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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Background:  Hepatitis C virus infection is more common in patients with inflammatory bowel disease than in general population. Limited data are available as to the safety and efficacy of α-interferon therapy for chronic active hepatitis C in patients with concomitant inflammatory bowel disease.

Aim:  To evaluate the efficacy and safety of α-interferon monotherapy in patients with chronic active hepatitis C and inactive or mildly active inflammatory bowel disease.

Methods:  A total of 513 consecutive inflammatory bowel disease patients at a single centre were tested for antibodies to hepatitis C virus (anti-hepatitis C virus) between 1995 and 2000. Twenty-one patients had detectable anti-hepatitis C virus Ab and were hepatitis C virus-RNA positive with histologically proved chronic active hepatitis. Each of these patients, whose inflammatory bowel disease was in clinical remission or mildly active, was sex- and age-matched to three controls with similar histological grade and stage of chronic hepatitis C virus but without inflammatory bowel disease; and all were treated with human leucocyte α-interferon 6 million units given thrice weekly for 12 months. Responses to treatment were classified as follows: complete response – persistently normal alanine aminotransferase and viral clearance (hepatitis C virus-RNA–ve) at the end-of-treatment, incomplete response – alanine aminotransferase normalization without viral clearance (hepatitis C virus-RNA+ve), and sustained response – alanine aminotransferase normalization and hepatitis C virus clearance 12 months after the end-of-treatment.

Results:  Twenty-one patients with chronic active hepatitis C and inflammatory bowel disease (10 with Crohn's disease and 11 with ulcerative colitis) and 63 sex- and age-matched controls with chronic hepatitis C virus alone received α-interferon monotherapy. Response rates to interferon were similar for inflammatory bowel disease patients compared with controls [CR 42% vs. 35% and SR 24% vs. 18% (P, not significant), respectively]. None of the 21 inflammatory bowel disease patients had severe adverse effects and the mild ones observed were comparable with those seen in the control group. No patients developed an inflammatory bowel disease relapse during the interferon treatment period or in the 12 months thereafter.

Conclusions:  The biochemical and virological response to a 12-month human leucocyte α-interferon treatment in patients with chronic active hepatitis C are similar to that observed in matched controls with chronic hepatitis C virus without inflammatory bowel disease. Adverse effects are similar in both groups of patients and unrelated to the underlying inflammatory bowel condition. This provides hepatologists with evidence that α-interferon can be safely administered to patients with chronic hepatitis C virus and inflammatory bowel disease provided that the inflammatory bowel condition is in clinical remission.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

In Europe, the prevalence of antibodies to the hepatitis C virus (anti-HCV) is higher in patients with inflammatory bowel disease (IBD) than in the blood donor population (5.9% vs. 1.1%).1–3 This may be explained by the increased requirement for surgery and blood transfusion in patients with IBD.

Interferon (IFN)-based anti-viral therapy was considered potentially hazardous in these patients because of the hypothetical risk of IBD relapse during therapy.4 In recent years, however, it has been shown that patients with IBD have dysregulation of IFN-alpha (IFN-α) production with increased immune activation.5 As a result, IFN-α has been proposed as an option for the treatment of steroid-resistant IBD patients. A preliminary controlled clinical trial has shown that IFN-α has no therapeutic effect in patients with steroid-resistant ulcerative colitis (UC).6 By contrast, few data exist concerning the safety and efficacy of IFN-α-based anti-viral therapy as treatment of chronic HCV in patients with a coexistent IBD.7

We therefore undertook a single centre prospective controlled study with two main aims: (i) to evaluate the safety and efficacy of IFN-α monotherapy in patients with chronic HCV and concomitant IBD when compared with a control group of patients with chronic HCV alone; and (ii) to determine whether IFN-α therapy influences the severity of the underlying IBD.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Setting

The L.Sacco University Hospital is a 573-bed tertiary care academic hospital located in western Milan. It is a national referral Centre for Inflammatory Bowel Disease, with the largest out-patient IBD clinic in the country. All patients undergo regular follow-up in the out-patient clinic including 6-monthly liver function tests (LFTs) and annual abdominal ultrasonography, which is routinely performed to assess the behaviour of IBD as well as the appearance of extraintestinal complications [such as gallstones in Crohn's disease (CD) patients].

Patients

From January 1995 to July 2000, 513 consecutive IBD patients, 301 with CD (M/F: 136/165, mean age 38 years, range 11–86) and 212 with UC (M/F: 128/84, mean age 39 years, range 10–75), were screened for anti-HCV using a third-generation enzyme-linked immunosorbent assay (ELISA-3).8 Reactive samples underwent confirmatory testing by recombinant immunoblot assay (RIBA-3).9 HCV-RNA was tested in serum by nested-polymerase chain reaction after reverse transcription (RT-PCR) and quantified by branched-DNA signal-amplification assay.10 HCV genotype was assessed in all HCV-RNA positive patients by analysis of PCR products, carried out with sequence-specific DNA probes.11 Other causes of liver disease were sought and excluded.

A liver biopsy was proposed to all patients with anti-HCV and alanine aminotransferase (ALT) elevations for at least 6-month duration. All liver biopsies were scored by two pathologists using the Knodell histologic activity index.12

Interferon-α treatment and patient monitoring

All IBD patients with anti-HCV Ab who were HCV-RNA positive (at quantitative determination of viraemia) and with elevated transaminases for over 6 months and at least mild chronic hepatitis (Knodell score of ≥4) were offered anti-viral therapy with human leucocyte IFN-α (Alfaferone; Alfa Wassermann, Milan, Italy). Treatment consisted of 6 million units given thrice weekly for 12 months by intramuscular route. This regimen, which is now superseded by IFN and ribavirin, was the treatment of choice when the study started. Exclusion criteria were: age <18 years or >70 years, pregnancy, serological or biochemical evidence of other causes of liver disease, current alcohol abuse, Child–Pugh class B or C cirrhosis, known autoimmune disease, severe IBD activity index (CDAI > 450 or DAI > 9, according to Sutherland 13). The IBD patients treated were sex- and age-matched to a control group of non-IBD patients (one case to three controls) treated with the same anti-viral schedule for chronic HCV.

All patients underwent monthly review during therapy, with full clinical evaluation (including an adverse effects assessment) and laboratory assessment of transaminases and full blood count. HCV-RNA quantification, autoantibodies, CDAI or DAI indexes were determined at 3, 6, 9 and 12 months during IFN therapy. Treatment was discontinued in the following cases: any side-effect not tolerated by the patient, increasing of CDAI or DAI over the normal range, positivity for antithyroid antibodies, positivity for antinuclear antibodies (ANA) with concomitant transaminase elevations, significant bone marrow suppression. At the end-of-treatment, the clinical assessment included assessment of IBD, LFTs and qualitative and quantitative HCV-RNA. LFTs were performed every 3 months for the following year.

Responses to treatment were classified in accordance with the Italian Association of the Study of the Liver (A.I.S.F.) guidelines.14 The criteria of response at the end-of-treatment were defined as: complete response (CR) if ALT normalization with virological clearance (HCV-RNA-ve finding) was obtained, or by the incomplete response (IR) in case of ALT normalization with detectable HCV-RNA in serum. Non-response (NR) was defined as absence of biochemical and virological response 4 months after starting therapy in which case treatment was discontinued; a sustained response (SR) was defined as ALT normalization and HCV-RNA persistently negative 12 months after the end-of-treatment. Relapse time in patients with primary response was defined as the time (in months) from the end of therapy and the first demonstration of ALT rising.

The study was approved by the L.Sacco Hospital Ethics Committee and written informed consent was obtained from all patients before entering the study.

Statistical analysis

Mean and standard deviations were used to describe the distribution of continuous variables. Statistical methods used to analyse the data included Chi-squared test, Fischer's exact test and Student's t-test with type I error of 0.05, two-tailed as appropriate.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Forty-two (8.1%) of the 513 patients with IBD had detectable anti-HCV [19 (6.2%) in 302 CD patients and 23 (10.9%) in 211 UC patients]. Twenty-four cases (57%) had no confirmed route of transmission identified (but 11 of them had a history of bowel surgery). The commonest identifiable risk factors for HCV infection was blood transfusion (12 patients, 28.5%) and probable intrafamily transmission in six cases (14.2%).

Twenty-one patients (10 with CD and 11 with UC) and 63 controls with chronic HCV alone received IFN-α treatment. The pre-treatment characteristics of these patients are summarized in Tables 1 and 2. The remaining 21 IBD patients not receiving IFN-α therapy were not offered anti-viral treatment for the following reasons: 10 patients were HCV-RNA negative, seven were HCV-RNA positive but had normal transaminases, two patients (who were HCV-RNA positive and had elevated transaminases) had severe UC flare (DAI > 9) and, finally, two HCV-RNA positive patients were not enrolled as they aged >70 years. No significant differences in the demographic characteristics as well as the histological features, and duration of IBD, between IFN-treated and -untreated IBD patients were documented (see Table 3).

Table 1.  Characteristics of 21 patients with IBD/chronic HCV and 63 HCV-infected controls prior to interferon therapy
 IBD patients (n = 21)Controls (n = 63)
  1. CAH, chronic active hepatitis, Knodell histologic activity index; IBD, inflammatory bowel disease; HCV, hepatitis C virus; ALT, alanine aminotransferase.

Sex (M/F)13/839/24
Mean age (range) (years)52.5 (39–68)49.9 (30–69)
ALT (U/I; normal value <50), mean ± SD100.4 ± 28.8115.6 ± 73.6
HCV viral load (UI/mL), mean425.762517.800
Histological grade 
 Mild CAH824
 Moderate412
 Severe721
 Cirrhosis26
Genotype 
 11545
 2618
Table 2.  Individual characteristics of the 21 IBD with chronic HCV treated with α-interferon
Patient no.SexAge (years)IBD typeRisk factorIBD therapyHCV typeCAH grading*Length therapy (months)ResponseFollow-up, relapse time (months)
  1. IBD, inflammatory bowel disease patients; HCV, hepatitis C virus; CAH, chronic active hepatitis; ICD, ileal Crohn's disease; CCD, colonic Crohn's disease; LUC, left-sided ulcerative colitis; PUC, pancolonic ulcerative colitis; UN, unknown; TR, blood transfusion in pre-HCV Ab era; None, no treatment; MES, mesalazine; BUD, budesonide; NR, non-response; IR, incomplete response; CR, complete response; SR, sustained response; drop-out, interrupted therapy for side-effects.

  2. * Knodell score: mild, 4–8; moderate, 9–12; severe, 13–18.

  3. † Previous history of intestinal surgery.

  4. ‡ Drop-out for bad tolerated fever and irritability.

  5. § Drop-out for alopecia.

 1F43ICDUN†BUD1Cirrhosis4NR
 2F44ICDUN†MES1Cirrhosis4NR
 3M40ICDTRMES2Moderate12CRSR
 4F63CCDTRBUD1Severe12IR3
 5F65CCDTRMES1Severe12IR6
 6M51ICDTRMES2Moderate2Drop-out‡
 7F68CCDTRMES1Severe12CR6
 8M39ICDTRMES2Moderate12CR12
 9F68CCDTRMES1Severe12CRSR
10M40ICDTRBUD2Mild12IR12
11F44PUCUN†MES1Severe5Drop-out§
12M48PUCTRMES1Mild12CR6
13M40PUCTRMES2Mild12CRSR
14M48PUCTRMES1Mild12CR9
15M52LUCTRMES1Mild12IR3
16M63PUCTRMES1Severe12IR3
17M53PUCTRMES1Mild4NR
18M65PUCTRMES1Severe4NR
19M68PUCTRNone1Moderate4NR
20M39LUCTRNone1Mild12CRSR
21F49PUCTRMES2Mild12CRSR
Table 3.  Characteristics of the 21 patients with IBD/chronic HCV receiving IFN therapy as compared to the 21 IBD/HCV-infected patients not enrolled in the study
 IBD patients receiving IFN (n = 21)Untreated IBD patients (n = 21)
  1. CAH, chronic active hepatitis, Knodell histologic activity index; IBD, inflammatory bowel disease; HCV, hepatitis C virus; IFN, interferon.

Sex (M/F)13/814/7
Mean age (range) (years)52.5 (39–68)54.1 (38–74)
Type of IBD
 Crohn's disease109
 Ulcerative colitis1112
 Mean duration of IBD (range)(years)14.3 (1–23)15.2 (2–32)
Histological grade
 Mild CAH85
 Moderate41
 Severe7
 Cirrhosis2

Treatment responses observed in the IBD patients with HCV are summarized in Table 2. Briefly, 14 patients (67%), seven from each IBD group, completed the 12-month therapeutic schedule. Five patients (24%; three in CD, two in UC group) had an IR, while a CR was observed in nine (42%; four in CD, five in UC group). Seven patients did not complete 12 months of treatment; five (24%) were non-responders and two (10%) patients discontinued therapy prematurely; one patient in the CD group discontinued treatment after 2 months because of the episodes of fever and irritability without evidence of sepsis with rapid recovery after discontinuation of IFN-α.

Of the nine patients with a CR after IFN-α treatment five patients (24%; two in CD, three in UC group) had a SR and four patients had a relapse with ALT rising and a HCV-RNA reappearance, after a median time of 7 months. All five of the patients with an IR had a relapse with rising ALT (median time relapse of 3 months) after completing treatment.

The response rates in our IBD patients were compared with those observed in the 63 treated HCV positive controls and there was no significant difference between the groups (Table 4).

Table 4.  Responses to α-interferon therapy in inflammatory bowel disease (IBD) patients and controls
 IBD patients (n = 21)Controls (n = 63)P (χ2)
  1. Percentage values are given in parenthesis.

Absence of response5 (24)16 (25)0.86
Drop-out2 (10)6 (10)0.66
End-of-treatment response
 Biochemical (incomplete response)5 (24)19 (30)0.88
 Virological (complete response)9 (42)22 (35)0.84
Sustained response5 (24)11 (18)0.83

The adverse events experienced are summarized in Table 5. Overall, two patients discontinued therapy prematurely because of toxicity (one case of irritability with fever and one case of alopecia); otherwise toxicity was common but self-limiting. No patients developed autoantibodies or clinical autoimmune diseases. There was no significant difference in terms of frequency and severity of side-effects between the two populations.

Table 5.  Side-effects of α-interferon in inflammatory bowel disease patients and in controls
 CD patients (n = 10)UC patients (n = 11)Total IBD patients (n = 21)Controls (n = 63)P (χ2)
  1. IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis.

  2. Percentage values are given in parenthesis.

Myalgia (mild)549 (43)31 (50)0.93
Fever (≤38.5 °C)8614 (67)22 (35)0.18
Fatigue (mild)2810 (48)34 (55)0.94
Irritability437 (33)12 (19)0.44
Alopecia213 (14)16 (25)0.57
Arthralgia33 (14)18 (28)0.45
Depressed mood22 (10)14 (23)0.44
Insomnia22 (10)15 (24)0.38
Anaemia22 (10)7 (12)0.82
Headache11 (5)21 (33)0.07
Diarrhoea11 (5)9 (14)0.50
Any of aforesaid symptoms  14 (67)38 (61)0.96

The surveillance of the bowel disease status in this study demonstrated that the CDAI score in CD patients and the DAI score in UC patients remained in the normal range prior to, throughout and for the 12 months following treatment in all the 21 IFN treated cases (Figures 1 and 2).

image

Figure 1. Crohn's disease activity index (CDAI) score during interferon (IFN) therapy and follow-up in 10 Crohn's disease patients (mean, range). Δ: mean (and range) CDAI score value at baseline and at 3, 6 and 9 months during IFN therapy; •: mean (and range) CDAI score value at the end of IFN therapy and 12 months thereafter.

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image

Figure 2. Disease activity index (DAI) score during interferon (IFN) therapy and follow-up in 11 ulcerative colitis patients (mean, range). Δ: mean (and range) DAI score value at baseline and at 3, 6 and 9 months during IFN therapy; •: mean (and range) DAI score value at the end of IFN therapy and 12 month thereafter.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

The prevalence of anti-HCV is higher in patients with IBD than in the blood donors (5.9% vs. 1.1%) in Europe.1–3 This is probably attributable to the higher risk of hospital transmission for these patients when compared with the general population. In addition, blood transfusion at the time of surgery represents a major risk factor for chronic HCV infection in Italy.15

Concomitant chronic HCV infection and IBD may cause several problems in affected patients, especially from the therapeutic point of view, because IFN-α, which is the most common treatment for HCV infection, is a proinflammatory cytokine and can theoretically induce IBD relapse.16 On the contrary, IFN-α has recently been evaluated as a treatment for active IBD, especially UC, based on the theoretical assumption that this compound also possesses some anti-inflammatory properties by regulating and downmodulating Th-2 cytokines, which have been shown to be upregulated in UC.17 The results of this study suggest that IFN-α is safe in the setting of active IBD although devoid of any therapeutic effectiveness on the inflammatory bowel condition.

To date, a few anecdotal reports exist on the IFN treatment of chronic active hepatitis (CAH) C in patients with a coexistent IBD;7, 16 only one retrospective multicentre study has been reported in one English literature so far, by Cottone et al.,7 who reported on the outcome of 12 IBD patients with concomitant HCV infection treated with IFN. They observed no apparent risk of IBD flare during anti-viral therapy but they did not assess IBD behaviour during the 12 months after IFN suspension. 7 We therefore undertook a single-centre case–control study in order to define prospectively the effectiveness and safety of IFN-α in patients with active chronic hepatitis C and inactive UC or CD.

Anti-HCV screening in this large cohort of IBD patients revealed a prevalence of HCV infection of 5.2% in CD and 11.6% in UC, which is consistent with the existing prevalence data which report a prevalence of 0.6–10%.1–3

In this study, we compared the virological and biochemical response rates to IFN-α in a cohort of patients with chronic HCV and IBD and in a well-matched control group of HCV patients without IBD and observed similar efficacy between the two groups. Primary response and SR rates to high-dose IFN-α monotherapy are in line with those reported in the medical literature for treatment naïve patients with chronic HCV, which range from 33 to 76% for primary response, and a SR rate of 0–40%.18–21 In addition, no statistically significant difference was noted in the frequency or severity of side-effects between the two groups.

The most important aspect of this study concerns the potential deleterious effects of anti-viral therapy on the activity of the coexisting inflammatory bowel condition. Immediately prior to therapy, all IBD patients had inactive or mild active disease (two patients with CDAI between 150 and 185) while receiving prophylactic treatment with oral mesalazine/budesonide or none. No patient experienced an IBD relapse during anti-viral therapy or the ensuing 12 months of follow-up. In particular, no IBD patients stopped IFN because of diarrhoea or rectal bleeding/haematochezia; but in both groups, the majority of complaints were constituted by the well-known side-effects of IFN. In addition, the proportion of patients who stopped treatment in both groups was quite similar to that observed in similar studies of this type.19 No major complication associated with anaemia or other adverse event occurred. Perhaps, one might speculate that patients with stable IBD were treated while those with more recent relapse (but not active disease) were excluded in view of concerns about IBD relapse during IFN therapy. This was not the case because no significant difference with respect to the duration of intestinal disease, the number of previous relapses as well as the type and duration of medical therapy between IBD patients with concomitant chronic HCV and those without HCV infection had been found in the same cohort of patients.3

In summary, high-dose IFN-α monotherapy is an effective treatment for chronic HCV in patients with concomitant IBD. The spectrum and frequency of IFN-α toxicity is similar in HCV-infected patients with and without IBD. Provided that concomitant IBD is in clinical remission at the time of commencing therapy, hepatologists should be reassured that commencing IFN therapy would not precipitate an exacerbation of the IBD.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  • 1
    Biancone L, Pavia M, Del Vecchio Blanco G, et al. Hepatitis B and C virus infection in Crohn's disease. Inflamm Bowel Dis 2001; 7: 28794.
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    Stevceva L. Cytokines and their antagonists as therapeutic agents. Curr Med Chem 2002; 9: 22017.
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    Alberti A, Chemello L, Bonetti P, et al. Treatment with interferon(s) of community-acquired chronic hepatitis and cirrhosis type C. J Hepatol 1993; 17: S1226.
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    Tanno H, Fernandez JL, Rendo P, et al. Hepatitis C virus RNA and long-term response to recombinant interferon-alpha 2b in patients with chronic hepatitis C. J Viral Hepat 1995; 2: 97104.
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