by a single pathologist. Histological improvement was defined as a decrease in the inflammation and/or fibrosis score of at least one point (METAVIR score 7, as compared to the pre-treatment biopsy. Statistical analysis The estimated sample size of patients was based on a first type error of a=O.O5, a second error type p=O. 10, with an assumption of treatment benefit given by 40% of biochemical SR in the UDCA group and 16% in the placebo group. Data were compared using Wilcoxon’s test or ANOVA for paired data with Bonferroni correction, Mann-Whitney test and X2. All p values were two-sided. p values so.05 were considered as statistically significant. The relationship between pre-treatment patient variables and response to treatment was examined by logistic regression analysis. The study protocol was approved by the Local Ethics Committee. Fully informed written consent was obtained from all patients.

We 1. Chmcteristics, et enmtment of W 107 petiencs mtyeed. No stetisticet differences were found bx&wm the bm gfcups.

(years f SD*1

k~iu&tkr~[meSn*6DsDf 2.5 f 1.7

ALT Ix tJlN**l AST o( ULNl Atkatinephmpkame Ix ULNI GGTlx ULNI

1.6+ 1.8 0.7 f 0.2 1.3* 1.4

2.3 f 1.4 1.3kl.2 0.7 f 0.2 1.1 f 1

Results

Study population Of the 203 patients included, 10 were excluded from statistical analysis because of protocol deviation. Thus, 193 patients were eligible for the analysis. In these, virological ETR was 71/193 (37%) and 107 patients (56%) exhibited a biochemical ETR and were then randomized at month 9: 54 into the UDCA group and 53 into the placebo group. The general characteristics of these 107 patients are summarized in Table I. During the UDCA or placebo treatment period, 11 patients were lost for follow-up, and 16 patients stopped the treatment either for personal convenience (n=8) or because of an adverse event (n=8): hypothyroidism (n=3), neutropenia and thrombopenia (n=2), psychological disturbance (n=2) or gastrointestinal intolerance (n=l). Finally, at month 21, 86 of the 107 randomized patients were assessable: 41 out of 54 in the UDCA group and 45 out of 53 in the placebo group. Comparison of the two groups Biochemical and virological assessment Biochemical and virological SR rates did not significantly differ between the UDCA and placebo groups: 16/54 patients (30%) in the UDCA group and 25/53 patients (47%) in the placebo group had a biochemical SR; 12/54 (22%) in the UDCA group and 16/53 (32%) in the placebo group had a virological SR. Monthly relapse rates did not differ between the two groups (Fig. 2). Histological assessment Of the 86 patients evaluable at month 21, 67 had a liver biopsy both at entry and after treatment completion. As shown in Table II, evolution both of fibrosis and activity as assessed by the

31

UOCH acid therapy in chronic hepatitis C

Ta4le II. Evolution of histological activity and fibrosis according to METAVIR scare in UDCA and placebo groups. Demonstration of absence of histological benefit of prolonged treatment with UDCA after interferon withdrawal.

USCA Worsening’

(n=l

Steady Improvement* state* [n=I In=1

* Worsening, steady state, ence was positive, evolution

Flhwsis

Aetisiry lwem4e

UDCA

PIecehI

1:

2:

5

4

6 32

9 35

ii 32

:; 35

impmvement were defined according to difference between hist&gical activity or fibrosis before and after treatment. was considered es “impmvement”: if nsgative, as “worsening”; if null as “steady state”, UDCA ursodaoxychokc acid.

METAVIR score did not differ between the two groups. Similarly, the post-treatment Knodell score was not significantly different between the two groups (UDCA: 6.6k3.1 vs placebo: 5.623.5). Correlation of baseline characteristics with response Logistic regression showed that a baseline viral load under lo6 copies/ml was the only factor related to a sustained virological response (p
Discussion In a previous open study on 80 patients with chronic hepatitis C 4, we showed that UDCA therapy delayed the time of biochemical relapse after IFN therapy when continued for a 3-month period after a six-month course of IFN. It was, therefore, necessary to determine whether prolonged UDCA administration could maintain the biochemical response and improve liver histology on long-term follow-up. Testing a 12-month course of UDCA therapy versus placebo after a course of IFN therapy alone would have been more accurate to assess the efficiency of UDCA as maintenance therapy. However, in our previous study4, we have noticed that treatment with the combination of IFN and UDCA slightly improved the ETR without any significant difference. Also, several studies had shown that combined therapy with UDCA plus IFN resulted in an increase of the biochemical response rate to IFN 4 8-‘2. We, therefore, considered that it would be more ethical to add UDCA to the initial treatment with IFN. Unfortunately, the present study failed to demonstrate any beneficial effect of the continuation of UDCA therapy for a 12-month period. Indeed, neither the biochemical and virological response durations nor liver histology showed any improvement in patients treated with UDCA as compared with patients given placebo. The fact that these findings are not in keeping with our previous results could be explained in several ways: i) a large number of patients dropped out of the present

/f differ-

study for personal reasons (n=27), ii) contrary to the previous non-controlled study, the present trial was randomized and multicentric and, iii) patients were treated with IFN 3 MU tiw instead of 5 MU tiw as in the previous study. On the basis of the present data, it can be concluded that continuation of UDCA therapy after a course of IFN does not result in any significant improvement, either in the maintenance of the response to IFN, or in liver histology. On the whole, the role of UDCA administration in the management of hepatitis C seems to be limited, especially when taking into account the potential interest of the combination of IFN plus ribavirin therapy 1 13. However, UDCA therapy alone could be proposed in those patients not eligible for IFN or ribavirin therapy, since its efficacy in reducing ALT levels has been proven I2 14-16.

References ’ Shiratori Y, Kato N, Yokosuka 0, Imazeki F, Hashimoto E, Hayashi N, et al. Predictors of the efficacy of interferon therapy in chronic hepatitis C virus infection. Gastroenterology 1997;113:558-66. 2 Sarraco G, Borghesia E, Prolonged treatment (2 MU) of interferon a-2b multicenter randomized

Mesina P, Solinas A, Spezia C, Macor F. years) with different doses (3 versus 6 for chronic hepatitis type C. Results of a trial. J Hepatol 1997;27:56-62.

3 Poynard T, Marcellin P, Lee S, Niederau C, Minuck et al. An international randomized trial of interferon ribavirin 48 or 24 weeks versus interferon alpha-2B for first line treatment of chronic hepatitis 1998352: 1426-32.

G, Ideo G, alfa-2B and 48 weeks, C. Lancet

J Boucher E, Jouanolle H, Andre P, Ruffault A, Guyader D, Turlin B, et al. Treatment of chronic viral C hepatitis by interferon plus ursodeoxycholic acid: results from a controlled randomized trial in 80 patients. Hepatology 1995;21:322-7. 5 Andre P, Clossais-Besnard N. Automated quantitative determination of hepatitis C viremia using reverse transcription-polymerase chain reaction. J Clin Microbial 1994;32: 1887-93. 6 Knodell R, Ishak K, Black WC. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 198 1; 1:43 l-5.

’ Bedossa P, Poynard T for the METAVIR Cooperative Study Group. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996;24:289-93. ’ Clerici C, Distrutti E, Gentilini G, Solinas A, Miglieti M, Balo S, et al. Interferon plus ursodeoxycholic acid versus interferon in the treatment of chronic C viral hepatitis. Minerva Med 1997;88:219-25. 9 Tanaka K, Kondo M, Sakaguchi T, Saito S, Arata S, Ikeda M, et al. Efficacy of ursodeoxycholic acid in combination with interferon alpha in treating chronic hepatitis C: result of a long term follow-up trial. J Gastroenterol Hepatol 1996; 11: 115.560. lo Angelic0 M, Gandin C, Pescarmona E, Ripicetta M, Del Vecchio C, Bini A, et al. Recombinant interferon-alpha and ursodeoxycholic acid versus interferon alpha alone in the treament of chronic hepatitis C: a randomized clinical trial with long term followup. Am J Gastroenterol 1995;90:263-9. ” Takiwara H, Yamanaka M, Miyake K, Kako M, Ohki H, Narita T,

et al. Ursodeoxycholic acid therapy for chronic type C hepatitis a multicenter, dose finding trial. Curr Ther Res 1994;55: 16-2 1. ‘* Crosignani A, Battezzati PM, Setchell KDR, Camisatca M, Bertolini E, Roda A, et al. Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: A dose-response study. Hepatology 1991;13:339-44. ” Reichard 0, Schvarcz, Weiland 0. Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology 1997;26(Suppl):lO8S-11. I4 Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosignani A, Petroni M, et al.. Effect of different doses of ursodeoxycholic acid in chronic liver disease. Dig Dis Sci 1989;34:S59-6.5. I5 Bellentani S, Podda M, Tiribelli C, Callea F, Marazzi M, Sodde M, et al. Ursodiol in the long-term treatment of chronic hepatitis: a double-blind multicenter clinical trial. J Hepatol 1993;19:459-64. I6 Deugnier Y, Boucher E. Iron and hepatitis viruses. Ital J Gastroenterol Hepatol 1998;30:467-9.

33