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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Background : The efficacy of interferon monotherapy in dialysis patients with chronic hepatitis C remains unclear, although a number of small clinical trials have been published addressing this issue.

Methods and aims : We evaluated the efficacy and safety of initial interferon monotherapy in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcome was sustained virological response (as a measure of efficacy); the secondary outcome was drop-out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses.

Results : We have identified 14 clinical trials (269 unique patients); two were controlled studies. The mean overall estimate for sustained virological response (SVR) and drop-out rate was 37%[95% confidence interval (CI) 28–48] and 17% (95% CI 10–28), respectively. The most frequent side-effects requiring interruption of treatment were flu-like symptoms (17%), neurological (21%) and gastrointestinal (18%). The overall weighted estimate for SVR in patients with hepatitis C virus genotype 1 was 30.6% (95% CI 20.9–48). In the sub-group of clinical trials (n = 5) with standard interferon administration (3 million units [MUI] thrice weekly, subcutaneous route, 24-week treatment), the overall mean estimate of SVR was 39% (95% CI 25–56). The studies were heterogeneous with regard to SVR and drop-out rate.

Conclusions : Tolerance to initial interferon monotherapy was lower in dialysis than nonuremic patients with chronic hepatitis C. However, more than one-third of haemodialysis patients with chronic hepatitis C have been successfully treated with interferon. Longer duration of interferon monotherapy does not appear to have a beneficial effect on the response rate. Further studies are warranted to define the optimal anti-viral regimen for chronic hepatitis C in dialysis population.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

The reported prevalence of hepatitis C virus (HCV) infection ranges from 8 to 20% in dialysis patients receiving maintenance dialysis in the developed world;1–5 the frequency of HCV is much higher in patients undergoing dialysis in less-developed countries.6–14 Recent studies have shown that HCV is an important cause of morbidity and mortality in chronic dialysis patients.15–19

Interferon-based therapy is the mainstay of therapy for HCV-related liver disease. Its use is not recommended after renal transplantation due to a significant risk of graft loss.20–23 Adverse consequences on long-term graft and patient survival related to the presence of HCV infection after kidney24–29 and kidney–pancreas30 transplantation have been clearly established. Thus, it is imperative that safe and effective therapy for chronic HCV infection be administered prior to renal transplantation.

The literature about treatment of acute31 or chronic hepatitis C32–54 with interferon in the dialysis population consists predominantly of small clinical trials. Data on alternative therapeutic options, such as combination therapy with ribavirin, are even more preliminary in nature.55–57 The optimal regimen for interferon monotherapy in dialysis patients with chronic hepatitis C remains poorly established.32–54 The primary goal of our study was to synthesize the available evidence on the tolerability and efficacy of initial interferon monotherapy in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical trials.

Search strategy and data extraction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

National Library of Medicine MEDLINE and manual searches were combined, as it had been previously demonstrated that a MEDLINE search alone may not sensitive enough.58 The key-words ‘hepatitis C’, ‘interferon’, ‘end-stage renal disease’, haemodialysis' and ‘dialysis’ were used. General reviews, references from published clinical trials, letters to pharmacological companies, and Current Contents were also used. All English and non-English articles were identified by a search from 1990 to July 2002. Data extraction was conducted independently by two investigators (F.F. and V.D.), and consensus was achieved for all data. Studies were compared to eliminate duplicate reports from the same patients, which included contact with investigators when necessary. Eligibility and exclusion criteria were prespecified.

Criteria for inclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

To be included in this meta-analysis a clinical trial had to fulfil certain criteria: it had to be published as a peer-reviewed article, report the results of primary interferon monotherapy, and use the sustained virological response (SVR) as a clinical end-point. Studies which included patients on maintenance haemodialysis or peritoneal dialysis were eligible. The decision as to the inclusion or exclusion of clinical trials was not related to results.

Ineligible studies

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Studies were excluded if they reported inadequate data on treatment or measures of response, or included patients with coexisting diseases such as infection with human immunodeficiency virus, haemophilia, or other specific aetiology of liver disease such as hepatitis B, hepatitis A, Epstein–Barr virus, cytomegalovirus, alcoholic hepatitis/cirrhosis, autoimmune hepatitis, hepatocellular carcinoma, Wilson's disease, haemochromatosis and alpha-1 antitrypsin deficiency. Trials that were only published as abstracts or as interim reports were excluded. Trials that involved previously treated patients, nonresponders or relapsers were excluded. We excluded clinical trials concerning patients with predialysis renal insufficiency or who had functioning renal grafts. Trials reporting viral response rates by methods other than polymerase chain reaction (PCR) (e.g. bDNA assay) were excluded.

Definitions

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

The primary outcome of interest in this systematic review was sustained virological response (SVR) as a measure of efficacy. SVR was defined as disappearance of HCV viremia (HCV RNA) by PCR at least 6 months after completion of therapy. Secondary end-points included the drop out rate as a measure of tolerability, end-of-treatment virological response (EVR), end-of-treatment biochemical response (EBR), and sustained biochemical response (SBR). EVR was the absence of HCV viremia, as detected by PCR, at the end of therapy. EBR and SBR were defined as the normalization of alanine aminotransferase (ALT) levels at the end of the treatment and at least 6 months after the completion of therapy, respectively. These definitions are now standards.59

Statistical methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Outcomes were analysed on an intention-to-treat basis, i.e. all patients included in these studies were considered for the calculation of the response rate, while patients without the end-point were considered as failures. When not given in the publication, the response rate according to the intention-to-treat method was calculated by the data abstractors (F.F. and V.D.). Quantitative, pooled, summary estimates of the SVR and drop-out rate across individual studies were generated using the random-effects model of Der Simonian and Laird.60 Confidence intervals for point estimates were computed using nonparametric resampling (bootstrap) methods. The estimate for each study was weighted inversely to its squared standard error when computing the overall estimate and its confidence interval. The confidence intervals for the random effects model were quoted, since the standard errors under the fixed effects model may be misleading, and the test for homogeneity was rejected.

Chi-square statistics were used to test for homogeneity across studies. Due to considerable variation in study characteristics, especially with regard to study design and HCV genotyping, we performed a sensitivity analysis by stratifying for these two variables. Spearman correlation coefficients were used to assess the association between outcomes of interest and variables thought to be potential sources of heterogeneity. Specifically, the effect of various subject and trial characteristics of interest on the reported size of the estimated intervention benefit (SVR) and drop-out rate were assessed by calculating Spearman correlation coefficients. The 5% significance level was used for alpha risk. Every estimate was given with its 95% confidence intervals (CI).

Clinical trials

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Our search identified 23 papers.32–54 All 23 candidate studies were written in English. Nine studies were excluded because they did not fulfil the inclusion criteria32, 34, 36, 37, 40, 46, 54 or contained duplicate reports of the same patients.38, 51 The remaining 14 studies, representing a total of 269 unique patients, were included in the meta-analysis.33, 35, 39, 41–45, 47–50, 52, 53 There was 100% concordance between reviewers with respect to final inclusion and exclusion of studies reviewed based on the predefined inclusion and exclusion criteria.

Shown in Table 1 are some salient demographic and clinical characteristics of subjects enrolled in the included clinical trials. All trials were published in English from 1994 to 2001 and included haemodialysis-dependent patients infected with HCV who received interferon monotherapy. The majority (10/14 = 71%) of studies were from centres in Western Europe. The mean age of subject cohorts ranged from 34 to 54 years of age. The gender distribution ranged from 31 to 74% male. The mean time on dialysis prior to initiation of treatment varied from 36 to 122 months, although three studies did not report data on this characteristic. As shown in Table 2, data on histologic and virologic characteristics were not as well documented in these studies. Based on the data provided it appears that the majority of enrolled subjects were noncirrhotic with HCV genotype 1.

Table 1.  Characteristics of clinical trials: demographic and clinical data
AuthorsAge, yearsCountryTime on HD, monthsMen, n (%)
  1. NA, not available.

Koenig P. et al.54 ± 14Austria84.2 ± 6422 (59)
Pol S. et al.45France94 ± 6514 (74)
Raptopoulou-Gigi M. et al.53.7GreeceNANA
Fernandez J.L. et al.44.5 ± 16.5Argentina45.1 ± 27.9 5 (36)
Izopet J. et al.47 ± 11France99 ± 5717 (74)
Chan T.M. et al.41.6 ± 7.7Hong Kong122.2 ± 47 8 (73)
Uchihara M. et al.50.1Japan96 4 (31)
Benci A. et al.38ItalyNA 4 (40)
Huraib S. et al.38.6 ± 11.1Saudi Arabia36 ± 13.2 9 (56)
Campistol J.M. et al.42 ± 12Spain76.8 ± 48 9 (47)
Espinosa M. et al.34Spain96 7 (54)
Casanovas-Taltavull T. et al.44.7 ± 10.9Spain69.84 ± 61.418 (62)
Hanrotel C. et al.39 ± 10France88 ± 69 8 (67)
Degos F. et al.45 ± 12FranceNA25 (68)
Table 2.  Characteristics of clinical trials: histologic and virological data
AuthorsCirrhosis, n (%)Genotype 1, n (%)Genotypes 2–3, n (%)Genotype 4, n (%)
  1. NA, not available.

Koenig P. et al.NANANANA
Pol S. et al. 2 (10)10 (67)3 (20)1 (7)
Raptopoulou-Gigi M. et al. 0NANANA
Fernandez J.L. et al. NA7 (54)5 (38)1 (8)
Izopet J. et al. 2 (9)13 (56)5 (38)4 (3)
Chan T.M. et al. 010 (91)1 (9)0
Uchihara M. et al. 04 (100)00
Benci A. et al. NANANANA
Huraib S. et al. 06 (35)NA11 (60)
Campistol J.M. et al. NA17 (89)1 (5)0
Espinosa M. et al. 1 (8)6 (86)00
Casanovas-Taltavull T. et al. 022 (83)NANA
Hanrotel C. et al. 08 (67)3 (25)1 (8)
Degos F. et al. NA29 (78)6 (16)0

Table 3 provides details of the study design, including dose and duration of interferon therapy, and duration of follow-up after interferon. In the majority of trials interferon was administered subcutaneously; in one study it was given by an intramuscular route.44

Table 3.  Design of clinical trials
AuthorsPatients, nInterferon dose, MUInterferon duration, monthsFollow-up duration after interferon, monthsYear of publication
Koenig P. et al.375491994
Pol S. et al.1936181995
Raptopoulou-Gigi M. et al.1936141995
Fernandez J.L. et al.141.5–36121997
Izopet J. et al.2336 (n = 12) 12 (n = 11)191997
Chan T.M. et al.1136181997
Uchihara M. et al.93 (n = 4) 6 (n = 5)661998
Benci A. et al.1011261998
Huraib S. et al.1731261999
Campistol J.M. et al.1936211999
Espinosa M. et al.13312602001
Casanovas-Taltavull T. et al.293–1.51262001
Hanrotel C. et al.1231262001
Degos F. et al.373 (n = 12) 1.5 (n = 6)1262001

Two (14.3%) studies were randomized clinical trials41, 48 while the others were prospective, cohort studies.

Data on the efficacy of treatment are summarized in Table 4. Seventy-one (26.4%) of 269 patients treated with interferon monotherapy discontinued treatment due to side-effects (Table 5). The reasons for discontinuation in these 71 patients were neurological (n = 15) or cardiovascular (n = 7) disorders, depression (n = 6), fever/flu-like symptoms (n = 12), anorexia (n = 1), haematological changes (n = 8), sepsis (n = 3), thromboembolism (n = 1), gastrointestinal changes (n = 13), hepatotoxicity (n = 1), rejection of nonfunctioning kidneys (n = 2) and myalgias (n = 2). In 15 (21%) of 71 cases the reasons for interferon withdrawal were incompletely reported.

Table 4.  Outcomes of clinical trials
AuthorsEBREVRSBRSVR
  1. Abbreviations: EBR, end-of-treatment biochemical response; EVR, end-of-treatment virological response; SBR, sustained biochemical response; SVR, sustained virological response; NA, not available.

Koenig P. et al.  50% (7/14) 41% (15/37)NA30% (11/37)
Pol S. et al.  85% (11/13) 53% (8/15) 61% (8/13)20% (3/15)
Raptopoulou-Gigi M. et al.  59% (10/19) 77% (10/13) 92% (12/13)68% (13/19)
Fernandez J.L. et al.  71% (10/14) 29% (4/14) 36% (5/14)21% (3/14)
Izopet J. et al.  85% (11/13) 91% (21/23) 46% (6/13)52% (12/23)
Chan T.M. et al. 100% (6/6)100% (11/11)  0% (0/6)27% (3/11)
Uchihara M. et al. NANA100% (1/1)33% (3/9)
Benci A. et al.  60% (6/10)NA 20% (2/10)20% (2/10)
Huraib S. et al.  83% (5/6) 88% (15/17) 67% (4/6)71% (12/17)
Campistol J.M. et al. 100% (10/10) 74% (14/19)100% (10/10)42% (8/19)
Espinosa M. et al.  69% (9/13) 61% (8/13) 61% (6/13)46% (6/13)
Casanovas-Taltavull T. et al.  79% (23/29) 83% (24/29)NA62% (18/29)
Hanrotel C. et al. NA 75% (9/12)NA33% (4/12)
Degos F. et al. NA 32% (12/37)NA19% (7/37)
Table 5.  Causes of IFN withdrawal in clinical trials
AuthorsPatients discontinuing treatment (%)Side-effects
Koenig P. et al.35% (13/37)Septicemia (n = 3) fever (n = 1), diarrhoea (n = 9)
Pol S. et al.  5% (1/19) anaemia
Raptopoulou-Gigi M.  et al. 31% (6/19)Fever (n = 1), leucopenia (n = 1), pericarditis (n = 1), myalgias (n = 2), thromboembolism (n = 1)
Fernandez J.L. et al. 21% (3/14)Leucopenia (n = 1), depression (n = 2)
Izopet J. et al. 13% (3/23)Severe confusion (n = 2), seizures (n = 1)
Chan T.M. et al. 0 
Uchihara M. et al. 33% (3/9)Fever (n = 2), depression (n = 1)
Benci A. et al. 10% (1/10)Fever
Huraib S. et al.  6% (1/17)Lethargy
Campistol J.M. et al. 53% (10/19)Flu-like symptoms (n = 4), leucopenia (n = 3), anaemia (n = 1), depression (n = 1), diarrhoea (n = 1)
Espinosa M. et al. 23% (3/13)Seizures (n = 1), flu-like simptoms (n = 1), leucopenia (n = 1)
Casanovas-Taltavull T.  et al. 24% (7/29)Depression (n = 1), fever (n = 2), cholecystitis (n = 1), heart failure (n = 1), hepatotoxicity (n = 1), pericarditis (n = 1)
Hanrotel C. et al.  8% (1/12)Acute rejection
Degos F. et al. 51% (19/37)Seizures (n = 1), depression (n = 1), cardiovascular disorders (n = 4), pancreatitis (n = 1), diarrhoea (n = 1), astenia (n = 9), anorexia (n = 1), necrosis of a previously nonfunctioning renal allograft (n = 1)

Primary analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Summary estimates for SVR and drop-out rate using random-effects models are shown in Figures 1 and 2, respectively. The mean overall estimate for SVR rate was 37% (95% CI 28–48), chi-square 36.02 (P = 0.0006). The mean overall estimate and standard error for SVR rate was 37% ± 3% under the fixed-effects model.

image

Figure 1. Percentage of dialysis patients with chronic hepatitis C having sustained virological response (SVR) after interferon monotherapy in the 14 included studies. The black dots represent point estimates of SVR from each of the individual studies. Reference numbers are reported in parentheses.

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image

Figure 2. Percentage of dialysis patients with chronic hepatitis C who discontinued interferon monotherapy in the 14 included studies. The black dots represent point estimates of the percentage of patients discontinuing treatment from each of the individual studies. Reference numbers are reported in parentheses.

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The overall point estimate for drop-out rate was 17% (95% CI 10–28), chi-square 39.03 (P = 0.0002). The point estimate and standard error for drop-out rate was 17% ± 2% under the fixed-effects model.

Sensitivity analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

The mean weighted estimate for SVR in those patients with HCV genoptype 1 was 30.6% (95% CI 20.9–48), chi-square 5.283 (P = 0.075).

The mean point estimate for SVR in studies involving (n = 5) standard interferon administration (3 MUI three times weekly, subcutaneous administration for 24 weeks) was 30% (95% CI 25–56), chi-square 9.880 (P = 0.0425). The mean point estimate and standard error for SVR rate was 39 ± 5% under the fixed-effects model.

Heterogeneity analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

The studies were heterogeneous with regard to the primary (SVR) and secondary outcome (drop-out rate) endpoints of interest. In other words, these studies may not be measuring the same underlying quantity from the same base population. The summary estimates may not be the best descriptive analysis, since they assume that all estimates from individual studies are from the same population. The sources of between study heterogeneity are unclear. As shown in Table 6, there was no association demonstrated between potential sources of heterogeneity (e.g. percentage of study patients with HCV genotype 1) and reported SVR. As reported in Table 7, a weak positive association between increasing mean age of a study's subjects, as well as a weak inverse relationship between the percentage of a study's subjects with male gender, and reported drop-out rate were demonstrated.

Table 6.  Heterogeneity analysis
VariableSpearman correlation coefficientsP
  1. Relationship between the percentage of study subjects achieving SVR and variables of interest in studies with available data. If the Spearman correlation coefficient is positive, then the SVR increases with an increase in the corresponding variable of interest. A correlation coefficient with an absolute value of P = 0.75 is generally considered to indicate a strong relationship.

Publication year0.120.683
Interferon dose02560.376
Interferon duration (months)01510.607
Follow-up duration after interferon (months)00990.737
Age (years)00170.955
Time on haemodialysis (months)− 02310.495
Men (%)− 00590.847
End-of-treatment biochemical response (%)− 01150.736
End-of-treatment virological response (%)06290.028
Sustained biochemical response (%)04740.166
Cirrhosis (%)− 03480.359
Genotype 1 (%)− 01350.693
Genotypes 2–3 (%)− 01730.656
Genotype 401850.608
Patients discontinuing treatment (%)00550.852
Table 7.  Heterogeneity analysis
VariableSpearman correlation coefficientsP
  1. Relationship between the percentage of study subjects discontinuing therapy and variables of interest in studies with available data. If the Spearman correlation coefficient is positive, then the percentage increases with an increase in the corresponding variable of interest. A correlation coefficient with an absolute value of P =0.75 is generally considered to indicate a strong relationship.

Publication year0.120.681
Interferon dose01390.636
Interferon duration (months)− 02010.491
Follow-up duration after interferon (months)− 00180.95
Age (years)04560.101
Time on haemodialysis (months)− 02550.449
Men (%)− 03960.18
End-of-treatment biochemical response(%)− 01150.736
End-of-treatment virological response (%)04550.138
Sustained biochemical response (%)07260.017
Cirrhosis (%)− 02570.504
Genotype 1 (%)03740.258
Genotypes 2–3 (%)− 0.420.26
Genotype 4− 0.50.142

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

Our meta-analysis showed that more than one-third of patients on haemodialysis with chronic hepatitis C were successfully treated by interferon monotherapy. This response was higher than that typically reported in non-uremic patients with chronic hepatitis C. A recent meta-analysis found that interferon-alpha at 3 MUI thrice weekly (24 weeks) achieved an SVR of 7–16% in naive patients with chronic hepatitis C and normal renal function.59 The majority of enrolled subjects had HCV genotype 1; they had a lower response to anti-viral therapy than non-1 HCV genotypes, as anticipated.61 Several biological mechanisms may be responsible for the relatively high response to interferon in dialysis patients in spite of immune compromise due to uremia. Haemodialysis patients with HCV have a low viral load62 Interferon could help to restore the cell-mediated immunity depressed by uremia; an increase of endogenous interferon activity during haemodialysis sessions has been shown recently63 HCV-related liver disease shows frequently mild histopathological features in haemodialysis patients.62 Importantly, clearance of interferon is lower in dialysis than in non-uremic patients.64 The hemodialysis procedure does not remove interferon because it is a large molecule (molecular weight ≥ 16 000 kDa). Recently, newer pegylated interferons have been made; therapeutic pegylation delays interferon clearance in patients with normal renal function. Patients with HCV genotype 1 treated with high-dose pegylated interferon alpha-2b plus ribavirin have higher responses than standard interferon alpha-2b plus ribavirin.65 Pegylated interferon alpha-2b plus ribavirin therapy for the treatment of chronic hepatitis C is currently under investigation in dialysis patients.

The overall mean estimate of drop-out rate was 17%. In published reports66, 67 the frequency of side-effects requiring interferon discontinuation ranged between 5 and 9% in non-uremic patients with chronic hepatitis C who received a standard interferon dose (3 MUI thrice weekly subcutaneously for 6 months). The altered pharmacokinetic parameters of interferon in the haemodialysis population,64 older age and high frequency of comorbid conditions in haemodialysis patients62 may, to some extent, explain the frequency of side-effects leading to interferon discontinuation. The profile of side-effects during interferon monotherapy in dialysis patients supports this assumption. Because of the heterogeneity in the quality of the adverse-events description and the absence of a placebo, the percentage of adverse effects that attributed to interferon was difficult to interpret. Nevertheless, the most frequent causes of interferon interruption were neurological disorders (21%), fever/flu-like syndrome (17%) and gastrointestinal abnormalities (18%). This is different from patients with chronic hepatitis C and normal renal function; a prior meta-analysis had calculated that the most frequent causes of interruption of interferon therapy were flu-like syndrome (41%), alopecia (16%) and depression (7%).68 Although the drop-out rate with interferon in the haemodialysis population was increased, a large number of haemodialysis patients completed the anti-viral regimen. This is at variance with the common belief held by many physicians that interferon is too toxic in the haemodialysis population.

This meta-analysis presents some limitations. There was a significant heterogeneity between studies. This implies that the summary estimates may not be the best descriptive statistics, since the way they were calculated assumes that all estimates are from the same population. This does not mean that these relationships would not emerge with an analysis of individual level (as opposed to study level) data. The heterogeneity in our meta-analysis could be related to the occurrence of several comorbidities in the HCV-infected dialysis population, and precludes definitive conclusions. Another weakness was that there were few analyses combining individual data, which would have permitted a better analysis of the treatment effect by taking into account the heterogeneity across studies. An additional limitation was the absence of histological end-points. Histological data at the end of treatment or in follow-up are particularly difficult to obtain. Even in trials focusing on histological criteria, the number of second biopsies available is as low as 50%. As with all meta-analyses, this study has the potential limitation of publication bias. Negative trials are sometimes likely to be published. One approach to this problem is to obtain data from as many sources as possible. However, we have not included trials published as abstracts. Preliminary data require the use of efficacy analysis rather than intention-to-treat analysis to calculate response because the number of patients who drop out are usually not reported in studies presented in abstract form. Calculating the response without accounting for the number of patients who drop out of a study tends to overestimate a treatment effect.69

Our sensitivity analysis of a more homogeneous sub-group (n = 5) of trials with standard interferon administration gave a mean weighted estimate for SVR of 39% (95% CI 25–56); the primary analysis gave an overall estimate of 37% (95% CI 28–48). These findings suggest that longer duration of interferon treatment may not give improvement in response rates. However, the limited number of trials concerning haemodialysis patients with a 12-month interferon regimen limited conclusions. Also, we pooled the patients according to the HCV genotype. The mean weighted estimate for SVR in HCV genotype 1 was 30.6% (95% CI 20.9–48); this is lower than that seen in the primary analysis [37% 995% CI 28–48)], further supporting the notion that HCV-infected patients with genotype 1 are less likely to respond to interferon than non-1 genotypes.61 It would have been desirable to extend the sensitivity analysis to other predictors of interferon response, such as body weight or fibrosis score, but the lack of data in the published trials does not permit us to do so.

In conclusion, this meta-analysis shows that the tolerance to interferon is lower in dialysis than in non-uremic patients with chronic hepatitis C. However, more than one-third of haemodialysis patients with chronic hepatitis C have sustained virological response. Therapy should not be withheld from this group of patients, although their tolerance to side-effects may be less than that of non-uremic populations. The optimal anti-viral treatment of chronic hepatitis C in dialysis population is currently under active investigation.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References

This work has been completely conducted at the Liver Transplant Program, Center for Liver and Kidney Diseases & Transplantation, Cedars–Sinai Medical Center and David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Search strategy and data extraction
  6. Criteria for inclusion
  7. Ineligible studies
  8. Definitions
  9. Source of support
  10. Statistical methods
  11. Results
  12. Clinical trials
  13. Primary analysis
  14. Sensitivity analysis
  15. Heterogeneity analysis
  16. Discussion
  17. Acknowledgements
  18. References
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