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Keywords:

  • hepatitis C virus;
  • interferon alpha;
  • ribavirin;
  • hereditary bleeding disorder;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Patients with hereditary bleeding disorders who received non-virally inactivated plasma-derived clotting factor concentrates before the mid-1980s invariably became infected with hepatitis C virus (HCV). Therapy with interferon alpha (IFN-α) alone has been disappointing in this group. We conducted an open-label study, using a combination of IFN-α2b (3 million units three times per week) and ribavirin 1–1.2 g/d in 28 patients with hereditary bleeding disorders. Twenty-one of the 28 patients had liver biopsy-confirmed chronic hepatitis (median histological activity index 5; range 1–10) and all patients were HCV RNA positive by PCR. Virological response rate to therapy at 3 months was 82% (23 out of 28). Three HIV co-infected patients showed an early virological response with loss of HCV RNA, but two subsequently relapsed after 3 and 6 months of therapy. Four patients stopped treatment early (one at 4, one at 7 and two at 9 months) because of treatment-related side effects, although three of these have maintained a virological response. Seventeen patients completed the 48-week course. Twenty of the 28 (71%) treated have had a durable virological response with a median follow-up of 16 months (range 1–24). Combination therapy represents a significant advance in the treatment of hepatitis C in patients with hereditary bleeding disorders.

The majority of patients with hereditary bleeding disorders who received plasma-derived blood products before the introduction of viral inactivation procedures in the mid-1980s were infected with hepatitis C virus (HCV) ( Watson et al, 1992 ). Most of these patients have developed chronic HCV infection and have been at subsequent risk of developing progressive liver disease ( Mauser-Bunschoten et al, 1995 ). It has been reported that 20 years after initial exposure to HCV about 10% of such patients have developed liver decompensation ( Telfer et al, 1994 ; Makris et al, 1996 ). The cumulative risk of death from liver disease in the UK haemophilia population 25 years after first exposure to blood products has been reported as 1.4% for HIV-negative patients and 6.5% for HIV-positive patients ( Darby et al, 1997 ). At least 25 haemophiliacs world-wide have undergone liver transplantation for chronic viral hepatitis with an overall 3-year survival rate of 83% ( Gordon et al, 1998 ). However, reinfection of the transplanted liver by HCV is almost universal and the prognosis for such patients remains uncertain in the long term.

It is crucial therefore to develop effective strategies to eradicate HCV infection. Interferon alpha (IFN-α) monotherapy has been used to treat HCV in patients with hereditary bleeding disorders, but results have been very disappointing. Reported response rates are less than 50%, with sustained remission rates after cessation of treatment being around 10% ( Makris et al, 1991 ; Hanley et al, 1996 ; Rumi et al, 1997 ). The oral antiviral agent ribavirin is a synthetic guanosine nucleoside analogue with in vitro antiviral activity against a range of RNA and DNA viruses. It has recently been introduced as a therapeutic agent in the treatment of HCV and may be a weak inhibitor of HCV RNA polymerase as well as having properties as an immunoregulator, shifting from a T helper (Th)2 to more of a Th1 response, favouring viral clearance ( Hultgren et al, 1998 ). Ribavirin is ineffective as a single agent and although it leads to normalization of transaminases it has no significant effect on serum levels of HCV RNA ( Di Bisceglie et al, 1995 ). In combination with IFN, however, ribavirin has been shown to double sustained response rates compared with IFN alone in non-bleeding disorder HCV-infected patients ( McHutchison et al, 1998 ; Poynard et al, 1998 ). There are currently no published data in patients with hereditary bleeding disorders as they have been excluded from trials of combination therapy because of the potential risk of haemorrhage from liver biopsy. This is not necessarily justified as we have previously reported that liver biopsies can be performed safely in this cohort given appropriate assessment and replacement of clotting factors ( Ahmed et al, 1996 ). In this study, we report our single-centre experience of the use of combination interferon alpha 2b and ribavirin therapy in patients with bleeding disorders who are chronically infected with HCV.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Patients and monitoring during therapy

Patients with hereditary bleeding disorders aged ≥ 18 years and registered at our Comprehensive Care Haemophilia Centre were invited to attend our HCV management outpatient clinic to be assessed for combination antiviral therapy. They underwent a full clinical assessment and blood tests, including full blood count, urea and electrolytes, liver function tests, thyroid function tests and serum HCV RNA using Amplicor HCV Monitor (Roche, Switzerland). If HCV was identified by PCR, genotype was determined using a line probe assay system (Inno-LiPa HCV 11 Innogenetics, Zwijnaarde, Belgium). HCV PCR-positive patients were considered eligible for treatment if they fulfilled the following criteria. Patients had intermittent or persistently elevated alanine aminotransferase (ALT) activities on retrospective review of liver function tests or had a histology activity index of ≥ 3 using a modified Knodell scoring system of liver biopsy material ( Ahmed et al, 1996 ) regardless of ALT. Patients undergoing therapy had compensated liver disease and fulfilled haematological and biochemical criteria as follows: haemoglobin > 13 g/dl for men, > 12 g/dl for women; white blood count > 3.0 × 109/l; platelets > 100 × 109/l; normal prothrombin time, normal albumin, normal serum creatinine and normal thyroid-stimulating hormone (TSH). Patients were hepatitis B (HBsAg) negative and had a serum alpha fetoprotein within the normal range. HIV-infected patients were included if they did not have an AIDS diagnosis, if their CD4 count was above 200 × 106/l and if they were not taking antiretroviral therapy. Because of the potential teratogenicity of ribavirin, sexually active patients had to be practising acceptable methods of contraception during treatment and for 6 months after cessation of therapy. All patients agreed to limit their alcohol intake during therapy to less than 30 g/d. Patients were assessed in the outpatient clinic at weeks 1, 2 and 4, and then every 4 weeks during therapy. All patients received interferon α2b (Intron A, Schering Plough, Kenilworth, NJ, USA) at a dose of 3 million units subcutaneously three times per week and ribavirin (Rebetol, Schering Plough, Kenilworth, USA) 1.2 g orally once daily (1 g in patients below 75 kg). Patients who failed to eradicate serum HCV RNA at 12 weeks were considered to have failed treatment and drug therapy was discontinued. Virological responders were treated for a total of 48 weeks. HCV RNA was rechecked at 24 weeks to confirm continued response to therapy. Patients underwent biochemical and virological assessment at 1, 3 and 6 months, and thereafter at 6-monthly intervals after discontinuation of therapy to assess their continued response to therapy. Duration of virological response was determined by the date of their most recent assessment of HCV RNA using PCR.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

One hundred and thirty-nine HCV recombinant immunoblast assay (RIBA)-positive patients known to our centre were assessed for suitability for antiviral therapy. Seventy-eight patients were considered eligible in that they had been shown to have either persistently or intermittently abnormal alanine aminotransferase activities in the preceding 12 months or had liver biopsy evidence of chronic hepatitis. Forty-seven patients were excluded on the basis of persistently normal ALT activities or because they were HIV co-infected with CD4 counts of less than 200 × 106/l. Of the 78 eligible patients, 54 accepted our offer to attend the HCV management clinic. Two patients were serum HCV RNA negative by PCR, and of the 52 HCV RNA-positive patients 24 (46%) declined therapy. Two patients failed to satisfy entry criteria, one because of subclinical autoimmune hypothyroidism and one because of excessive alcohol intake. Table I summarizes the characteristics of the 28 patients who have begun combination treatment since December 1996. Three patients were HIV positive; one had a CD4 count of 710, one had a count of 310 and one had a count of 240 × 106/l at the start of therapy. Twenty-one patients had undergone a liver biopsy within 3 years before beginning therapy. The median histological activity index (HAI) in these patients was 5 (range 1–10) and median fibrosis score was 1 out of 4. HCV genotyping was possible in 26 patients and the genotypes were as follows: 1a, nine patients; 1b, six patients; 2a, one patient; 2b, one patient; 3a, nine patients. Median level of serum HCV RNA before therapy was 5.45 × 105 (range 3.2 × 103–7.4 × 106) copies per ml. Three patients had previously been treated with interferon monotherapy, but had failed to achieve any biochemical response during IFN therapy. Of these three patients, two remained HCV RNA positive during IFN and ribavirin combination therapy and one became HCV RNA negative, although this patient relapsed, with reappearance of HCV RNA 3 months after discontinuation of therapy. Of the 28 patients who underwent antiviral therapy, 23 (82%) patients showed an early virological response in that they became HCV RNA negative, according to PCR after 3 months of therapy. There were five early non-responders who remained HCV RNA positive at 3 months and had therapy discontinued according to our protocol. HCV RNA PCR at 6 months revealed two relapses in HIV co-infected patients. Their therapy was therefore discontinued. Four patients stopped therapy (one at 4, one at 7 and two at 9 months) because of severe side effects associated with therapy (severe lethargy in one, arthropathy in another and depression in two). Three of these patients remained HCV RNA negative after discontinuation of therapy, and virological responses persist in one patient at 24, in one patient at 20 and in one patient at 15 months after treatment. After 6 months, 19 out of 22 patients continuing therapy were HCV RNA negative. Seventeen patients completed a full course of therapy (48 weeks). In total, 20 of the 28 patients (71%) who have completed therapy have had a durable virological response at a median of 16 (range 1–24) months. Figure 1 summarizes the patients' responses to therapy.

Table 1. Table I. Patient and virological details in patients receiving combination therapy. Thumbnail image of
image

Figure 1. Fig 1. Virological response rates during and after combination therapy. FU, follow-up.

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Median viral load before therapy was compared in patients who subsequently responded (with loss of HCV RNA) with combination therapy and in those who did not. Median HCV RNA before therapy was 6.1 × 105 copies/ml in responders compared with 4.4 × 105 copies/ml in non-responders (P = 0.44, Mann–Whitney U-test). There was no statistically significant excess of HCV genotype 2 or 3 infections in those that had a durable response to therapy and, of the 21 patients who had undergone liver biopsy, histological activity scores were no less severe in responders to therapy.

A successful response to combination therapy included normalization of ALT activities within the first month of treatment and subsequent clearance of serum HCV RNA. Four patients showed an atypical biochemical response with persistently raised ALT activities despite loss of serum HCV RNA during therapy. Levels of ALT did not change compared with pre-therapy values. One of these patients stopped therapy early (after 7 months) because of severe depression, and serum HCV RNA was detected 3 months after discontinuation. Another patient relapsed 1 month after the full course of therapy with recurrence of serum HCV RNA. The two other patients who had a sustained virological response showed a rapid normalization of ALT activities after cessation of therapy. Autoimmune profiles performed to exclude the development of autoimmune hepatitis were negative during therapy and at 3 months after therapy in these last three patients.

Table II shows treatment-related side effects experienced by our patient cohort. All patients developed ribavirin-associated haemolytic anaemia, as shown in Fig 2. Anaemia was well tolerated by most patients, but five required a dose reduction in ribavirin because of a fall in their haemoglobin levels to < 10 g/dl. Ribavirin dose reduction to 600 mg/d rapidly resulted in improvement in haemoglobin levels and anaemia-associated side effects. Patients did not experience increased haemophilia-related bleeding during therapy and, in particular, subcutaneous injection of IFN was not associated with haematoma formation.

Table 2. Table II. Number of patients experiencing specific side-effects of combination therapy. Thumbnail image of
image

Figure 2. Fig 2. Mean haemoglobin concentration ± SEM (g/dl) during combination therapy. Anaemia due to ribavirin-induced haemolysis rapidly recovers on cessation of therapy.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

This report describes a single-centre experience of the use of combination antiviral therapy in patients with bleeding disorders who are infected with chronic hepatitis C. We report sustained virological response rates similar to those published for non-bleeding disorder patients in recent randomized controlled trials ( McHutchison et al, 1998 ; Poynard et al, 1998 ). Side effects of therapy were observed in our patients, but these were tolerated by the majority and we believe this therapy to be safe if carefully monitored.

Previous studies of antiviral therapy in HCV-infected patients with bleeding disorders have examined only interferon monotherapy, which has proved to be a disappointing single agent in this context. Two out of 29 (7%) patients in one study had a sustained remission after a 6-month course of IFN ( Hanley et al, 1996 ), and, in another study, six out of 45 patients (13%) had a sustained response after 12 months of IFN ( Rumi et al, 1997 ).

Large multicentre randomized controlled trials have now clearly demonstrated that the addition of the guanosine nucleotide analogue ribavirin to IFN results in a more effective treatment regimen against HCV than IFN therapy alone ( Schalm et al, 1997 ; McHutchison et al, 1998 ; Poynard et al, 1998 ). A sustained virological response measured 6 months after therapy was achieved in 119 (43%) of 277 European patients treated with combined IFN and ribavirin for 48 weeks compared with 53 (19%) of 278 patients treated with IFN alone ( Poynard et al, 1998 ). Similar results were obtained in an equivalent American study ( McHutchison et al, 1998 ). In these studies, five factors were independently associated with a favourable response to combination treatment, namely HCV genotype 2 or 3, a pretreatment viral load < 2 million copies/ml, age < 40 years, minimal fibrosis and female sex.

From this study, we report a durable virological response in 71% (20 out of 28) of HCV-infected patients with hereditary bleeding disorders treated with combination therapy. Median follow-up and assessment of sustained virological response in our patients were longer (16 months; range 1–24) than those reported by the majority of published studies in which sustained response was usually determined at 6 months. We have not seen any cases of virological relapse after a complete course (48 weeks) of treatment. The number of patients treated represents only a small proportion of the total number of HCV-infected patients with hereditary bleeding disorders identified at our centre. Patient selection may therefore be a factor accounting for the high response rate observed compared with previous studies using combination therapy. Favourable prognostic factors, including young age, low fibrosis scores and low pretreatment viral load, may have contributed to the good response to therapy. The presence of less favourable factors, including male predominance and high prevalence of genotype 1, appear not to have influenced overall outcome in our patient cohort. Viral load in non-responders to combination therapy was not significantly different from responders in this study, as has been suggested in larger studies. Our failure to detect a lower viral load or an excess of genotype 2 or 3 infection in sustained responders is almost certainly a result of the relatively small number of patients treated. Similarly, histological scores for inflammation and fibrosis were not significantly worse in non-responders than in those with a durable response in the 21 patients who underwent biopsy. Two out of three HIV co-infected patients failed to maintain a virological response during therapy, suggesting that HCV may be difficult to eradicate in this patient group.

Four patients had persistently elevated ALT activities despite elimination of serum HCV RNA during therapy. Two of these patients had a sustained virological response and there was normalization of ALT upon discontinuation of therapy. Autoimmune profiles were negative, making it unlikely that this represents de novo autoimmune hepatitis as has been observed in patients undergoing IFN therapy ( Eisenburg, 1994). The persistent ALT elevation during therapy may have been a direct effect of IFN. A granulomatous hepatitis has been described in hepatitis C patients treated with IFN ( Veerabagu et al, 1997 ). There were no other concomitant medical conditions or drug therapies to account for this observation in our two patients however. A further possibility is that viraemia persisted in these patients that was sufficient to cause ongoing hepatitis but at a level undetectable using our PCR assay. If this were the case, then we would have perhaps expected overt relapse after stopping therapy, although patients have remained HCV RNA negative (one at 18 and one at 19 months). The observation that ALT may be discordant with virological response suggests that ALT levels alone should not be relied upon for assessment of treatment response.

The issue of whether or not patients with hereditary bleeding disorders should be required to undergo liver biopsy is debatable. We treated seven patients without a histological diagnosis of chronic hepatitis if they had biochemical hepatitis and detectable HCV RNA in their serum.

The results of treatment with IFN and ribavirin presented here are consistent with those reported in other large multicentre trials ( McHutchison et al, 1998 ; Poynard et al, 1998 ) with similar sustained response rates and levels of tolerability. We would therefore support the use of combination therapy in patients with hereditary bleeding disorders as in other HCV-infected individuals. The long-term outcome in patients treated with combination therapy remains uncertain and further follow-up will be important to ascertain whether sustained responses in the short term translate to long-term cure of this infection.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References
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