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JAC Advance Access originally published online on March 19, 2008
Journal of Antimicrobial Chemotherapy 2008 61(6):1191-1200; doi:10.1093/jac/dkn119
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Systematic review

Treatment of chronic hepatitis C in haemophilic patients with interferon and ribavirin: a meta-analysis

Massimo Franchini1,*, Carlo Mengoli2, Dino Veneri3, Romualdo Mazzi4, Giuseppe Lippi5 and Mario Cruciani4

1 Hemophilia Center, City Hospital, Verona, Italy 2 Department of Histology, Microbiology and Medical Biotechnology, University of Padua, Padua, Italy 3 Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Verona, Italy 4 Center of Preventive Medicine, HIV Outpatient Clinic, Verona, Italy 5 Section of Clinical Chemistry, Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy

* Corresponding author. Tel: +39-045-8123610; Fax: +39-045-8123612; E-mail: massimo.franchini{at}azosp.vr.it

Received 13 December 2007; returned 1 February 2008; revised 20 February 2008; accepted 23 February 2008


   Abstract
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 Abstract
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Background: Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality among haemophilic patients who were treated with clotting factor concentrates before the availability of virus-inactivated factors in the mid 1980s. In order to analyse the effect of the current combination anti-HCV treatment [i.e. ribavirin plus interferon (IFN)] in this subset of HCV-infected patients, we performed a systematic review with meta-analysis of the available literature.

Methods: The outcome was sustained viral suppression. When trials included for the main predictors two arms (positive and negative), the effect size was described as a comparative index [odds ratio (OR)] and a standard meta-analytical procedure was applied. However, when trials did not report the outcome in separate study arms, the effect size was a non-comparative index (success rate) and comparisons between predictor-positive and -negative studies were performed by meta-regression.

Results: Data involving 824 haemophilic HCV-infected patients treated with IFN plus ribavirin were collected from 18 articles (14 prospective cohort studies, 1 retrospective study and 3 randomized controlled trials). The higher rate of sustained viral response was observed in human immunodeficiency virus (HIV)-negative naive haemophiliacs treated with pegylated-IFN in combination with ribavirin (61%, ranging from 45% for genotype 1 to 79% for non-1 genotypes). Genotype 1 (OR, 0.15; 95% CI, 0.09–0.25) and co-infection with HIV (OR, 0.25; 95% CI, 0.08–0.81) were strong predictors of worse response to IFN therapy.

Conclusions: Our meta-analysis shows that the pattern of response to combination anti-HCV therapy of chronically HCV-infected haemophiliacs is similar to that achieved in the general HCV-infected population.

Keywords: HCV , haemophilia , response


   Introduction
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Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in haemophilic patients.1 In fact, virtually all haemophiliacs who were infused with clotting factor concentrates before the introduction of viral inactivation techniques in the mid 1980s were infected with HCV.2 Of all infected patients, ~10% to 20% spontaneously clear the virus, as documented by the persistence of serum anti-HCV antibodies with negative serum HCV-RNA, whereas the majority (~80%) develop a chronic hepatic infection which in ~20% of cases progresses to the end stages (cirrhosis, liver failure and hepatocellular carcinoma) after 20 years of infection.3,4 HCV genotype 1, duration of HCV infection and co-infection with human immunodeficiency virus (HIV) have been identified as important predictors of disease progression.5–7

Thus, the antiviral treatment is applied in such patients in order to eradicate HCV and to prevent the development of severe liver disease.8,9 Results in HCV-infected non-haemophilic population have shown that the addition of ribavirin to interferon (IFN) monotherapy has improved the sustained viral response (SVR) from 10–20% to 30–40%.10–12 When IFN was substituted by pegylated formulation (Peg-IFN), the response to combination therapy increased to 50–60%.13–15 This association has also rescued a significant proportion of patients refractory (8% to 21% of SVR) or relapsed (42–55 of SVR) to a previous course with IFN alone or in combination with ribavirin.16,17

Although treatment response rates seem to be similar in HCV-chronically infected haemophiliacs, the studies published so far are limited and often include a small number of patients.7,18

This systematic review is aimed to analyse the existing literature on the combination therapy (IFN or Peg-IFN and ribavirin) in the treatment of chronic hepatitis C in haemophilic patients and to evaluate the influence of factors predictive of the efficacy of therapy on sustained treatment response.


   Materials and methods
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Literature search

We first performed an electronic search on chronic anti-HCV therapy in haemophiliacs on MEDLINE, EMBASE, SCOPUS and the Cochrane Library without temporal limits using different combinations of the following keywords: ‘haemophilia’, ‘haemophilic patients’, ‘congenital bleeding disorders’, ‘hereditary coagulation disorders’, ‘haemorrhage’, ‘coagulopathy’, ‘hepatitis C virus’, ‘HCV’, ‘chronic hepatitis C’, ‘interferon’, ‘IFN’, ‘pegylated interferon’, ‘Peg-IFN’, ‘ribavirin’, ‘antiviral therapy’ and ‘treatment’. In addition, the bibliographic references of all retrieved studies and reviews were assessed for additional reports of clinical trials. Unpublished works were identified by searching the abstract books of the most important conferences on infectious and haematological diseases.

Selection criteria, data collection, outcome and predictors

We included controlled and uncontrolled trials, and randomized or non-randomized studies in the analysis. For inclusion, studies had to enrol patients with a diagnosis of hereditary bleeding disorders and chronic hepatitis with detectable HCV viraemia treated with IFN plus ribavirin or Peg-IFN plus ribavirin. Combination therapies in the studies had to be planned for ≥6 months.

The outcome evaluated was the SVR, defined as undetectable HCV-RNA 6 months after the end of treatment. We also recorded, when available, data related to variables that have been proposed as predictors of response to treatment, such as data on HCV genotype, HIV infection status, previous IFN treatment, age at treatment, age at infection and duration of HCV infection.

Quality assessment

The quality assessment varied according to the design of the study. The methodological quality of cohort studies was assessed using an application of the Newcastle–Ottawa quality assessment scale for cohort studies.19 The scale is aimed to assess for selection bias, comparability of cohorts on the basis of the design or analysis and outcome assessment. The quality of randomized trial was assessed with a scale developed by Jadad et al.20 This scale evaluates the randomization and double-blinding processes, and reports of dropouts and withdrawals; trial scores range from 0 to 5 points. The randomization process was evaluated in terms of adequacy of sequence generation and allocation concealment. Each trial was independently scored by two of us and any areas of disagreement arbitrated by a third.

Statistical analysis

In all studies selected for inclusion in the meta-analysis, the outcome was the sustained viral suppression, defined as the absence of HCV-RNA at the end of treatment and at the follow-up (24 weeks after the end of treatment). When trials included for the main predictors (e.g. HCV genotype 1, HIV co-infection and Peg-IFN use) two arms (positive and negative), the effect size was described as a comparative index [odds ratio (OR)] and a standard meta-analytical procedure was applied. However, when trials did not report the outcome in separate study arms, the effect size was a non-comparative, descriptive index (success rate) and comparisons between predictor-positive and -negative studies were performed by meta-regression. This index was calculated after logarithmic odds (logit) transformation of proportions, which allows better behaved (e.g. more normally distributed) quantities to be obtained. Weighting of the study results was obtained through the inverse variance method.

A meta-regression was performed in order to estimate the influence of predictors on the outcome (success rate in HCV eradication). The predictors used were presence of HIV-1 co-infection (yes or no), use of Peg-IFN (yes or no) and presence of HCV genotype 1 (yes or no).

Assessment of publication bias and heterogeneity

Clinical heterogeneity was explored and statistical heterogeneity assessed by using the Cochran’s Q and estimated using the I2 statistic and {tau}2, which examines the percentage of total variation across studies due to heterogeneity rather than to chance.21 In order to address the heterogeneity issue and to calculate {tau}2, the DerSimonian–Laird method for study weighting and confidence interval (CI) establishing was used. Finally, logits were re-converted into rates and as such reported and graphically plotted.

To inspect for publication bias visually, we generated graphical funnel plots according to Egger et al.22 The statistical methods used for detecting publication bias were the rank correlation tests of Begg and Mazumdar.23

Data analysis was completed using STATA 9.2.


   Results
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Discussion
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In total, we identified 163 references through the electronic and hand searches. After reading the full text of the articles, we excluded 131 irrelevant references (116 focusing on other topics and 15 editorial/reviews) and retrieved 32 potentially relevant references for further assessment. A further 14 studies were excluded because of duplicates of already included studies (7 references) or because the relevant data could not be extracted (7 references). Thus, we have considered 18 studies for this systematic review, with information on 824 patients.24–41

Qualitative review

Tables 1 and 2 report the studies in detail with design, patient and treatment characteristics. The majority of the studies utilized a non-controlled and non-randomized design. There were 14 prospective cohort studies, 1 retrospective study and 3 randomized controlled trials. Twelve studies were performed in HIV-negative patients, 5 studies included both HIV-negative and -positive patients and 1 study included HIV-positive patients only. Of the 824 patients evaluated, 110 (13.3%) were non-responders to previous antiviral therapy, whereas 714 (86.7%) were untreated.


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  		Table 1. Summary of the literature data: characteristics of the patients

 


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  		Table 2. Summary of the literature data: characteristics of treatment and response

 
According to the Newcastle–Ottawa quality assessment scale [Table S1, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)], the criteria for selection of patients and comparability of cohorts as well as the outcome evaluation were, with few exceptions, satisfactory and homogeneous.

The sequence generation of the randomization process was adequate in all of the three randomized clinical trials; allocation concealment was adequate in one study and unclear in two. One study was described merely as double blind, but no details about blinding were provided. Information regarding withdrawals was described in two studies. The Jadad score of individual studies was 3.

Quantitative analysis

Rates of sustained response to IFN treatment are shown in Tables 2 and 3 and in Figures 1–4. Twelve studies reported the outcome in patients with HCV infection sustained by genotype 1 and in patients with HCV infection sustained by other genotypes (Figure 1), and five studies reported the outcome separately in HIV-infected and non-infected patients (Figure 2). The availability of outcome data in separate arms allowed to calculate conventional pooled estimates and, for this purpose, we used OR and 95% CI. As expected, genotype 1 was associated with lower probability of response compared with other genotypes (OR, 0.15; 95% CI, 0.09–0.25). Moreover, the response to antiviral therapy in HCV–HIV-co-infected patients was lower than in patients without HIV co-infection (OR, 0.25; 95% CI, 0.08–0.81). For other predictive variables (previous IFN treatment, use of Peg- or non-Peg-IFN), since the trials included in the analysis did not report the outcome in separate study arms, or the number of patients analysed in separate arms was too small and the heterogeneity too high to allow a meaningful comparison, we calculated the average proportion of patients with SVR across individual studies, as shown in Table 3. The higher rate of SVR (61%) was reached in HIV-negative naive haemophiliacs treated with Peg-IFN (Figure 3). Moreover, this rate increased up to 79% if the genotype was different from 1. In contrast, the lower SVR rate was observed in HIV-positive naive haemophiliacs treated with Peg-IFN (29%, Figure 4).


Figure 1
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  		Figure 1. Pooled OR estimates and their 95% CI for the outcome sustained viral response in patients with genotype 1 compared with non-1 genotypes. Studies are identified by the first author. Size of squares is proportional to weighted OR.

 


Figure 2
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  		Figure 2. Pooled OR estimates and their 95% CI for the outcome sustained viral response in HIV-1-co-infected patients compared with patients with HCV infection only. Studies are identified by the first author. Size of squares is proportional to weighted OR.

 


Figure 3
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  		Figure 3. Summary random-effects weighted rates of sustained viral response and 95% CI in patients without HIV co-infection and IFN-naive. Top: subgroup of patients treated with non-Peg-IFN plus ribavirin. Bottom: subgroup of patients treated with Peg-IFN plus ribavirin. Studies are identified by the first author.

 


Figure 4
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  		Figure 4. Summary random-effects weighted rates of sustained viral response and 95% CI in patients with HIV co-infection and IFN-naive. Top: subgroup of patients treated with non-Peg-IFN plus ribavirin. Bottom: subgroup of patients treated with Peg-IFN plus ribavirin. Studies are identified by the first author.

 


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  		Table 3. Rates of sustained viral response in subgroups of patients stratified according to predictors; a non-comparative index was calculated after logarithmic odds (logit) transformation of proportions

 
Rates of response from randomized trials are limited to three studies conducted in HIV-negative patients (Table 1). In one of these studies, patients were randomized to receive non-Peg-IFN with or without ribavirin; for the purpose of this analysis, we extracted data limited to the combination arm.29 The other two studies conducted in patients receiving non-Peg-IFN in combination with ribavirin were randomized to a different induction therapy schedule or to a different duration of IFN treatment: in both cases, we extracted data from all patients receiving combination treatment.28,34 Rate of SVR was 28.5% in the study by Fried et al.29 The studies by Schulman et al.28 and by Meijer et al.34 reported rates of SVR separately for genotype 1 and non-1 genotypes: these figures were 21.9% and 80.0%, and 39.2% and 86.6%, respectively. Overall, rates of responses from randomized trials were within the range of values observed in the cumulative analysis.

Combination of Peg-IFN plus ribavirin was superior in terms of rate of SVR to the combination of non-Peg-IFN plus ribavirin (61% versus 43% in HIV-negative patients, Table 3), though this difference was not statistically significant by meta-regression (Table 4). Moreover, rates of SVR towards HCV genotype 1 infection were higher in patients treated with Peg-IFN compared with patients treated with non-Peg IFN (45% versus 34%), but they were substantially similar in patients with non-1 genotypes (77% in non-Peg-IFN treated and 79% in Peg-IFN treated). The effect of other variables (e.g. age at treatment, age at infection and duration of HCV infection) on response to treatment was not uniformly addressed across studies and could not be further analysed.


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  		Table 4. Results of the random effects meta-regression, odds ratio estimates and heterogeneity assessment

 
Visual examination of the funnel plot [Figure S1, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)] showed no evidence of publication bias, which was confirmed by the Begg and Mazumdar test.


   Discussion
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Many patients with haemophilia and other congenital bleeding disorders have been infected by HCV, which has become a significant cause of morbidity and mortality in this patient group.1 Haemophiliacs therefore represent a unique model for studying the natural history of HCV infection and associated complications because the onset of the infection is known (the time of the first treatment with non-virus-inactivated blood products), and the course of hepatitis can be accurately assessed because these patients have usually had periodic laboratory, clinical and instrumental follow-ups over long periods in haemophilia centers.42,43

Literature data show that in many infected haemophiliacs, the liver disease has a mild, slowly progressing course.2 These findings have been recently confirmed by Assy et al.44 who compared liver histology from 12 haemophiliacs and 20 non-haemophilic controls with chronic hepatitis C and found significantly lower histological activity and fibrosis scores in haemophilic patients. The authors hypothesized the importance of thrombosis and vascular factor in the pathogenesis of HCV cirrhosis to explain the more benign course in haemophiliacs than in non-haemophiliacs.

In the present study, we evaluated whether, besides the previous documentation of a slowly progressive natural history of chronic hepatitis C,2 haemophiliacs also had a favourable response to antiviral therapy.

Some limitations of our analysis should be acknowledged. First, we found few randomized controlled trials, as the majority of trials analysed were cohort studies. In this respect, meta-analysis of observational data is known to have more biases than meta-analysis of randomized controlled trials.45 Nonetheless, we tried to provide more insights to the topic considering possible sources of heterogeneity between the results from observational studies. In particular, we attempted to evaluate the effect of combined treatment of HCV with IFN plus ribavirin comparing studies that involved cohort of patients who had haemophilia. However, outcome data were available in separate arms only according to genotype (genotype 1 versus others) and to HIV-1 infection status. The influence of other predictive variable was addressed by means of meta-regression.

In this systematic review, the first performed on HCV-infected haemophilic patients, we observed that the combination of Peg-IFN plus ribavirin was superior in terms of rate of SVR to the combination of non-Peg-IFN plus ribavirin (61% versus 43%), though this difference was not statistically significant by meta-regression. However, the relationship between SVR and type of IFN used, at least for non-1 genotypes, was not as clear as expected.

These results were comparable to those observed in the general population of HCV treated patients.46 As observed in non-haemophilic patients,47 genotype 1 (OR, 0.15; 95% CI, 0.09–0.25) and HIV-1 co-infection (OR, 0.25; 95% CI, 0.08–0.81) were strong predictors of worse response to IFN therapy. Pooled response rates observed with IFN plus ribavirin in HIV-co-infected haemophiliacs were comparable to rates in HIV-co-infected non-haemophilic patients from other meta-analyses.48,49 These data also confirm for haemophiliacs the worse influence of HIV infection not only on the course of hepatitis C,50 but also on the response to antiviral therapy.51

In conclusion, this meta-analysis documents that chronic hepatitis C in haemophiliacs has a behaviour similar to that in non-haemophilic patients both in terms of response to ribavirin plus IFN therapy and in terms of negative predictors of IFN therapy efficacy. The heterogeneity of treatment effect was explained by HCV genotype, HIV infection status and, to a lesser extent, to the type of IFN used. Also, the results in the general population of HCV-infected people are in agreement with the findings that a substantial percentage of HIV-co-infected haemophiliacs (up to 40%) can eradicate the HCV virus with combination antiviral therapy.


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No specific funding was received.


   Transparency declarations
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None to declare.


   Supplementary data
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Table S1 and Figure S1 are available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/>).


   References
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1 Franchini M. Hepatitis C in haemophiliacs. Thromb Haemost (2004) 92:1259–68.[Web of Science][Medline]

2 Franchini M, Rossetti G, Tagliaferri A, et al. The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders. Blood (2001) 98:1836–41.[Abstract/Free Full Text]

3 Lee CA. Hepatitis C infection and its management. Haemophilia (2000) 6:133–7.[CrossRef][Web of Science][Medline]

4 Posthouwer D, Makris M, Yee TT, et al. Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study. Blood (2007) 109:3667–71.[Abstract/Free Full Text]

5 Kessler CM. Update on liver disease in hemophilia patients. Semin Hematol (2006) 43(Suppl 1):S13–7.[Web of Science][Medline]

6 Wilde JT. HIV and HCV coinfection in haemophilia. Haemophilia (2004) 10:1–8.[Web of Science][Medline]

7 Goedert JJ, Brown DL, Hoots K, et al. Human immunodeficiency and hepatitis virus infections and their associated conditions and treatments among people with haemophilia. Haemophilia (2004) 10(Suppl 4):205–10.[CrossRef][Web of Science][Medline]

8 Franchini M, Nicolini N, Capra F. Treatment of hepatitis C in hemophiliacs. Am J Hematol (2006) 81:696–702.[CrossRef][Web of Science][Medline]

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13 Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon {alpha}-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med (2000) 343:1673–80.[Abstract/Free Full Text]

14 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon {alpha}-2b plus ribavirin compared with interferon {alpha}-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet (2001) 358:958–65.[CrossRef][Web of Science][Medline]

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19 Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. (30 October 2006, date last accessed).

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23 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics (1994) 50:1088–11.[CrossRef][Web of Science][Medline]

24 Shields PL, Mutimer DJ, Muir D, et al. Combined {alpha}-interferon and ribavirin for the treatment of hepatitis C in patients with hereditary bleeding disorders. Br J Haematol (2000) 108:254–8.[CrossRef][Web of Science][Medline]

25 Sauleda S, Esteban JI, Altisen C, et al. Treatment with interferon plus ribavirin in anti-HIV negative patients with congenital coagulation disorders and chronic hepatitis C. Thromb Haemost (2000) 83:807–10.[Web of Science][Medline]

26 Sauleda S, Juarez A, Esteban JI, et al. Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus-infected patients with congenital coagulation disorders. Hepatology (2001) 34:1035–40.[CrossRef][Web of Science][Medline]

27 Lethagen S, Widell A, Berntorp E, et al. Clinical spectrum of hepatitis C-related liver disease and response to treatment with interferon and ribavirin in haemophilia or von Willebrand disease. Br J Haematol (2001) 113:87–93.[CrossRef][Web of Science][Medline]

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30 Santagostino E, Rumi MG, Rivi M, et al. Sustained suppression of hepatitis C virus by interferon and ribavirin in hemophilic patients not responding to interferon monotherapy. Blood (2002) 99:1089–91.[Abstract/Free Full Text]

31 Franchini M, Tagliaferri A, Rossetti G, et al. Interferon and ribavirin in HIV-negative haemophiliacs with chronic hepatitis C who were nonresponders to a previous interferon treatment. Haemophilia (2002) 8:794–7.[CrossRef][Web of Science][Medline]

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33 Puetz J, Thrower M, Kane R, et al. Combination therapy with ribavirin and interferon in a cohort of children with hepatitis C and haemophilia followed at a pediatric haemophilia treatment center. Haemophilia (2004) 10:87–93.[CrossRef][Web of Science][Medline]

34 Meijer K, Haagsma EB, van der Meer J. A randomized, double-blind, placebo-controlled clinical trial of high-dose interferon-{alpha} induction treatment combined with ribavirin for chronic hepatitis C in hemophilia. J Thromb Haemost (2004) 2:194–6.[CrossRef][Web of Science][Medline]

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38 Mancuso ME, Rumi MG, Santagostino E, et al. High efficacy of combined therapy with pegylated interferon plus ribavirin in patients with hemophilia and chronic hepatitis C. Haematologica (2006) 91:1367–71.[Abstract/Free Full Text]

39 Shire NJ, Horn PS, Rouster SD, et al. HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia. Hepatology (2006) 44:1146–57.[CrossRef][Web of Science][Medline]

40 Posthouwer D, Fischer K, De Heusden N, et al. Pegylated interferon and ribavirin combination therapy for chronic hepatitis C in patients with congenital bleeding disorders: a single-centre experience. Haemophilia (2007) 13:98–103.[CrossRef][Web of Science][Medline]

41 Posthouwer D, Yee TT, Makris M, et al. Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study. J Thromb Haemost (2007) 5:1624–9.[CrossRef][Web of Science][Medline]

42 Makris M, Preston FE, Rosendaal FR, et al. The natural history of chronic hepatitis C in hemophiliacs. Br J Haematol (1996) 94:746–52.[CrossRef][Web of Science][Medline]

43 Telfer P, Sabin C, Devereux H, et al. The progression of HCV-associated liver disease in a cohort of hemophilic patients. Br J Haematol (1994) 87:555–61.[Web of Science][Medline]

44 Assy N, Pettigrew N, Lee SS, et al. Are chronic hepatitis C viral infections more benign in patients with hemophilia? Am J Gastroenterol (2007) 102:1–5.[CrossRef][Web of Science]

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