SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Background

: Non-steroidal anti-inflammatory drugs may amplify the anti-viral effect of α-interferon in vitro but in vivo data are still controversial.

Aim

: To test the hypothesis that ketoprofen may increase the rate of response to α-interferon of chronic hepatitis C patients.

Methods

: Fifty patients with chronic hepatitis C who had never received α-interferon were randomly assigned to receive 3–8 MU of α2b-interferon, three times weekly for 6 months, alone or in association with ketoprofen at a dose of 200 mg/day five times weekly. The virological response to treatment (undetectable HCV RNA in serum) was evaluated after 3 months and at the end of treatment, and 6 and 12 months after therapy withdrawal.

Results

: One patient under combination therapy stopped the ketoprofen for persisting epigastric pain. Complete response under treatment was observed in 15 out of 24 (62.5%) patients receiving α2b-interferon alone and in 14 out of 26 (53.8%) patients under combination therapy (P=N.S.). One year after the end of treatment, a sustained response was seen in 4 out of 24 (16.2%) patients treated with α2b-interferon and in 5 out of 26 (19.2%) patients having received the combination (P=N.S.).

Conclusion

: Administration of ketoprofen does not increase either the primary or the sustained response to α2b-interferon therapy of interferon-naive chronic hepatitis C patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Several clinical trials have shown that α-interferon (α-IFN) therapy is effective in the treatment of chronic hepatitis C, but the sustained response is obtained only in 15–20% of treated patients.1 As a result, many compounds, such as ursodeoxycholic acid, macrophage colony stimulating factor, N-acetylcysteine, ribavirin, amantadine, glicyrrhizin, thymosin, ofloxacin and non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to increase the rate of response when combined with α-IFN.2[3][4][5][6][7][8][9]–10 The use of NSAIDs is supported by the demonstration that the release of prostaglandin E2 (PGE2), a metabolite of arachidonic acid through the cyclo-oxygenase pathway, is increased in cultured liver biopsies after stimulation with α-IFN. This results in an inhibition of both lymphokines production and of lymphocyte proliferation.11[12][13][14]–15 The addition of indomethacin either to cultured fibroblasts or to cultured liver biopsies prestimulated with α-IFN leads to a 3- to 5-fold increase of the 2′,5′-oligoadenylate synthetase activity.14 More recently, the modulation of α-IFN signalling by NSAIDs has also been confirmed in hepatoma cell lines, thus providing the rationale for the addition of NSAIDs to the α-IFN therapy of chronic hepatitis C patients.16 As of today, data concerning the in vivo efficacy of the NSAIDs/α-IFN combined treatment of patients with chronic hepatitis C and who have never received α-IFN is limited.17

This study was aimed at evaluating whether ketoprofen could increase the primary and sustained response to α-IFN of α-IFN-naive patients, as well as at assessing the tolerability of such combined treatment.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Patients population

Fifty consecutive patients with histologically proven chronic hepatitis C without cirrhosis, who had never received α-IFN, accepted to participate into the present study. There were 40 males and 10 females; their mean age was 33.9 years (range 22–57 years). Thirty-eight patients (76%) had a history of previous intravenous drug use, four (8%) had received blood transfusion(s), and the remaining eight (16%) had no apparent risk for blood-borne infections. All had anti-HCV antibodies, as evaluated by a second-generation EIA (Ortho Diagnostic Systems, Raritan, NJ) and confirmed by a third-generation assay (RIBA III, Chiron Corp., Emeryville, CA), and serum alanine aminotransferase (ALT) activity higher than 1.5 times the normal range for at least 1 year. All patients had a proven chronic hepatitis established by percutaneous liver biopsy performed within 12 months before enrolment. Histological evaluation was performed by a single pathologist in a blind fashion. Hepatitis grading and staging were scored according to the Knodell’s criteria.18 Patients who were HBsAg- or anti-HIV-positive by commercial ELISA’s (from Organon Teknika, Belgium and Abbott Laboratories, North Chicago, IL, respectively) and those with a history of current alcohol abuse or of gastroduodenal diseases were excluded from the study. HCV genotypes were analysed by nested PCR using genotype-specific primers within the core region19 and classified according to Simmonds et al.20 Viral load at baseline was measured by branched DNA (bDNA) assay (QuantiplexTM version 2, Chiron Corp., Emeryville, CA)21 while serum HCV RNA was monitored (at 3-month intervals while on treatment and 6 and 12 months after therapy withdrawal) by qualitative RT-PCR (AmplicorTM, Roche, Switzerland).

Study conduct

Patients were stratified according to the body weight (< 60 vs. > 60 kg) and genotype (1b vs. other than 1b) to receive recombinant α2b-IFN (Intron A, Schering-Plough, Italy) with a dose ranging from 3 MU to 8 MU three times weekly (Monday, Wednesday and Friday) for 6 months. The α-IFN dose was adjusted based on body weight and viral genotype, as proposed in previous work.22 The general outline of the study is shown in Figure 1. After stratification, patients were randomized to received either α2b-IFN alone (24 patients) or α2b-IFN plus ketoprofen (Ketoprofen R, IBI, Italy) 200 mg daily for five days per week (from Monday to Friday; 26 patients). Patients treated with ketoprofen also received a prophylaxis with ranitidine (Zantac, Glaxo, Italy) at a daily dose of 150 mg, per os. All patients gave written informed consent to the study. Patients were followed monthly during the 6 months of treatment and for 1 year after the end of therapy.

image

Figure 1. . Design of the study. Duration of treatment was 6 months.

Download figure to PowerPoint

Definition of response

A complete response was defined as the undetectability of serum HCV RNA (by the above qualitative RT-PCR). Patients with detectable HCV RNA in serum 3 months after starting the treatment were considered as non-responders and exited from the study. A sustained response was defined as the lack of detection of HCV RNA in serum 6 and 12 months after therapy withdrawal. A relapse was defined as the reappearance of serum HCV RNA following the achievement of a complete response and occurring at any time during and/or after treatment withdrawal.

Statistical analysis

Data were statistically analysed by using the two-tailed Student’s t-test. Chi-squared test or, when appropriate, the Fisher exact test were applied in order to compare the proportions between two groups. Significance was established in case of a P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Baseline features of patients assigned to receive α2b-IFN alone were comparable to those of patients who received the α2b-IFN/ketoprofen combination (Table 1). Overall, a complete virological response was achieved at the end of treatment in 29 patients (58%), i.e. in 15 out of 24 (62.5%) patients under α2b-IFN alone and in 14 out of 26 (53.8%) patients receiving the α2b-IFN/ketoprofen combination (P= N.S.) (Table 2). Treatment was stopped at the third month of treatment in 21 patients because of a lack of virological response. None of the initially responding patients lost response while on treatment. Among the 29 complete responders, 20 (68.9%) relapsed within 6 months after treatment withdrawal. The proportion of relapsers was comparable between the groups of patients receiving the two different schedules (Table 2). A sustained response was significantly associated with the HCV genotype (other than 1b), a lower baseline viremia and the female sex (Table 3). The α2b-IFN/ketoprofen combined therapy was well tolerated, as shown by the frequency of the adverse events reported in Table 4. Both groups completed the protocol of α2b-IFN therapy and only one patient stopped ketoprofen intake after 3 months of treatment when he started complaining of a persisting epigastric pain despite the ranitidine prophylaxis. Symptoms resolved promptly after ketoprofen withdrawal. This patient went ahead to show a complete response at the end of treatment, but relapsed thereafter.

Table 1.  . Main baseline features of patients enrolled in the study after randomization, according to the group of treatment Thumbnail image of
Table 2.  . Rate of response according to treatment schedule Thumbnail image of
Table 3.  . Baseline features of the patients considered in the present study and divided according to pattern of response Thumbnail image of
Table 4.  . Side-effects according to the treatment schedule Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Evidence exists showing that NSAIDs may amplify in vitro the anti-viral effect of α-IFN.11[12][13][14][15]–16 In contrast, in vivo findings are controversial. The majority of the data currently available come from small pilot studies where the effect of a combined therapy with α-IFN plus NSAIDs was evaluated in chronic hepatitis C patients who had not responded to a previous treatment with α-IFN alone. Although a synergistic effect with the α-IFN activity on serum ALT levels and of the rate of disappearance of HCV RNA from serum has been reported for ketoprofen,23, 24 other studies using ketoprofen,25, 26 sulindac27 or tenoxicam17 have provided negative results. However, the patient populations studied were heterogeneous, and sometimes not even fully characterized in terms of HCV genotype and liver histology. In a large, prospective, randomized, double-blind clinical trial,17 the biochemical and virological response rate was not statistically different between two groups of patients receiving α-IFN plus placebo or a combination of α-IFN and 20 mg/day of tenoxicam. Tenoxicam was selected because of its favourable pharmacological profile: it is fully bioavailable after oral intake, and its long half-life allows a single daily administration. In the same study, no significant increase of the 2′5′-oligoadenylate synthetase activity, as tested on peripheral blood mononuclear cells, was found to be associated with the tenoxicam administration. The activity of this enzyme has been reported to be stimulated by the α-IFN treatment, especially among patients responding to therapy.28, 29 However, the in vitro activity of tenoxicam on α-IFN cellular effects has never been tested, and its lack of synergistic effect with α-IFN may have been due to a weak inhibition of the ciclo-oxygenase/lipo-oxygenase activity.

Andreone et al.23 have presented some preliminary data suggesting an increased anti-viral efficacy of the α-IFN/ketoprofen association as compared to the combined administration of α-IFN and ribavirin or the α-IFN monotherapy in chronic hepatitis C patients non-responding to a previous treatment with α-IFN alone. These data are corroborated by some preliminary in vitro observations obtained by the same authors, suggesting that NSAIDs may increase the Th1-like cytokine production by peripheral blood mononuclear cells, an effect synergistic with that of α-IFN.30 We therefore tested the hypothesis that this combination may be effective in α-IFN-naive patients. However, the rate of virological response after 3 months of treatment was similar between the patients receiving the α-IFN alone and those treated with the α-IFN/ketoprofen combination. The lack of a significant adjuvant effect of ketoprofen was confirmed at the end of treatment as well as at the end of the 1-year follow-up. We have no clear explanation for the discrepancy between the in vitro and in vivo data. This may depend on the daily dose of NSAIDs. In the study by Andreone et al., 23 300 mg/day of ketoprofen were administered, while in our study patients received 200 mg/day of ketoprofen, and this for 5 days a week. Thus, we cannot exclude that the minimal dosage of ketoprofen to obtain an adjuvant effect may be higher than used in the present work. Furthermore, we did not assess the 2′,5′-oligoadenylate synthetase activity following the administration of ketoprofen, even though it has to be kept in mind that its stimulation may occasionally be insufficient to overcome resistance to the α-IFN.27 According to the data reported by Zarski et al.17 the most important predictive factor of sustained response was the low baseline viral titre. We were able to confirm this and identified HCV genotype and the sex as further factors influencing the response. These observations are in agreement with what is generally accepted.31

The administration of ketoprofen was in general well tolerated. One patient had to stop the drug after 3 months of therapy because of epigastric pain, and this despite the ranitidine prophylaxis. As far as the other side-effects generally observed while on treatment with α-IFN, flu-like symptoms and persistent fever were less likely with the combination regimen, although the difference was statistically not significant, possibly due to the small size of the study. Our data are in agreement with previous studies.17

In conclusion, the present clinical trial seems to exclude, at the dosage used, an adjuvant effect of ketoprofen on the response to α-IFN therapy of α-IFN-naive chronic hepatitis C patients. Future avenues of research may encompass dose-ranging studies, using higher doses of NSAIDs, possibly in the form of triple associations with α-IFN and ribavirin, as recent observations seem to suggest.32

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References
  • 1
    Poynard T, Bedossa P, Chevallier M, et al.A comparison of three interferon alpha-2b regimes for long term treatment of chronic non-A, non-B hepatitis. N Engl J Med 1995; 332: 1457 62.
  • 2
    Boucher E, Jouanolle H, André P, et al.Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: results from a controlled randomized trial in 80 patients. Hepatology 1995; 21: 322 7.
  • 3
    Van Thiel DH, Friedlander L, Kania RJ, Molloy PJ, Hassanein T, Faruki H. A preliminary experience with GM-CSF plus interferon in patients with HBV and HCV resistant to interferon therapy. J Viral Hepat 1997; 4: 101 6.
  • 4
    Beloqui O, Prieto J, Suarez M, et al.N-acetylcysteine enhances the response to interferon-alpha in chronic hepatitis C. A pilot study. J Interferon Res 1993; 13: 279 82.
  • 5
    Reichard O, Norkrans G, Frydé NA, et al.Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998; 351: 83 7.
  • 6
    Smith JP. Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 1997; 42: 1681 7.
  • 7
    Okano T, Ari K, Shindo M. Efficacy of interferon combined glycyrrhizin in patients with chronic hepatitis C resistant to interferon therapy. Nippon Rinsho 1994; 52: 1823 7.
  • 8
    Sherman KE, Sjogren M, Creager RL, et al.Combination therapy with thymosin and interferon for the treatment of chronic hepatitis C infection: a randomised, placebo-controlled double-blind trial. Hepatology 1998; 27: 1128 35.
  • 9
    Negro F, Male PJ, Perrin L, Giostra E, Hadengue A. Treatment of chronic hepatitis C with alpha-interferon plus ofloxacin in patients not responding to alpha-interferon alone. J Hepatol 1998; 29: 369 74.
  • 10
    Caldwell SH, Dickson RC, Driscoll C, Sue M, Yeaton P. A pilot study using piroxicam with interferon α 2b in the retreatment of refractory hepatitis C [abstract]. Gastroenterology 1995; 108: 1043A1043A.
  • 11
    Hannigan GE & Williams BRG. Signal transduction by interferon-alpha through arachidonic metabolism. Sci 1991; 251: 204 7.
  • 12
    Tsuboi I, Tanaka H, Nakao M, Shichijo S, Itoh K. Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-gamma and IL-2, in contrast to down regulation of IL-6 production. Cytokine 1995; 7: 372 9.
  • 13
    Baskin G. Interferon-signalling through arachidonic acid-dependent pathways: a clue to adjuvant therapy for chronic hepatitis? Hepatology 1991; 14: 392 4.
  • 14
    Andreone P, Cursaro C, Gasbarrini G. Interferon-alpha increases prostaglandin E2 production by cultured liver biopsy in patients with chronic viral hepatitis: can non-steroidal anti-inflammatory drugs improve the therapeutic response to interferon? J Hepatol 1993; 19: 228 31.
  • 15
    Andreone P, Cursaro C, Gramenzi A, et al.Indomethacin enhaces serum 2′5′-oligoadenylate synthetase in patients with hepatitis B and C virus chronic active hepatitis infection. J Hepatol 1994; 21: 984 8.
  • 16
    Giambartolomei S, Artini M, Almerighi C, Levrero M, Balsano C. Modulation of IFN-alpha signalling by NSAIDs: therapeutical implication in HCV patients [abstract]. J Hepatol 1998; 28(Suppl. 1): 103103.
  • 17
    Zarski JP, Maynard-Muet M, Chousterman S, et al.Tenoxicam, a non-steroid anti-inflammatory drug, is unable to increase the response rate in patients with chronic hepatitis C treated by alpha interferon. Hepatology 1998; 27: 862 7.
  • 18
    Knodell RG, Ishak K, Black W, et al.Formulation and application of a numerical scoring system for assessing histological activity in asymtomatic chronic active hepatitis. Hepatology 1981; 1: 431 5.
  • 19
    Imberti L, Cariani E, Bettinardi A, Zonaro A, Albertini A, Primi D. An immunoassay for specific amplified HCV sequences. J Virol Meth 1991; 34: 233 43.
  • 20
    Viasoz S, Zilbert A, Ramakrishnan K, et al.Typing of hepatitis C virus isolates by DNA enzyme immunoassay. J Virol Meth 1994; 48: 81 92.
  • 21
    Detmer J, Lagier R, Flyn R, et al.Accurate quantification of hepatitis C virus RNA (HCV-RNA) from all HCV genotypes by using branched DNA technology. J Clin Microbiol 1996; 34: 901 7.
  • 22
    Bellobuono A, Mondazzi L, Tempini S, et al.Should patients with early loss of serum HCV RNA during alpha interferon therapy for chronic hepatitis C be treated for 6 or 12 months? J Hepatol 1999; 30: 8 13.
  • 23
    Andreone P, Gramenzi A, Cursaro C, et al.A randomised controlled trial of IFN α + ketoprofen or IFN α + Ribavirin in HCV chronic active hepatitis (CAH) non responder to IFN α alone [abstract]. Hepatology 1995; 22: 119A119A.
  • 24
    Muñoz A, Levi D, Podestà A, et al.Evaluation of different doses of ketoprofen associated to interferon in the treatment of chronic hepatitis C. A prospective and randomized study [abstract]. Hepatology 1998; 28: 712A712A.
  • 25
    Anderson FH, Zeng L, Yoshida EM, Rock NR. Failure of ketoprofen and interferon combination therapy to improve interferon-resistant chronic hepatitis C. Can J Gastroenterol 1997; 11: 294 7.
  • 26
    Nunes FA, Santoro J, Kaufman B, et al.Interferon-alpha and ribavirin alone or in combination with ketoprofen for the treatment of patients with chronic hepatitis C who have not responded to previous interferon therapy [abstract]. Hepatology 1998; 28: 579A579A.
  • 27
    Di Costanzo GG, Ascione A, Lanza AG, Utech W, Capibianco G, Vacco C. Adjuvant therapy for interferon-resistant patients: do cycloxygenase inhibitors have any role? A pilot study. J Hepatol 1995; 23: 359 60.
  • 28
    Giannelli G, Antonelli G, Fera G, Dianzani F, Schiraldi O. 2′,5′-oligoadenylate synthetase activity as a responsive marker during interferon therapy for chronic hepatitis C. J Interferon Res 1993; 13: 57 60.
  • 29
    Pawlotsky JM, Hovanessian A, Roudot-Thoraval F, et al.Activity of the interferon-induced 2′,5′-oligoadenylate synthetase in patients with chronic hepatitis C. J Interfer Res 1995; 15: 857 62.
  • 30
    Andreone P, Cursaro C, Gramenzi A, et al.Modulation of Th1/Th2 cytokine profile and antiviral response by interferon a (IFNa) and non steroidal anti-inflammatory drugs (NSAIDs) in hepatitis C virus (HCV) [abstract]. Hepatology 1997; 26: 410A410A.
  • 31
    Davis GL & Lau JYN. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997; 26(Suppl. 1): 122S 7S.
  • 32
    Marchetto S, Fabbri C, Mazzeo C, et al.Cocktail therapy for chronic hepatitis C preliminary results [abstract]. Hepatology 1998; 28: 211A211A.