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Summary

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

Background  Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. Some authors have claimed that dialysis mode has an impact on the immune response to hepatitis B virus vaccine but consistent information is lacking on this issue.

Aim  To evaluate the relationship between dialysis mode and immune response to hepatitis B vaccine in dialysis population by performing a systematic review with a meta-analysis of clinical trials.

Method  We used the random effects model of DerSimonian and Laird; sources of heterogeneity in effect estimates were explored by performing sensitivity analyses.

Results  The relative risk of failure to respond to hepatitis B vaccine among patients who underwent maintenance haemodialysis vs. peritoneal dialysis was the end point of interest. We identified 14 clinical trials involving 1211 unique patients on maintenance dialysis. Pooling of study results did not show a significant decreased risk of response to hepatitis B vaccine among haemodialysis patients (overall risk ratio: 1.0, 95% confidence intervals: 0.92–1.1). The P-value was 0.13 for our test of study heterogeneity.

Conclusion  There is no significant link between dialysis mode and seroresponse to hepatitis B virus vaccine in dialysis population.


Introduction

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

It is well known that chronic uraemic patients, whether dialysed or not, have an impaired response to hepatitis B vaccine.1 Indeed, end-stage renal disease (ESRD) patients show reduced seroconversion rates compared with healthy subjects. Moreover, after completion of vaccine schedule anti-HBs titres of responder patients on regular dialysis are low and decline logarithmically over time.1

Recent surveys2, 3 have demonstrated a low but not negligible frequency of hepatitis B virus (HBV) infection in dialysis facilities of developed countries. On the contrary, prevalence and incidence rates of HBV remain high within dialysis units of developing world.4 Also, outbreaks of HBV infection among haemodialysis (HD) patients continued to be reported in industrialized countries.5 The control of spread of HBV infection in dialysis facilities has been an important goal in the management of ESRD.1

The impaired efficacy of HBV vaccine in dialysis patients has been attributed to numerous factors such as immune compromise conferred from uraemia,1 older age,6 male gender,7 body weight,8 nutritional status,9 serological positivity for antibody against hepatitis C virus (HCV) infection,10 human immunodeficiency virus (HIV) infection,11 serum albumin,12 possession of the major histocompatibility complex aplotype HLA-B13 and blood transfusion history.14 In addition, the failure to complete a full course of HBV vaccination may cause a poor active immunization.15

It has been suggested that the responsiveness to HBV vaccine in patients on PD is better than HD patients. In fact, some authors have claimed that peritoneal dialysis (PD) improves the immune compromise conferred from chronic uraemia more satisfactory than HD, and a greater clearance of middle molecules by PD has been cited.16, 17 However, the comparison on the response rate to HBV vaccine in HD vs. PD patients has given controversial results.

The aim of this study was to investigate the available evidence on the relationship between dialysis mode and immune response to HBV vaccination in ESRD patients by performing a systematic review of the literature with a meta-analysis of clinical trials.

Material and methods

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

Search strategy and data extraction

Electronic searches of the National Library of Medicine's MEDLINE database, Current Contents and manual searches of selected specialty journals were performed to identify all pertinent literature. It has been previously demonstrated that an electronic search alone may not be sensitive enough.18 Four MEDLINE database engines (Ovid, PubMed, Embase and GratefulMed) were used. The key words are ‘hepatitis B’, ‘vaccine’, ‘peritoneal dialysis’ and ‘hemodialysis’. Reference lists from qualitative topic reviews and published clinical trials were also searched. Our search regarded human studies that were published in the English and non-English literature. All articles were identified by a search from 1980 to December 2005. Data extractions were conducted independently by two investigators (F.F., V.D.) and consensus was achieved for all data. Studies were compared to eliminate reports for the same patients, which included contact with investigators when necessary. Eligibility and exclusion criteria were prespecified.

Criteria for inclusion

To be included in this systematic review, a clinical trial had to fulfil a set of criteria. It had to be published as a full paper; only clinical trials that (i) specified either a relative risk and a measure of variance for vaccine response among HD patients, compared with PD individuals, or (ii) presented data in a form that could be used to construct a 2 × 2 contingency table were considered eligible for final inclusion. Both randomized-controlled trials and observational studies were considered eligible for inclusion in the analysis. We included trials using plasma-derived or recombinant DNA hepatitis B vaccine.

The decision as to inclusion or exclusion of clinical trials was not related to results. All dose schedules and routes of vaccine administration were included, as long as they involved primary vaccination regimens and not booster doses only.

Ineligible studies

Studies were excluded if they reported inadequate data on measures of response, or included individuals with positive serology for HBsAg, antibodies to HBsAg (HBsAb), or HIV. Trials that were only published as abstracts or as interim reports were excluded; letters and review articles were not considered for this analysis. Trials that involved previously vaccinated patients or renal transplant recipients were excluded. Studies based on HB vaccine plus adjuvant administration were not enrolled.

End points of interest

We evaluated the association of dialysis mode with seroresponse to HB vaccine in clinical trials. Individuals vaccinated against HB are considered immune if protective titres of anti-HBs antibody can be demonstrated after completion of vaccination. The level of antibody production that defines immunity was 10 IU/mL. These definitions were consistent with standards published in the scientific literature.

Source of support

This meta-analysis was not supported by any pharmaceutical company, by any governmental agency or other grants.

Statistical methods

In all trials included in this analysis, data from patients who did not complete the vaccination schedule were excluded from the final analysis; thus, analysis was made by per-protocol, not by intention-to-treat. Data on serological response were collected and when studies presented sparse data, we added a value of 0.5 to all cells of the contingency table, so that relative risks and 95% confidence intervals (CI) could be approximated. A summary estimate of the relative risk of failure to respond to vaccination among HD vs. PD patients was generated by use of a random effects approach, as described by DerSimonian and Laird.19 The Cochrane's Q test was used for quantifying heterogeneity. Possible sources of heterogeneity were explored in subgroups analyses and in sensitivity analyses in which certain subgroups were excluded. Chi-square test statistics were used for heterogeneity across studies. Spearman correlation coefficients were used to assess the association between outcomes of interest (e.g. the reported size of the estimated intervention benefit) and variables thought to be potential sources of heterogeneity (e.g. various subjects and trial characteristics of interest). The 5% significance level was used for α-risk. Every estimate was given with its 95% CI. In this study, the statistical software (revman 4.1; Update Software Ltd, Oxford, UK) freely provided by the Cochrane Collaboration was used.

Results

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

Literature review

Our electronic and manual searches identified 132 manuscripts which were selected for full text review. One hundred and eighteen (89%) studies were excluded because they did not fulfil the inclusion criteria. A list of the 118 bibliographical references is available from the authors on request. Fourteen (10%) papers, representing a total of 1211 unique patients, were included in our meta-analysis. There was a 100% concordance between reviewers with respect to final inclusion and exclusion of studies reviewed based on the predefined inclusion and exclusion criteria.

Patient characteristics

Shown in Table 1 are some salient demographic characteristics of subjects enrolled in the included clinical trials. The majority (eight of 14, 57%) of studies were from centres in Europe and North America. Ten were cohort studies; four were prospective, controlled trials (CCTs) enrolling 248 (21%) patients.

Table 1.  Baseline characteristics of studies included in the analysis
Authors and reference numberPatients, n (HD/PD)Country of origin
Michel et al.4239 (27/12)France
Schmid et al.2252 (30/22)Germany
Steketee et al.23444 (374/70)USA
Drachman et al.2421 (13/8)Israel
Moxey-Mims et al.4323 (6/17)USA
Fleming et al.4483 (68/15)Australia
El-Reshaid et al.4548 (33/15)Kuwait
Fraser et al.4638 (14/24)Israel
Majdan et al.2030 (16/14)Poland
Khan et al.2597 (50/47)USA
Mitwalli2642 (27/15)Saudi Arabia
Bel'eed et al.47191 (136/55)UK
Watkins et al.4834 (13/21)USA
Liu et al.2169 (47/22)Taiwan

As listed in Table 2, recombinant HB vaccine was used in nine (64%) clinical trials. The mean age of subject cohorts ranged from 12.2 to 61.0 years of age (Table 3). The gender distribution ranged from 41% to 64% male. All clinical trials included patients receiving maintenance dialysis: 854 (71%) and 357 underwent regular HD and PD respectively. All PD patients received continuous ambulatory peritoneal dialysis (CAPD). Only two reports20, 21 gave information on anti-HCV-seropositive rate in their ESRD patients; it ranged between 22% and 43%. Data on the rate of patients having diabetes mellitus (DM) was given in six (41%) clinical trials,21–26 DM frequency being 0–29%.

Table 2.  Vaccination schedules of studies included in the analysis
AuthorsVaccine (type)Vaccine (dose)Schedule (months)
  1. NR, not reported.

Michel et al.42Plasma-derived (Hevac-B)5 mcg0, 1, 2, 3, 4 and 5
Schmid et al.22Plasma-derived (Heptavax-B)40 j.L.g.0, 1 and 6
Steketee et al.23Plasma-derived (Heptavax-B)40 mcg0, 1 and 6
Drachman et al.24Plasma-derived (Heptavax-B)20 mcg0, 1 and 2
Moxey-Mims et al.43Plasma-derived (Heptavax-B)40 mcgNR
Fleming et al.44Recombinant (Engerix-B)20 mcgNR
El-Reshaid et al.45Recombinant (Engerix-B)40 mcg0, 1 and 6 (n = 24) 0, 1, 2 and 6 (n = 24)
Fraser et al.46Recombinant (Engerix-B)20 mcg0, 1, 2 and 6
Majdan et al.20Recombinant (Engerix-B)40 mcg0, 1, 2 and 6
Khan et al.25Recombinant (Engerix-B)40 mcg0, 1, 2 and 6
Mitwalli26Recombinant (NR)10 mcg (n = 15) 20 mcg (n = 17) 20 mcg (n = 10)0, 1 and 2 (n = 15) 0, 1 and 2 (n = 17) 0, 1, 2 and 6 (n = 10)
Bel'eed et al.47Recombinant (Engerix-B)40 mcg0, 1, 2 and 3
Watkins et al.48Recombinant (Recombivax-B)40 mcg0, 1 and 6
Liu et al.21Recombinant (Engerix-B)40 mcg0, 1, 2 and 6
Table 3.  Baseline characteristics of studies included in the analysis
AuthorsAge (years)Male, n (%)Time on dialysis (months)
  1. Figures are given for HD/PD where appropriate.

  2. NR, not reported.

Michel et al.425926 (64)NR
Schmid et al.2251.1 ± 14.6/52.7 ± 16.7NRNR
Steketee et al.2356 (2–90)251 (57)28.8 (12–180)
Drachman et al.2412.2 ± 5.213 (62)9.1 ± 13.8
Moxey-Mims et al.4316.8 ± 1.3/12.8 ± 1.113 (57)14.8/13.2
Fleming et al.4465 (19–77)25 (37)/8 (53)25 (1–204)
El-Reshaid et al.4547.0 ± 14.725 (52)34.5 ± 36
Fraser et al.4648.2 ± 2.528 (59)NR
Majdan et al.2044.8 ± 11.6/55.9 ± 11.1NR91.1 ± 69/19.8 ± 6.3
Khan et al.2551 ± 18.4/47.3 ± 14.426 (52)/26 (55)56 ± 73.1/17.6 ± 22.6
Mitwalli2639.9 ± 14.617 (63)/7 (47)NR
Bel'eed et al.4759 ± 16.7/52.6 ± 16128 (41)NR
Watkins et al.4813.4 (4–18)/10.4 (1–18)9 (53)/17 (68)NR
Liu et al.2161.0 ± 11.4/51.9 ± 15.720 (43)/8 (36)59.9 ± 49.3/42.9 ± 32.5

Summary estimates of outcome

Figure 1 lists the risk ratios (RR) for seroprevention by dialysis mode (HD vs. PD) and the corresponding 95% CI for each study. The overall RR is 1.0, the 95% CI were 0.92–1.1. The test for heterogeneity was not significant (P = 0.13).

image

Figure 1. Seroprotection  rate after HBV vaccine: HD vs PD.

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Figure 2 illustrates the Funnel plot where all the trials are plotted on XY axes. The X-axis represents the RR with a log-scale while the Y-axis shows the sample size also with a log-scale. The trials included in the Funnel plot seem to be distributed quite symmetrically around the axis represented by the pooled RR.

image

Figure 2. Seroprotection rate after HBV vaccine and dialysis made: funnel plot.

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Despite the test for heterogeneity was not significant, we explored some of the possible sources of study heterogeneity. The RR was 1.0 (95% CI: 0.92–1.2) in the subset of trials (n = 6) where the comparison on the response rate after HB vaccine was the primary objective of the investigation. The RR was 1.1 (95% CI: 0.90–1.3) in the subgroup of studies based on HBV recombinant vaccine (n = 9). Among studies concerning adults only (n = 11), the pooled RR was 1.0 (95% CI: 0.90–1.2). The RR of response to hepatitis B vaccine was 1.0 (95% CI: 0.93–1.1) after inclusion of studies from developed world only (n = 11).

Discussion

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

The mechanisms responsible for the suboptimal immune response to HBV vaccine in dialysis population have been discussed by numerous investigators. Dumann et al.27 found that non-responsiveness to hepatitis B vaccination was related to decreased production of interleukin-2. Eega et al.28 observed a lowered uptake by antigen-presenting cells (APCs) leading to a defect in HBsAg presentation to T lymphocytes. The conclusion of Verkade et al.29 was that an impaired function of dendritic cells, the most important APCs, decrease the memory T-cell proliferation responses in primary non-responders dialysis patients.

Various approaches have been made in order to improve the response rate to hepatitis B vaccine in end-stage renal disease including increased vaccine doses,30 higher number of vaccine shots,30 or intradermal vaccine route.31 HB vaccine has been administered to chronic uraemic patients not yet requiring regular dialysis.32 Also, several authors have administered vaccine adjuvants, such as thymopentin,33 erythropoietin,34 zinc supplements,35 interleukin,36 interferon37 and AS0438 to improve the response rate to hepatitis B vaccine in this group of immunocompromised patients. Finally, some authors have suggested that patients undergoing maintenance PD have an increased response rate to HB vaccine compared with HD patients.16, 17

We have performed a systematic review of the medical literature that described the impact of dialysis modality on response to HBV vaccine among dialysis patients. We observed that PD patients did not have an increased seroresponse rate to HB vaccine – the overall RR was 1.0 (95% CI: 0.92–1.1). The test for heterogeneity was not significant, and our results were very robust and persisted in subgroup analyses. Thus, it seems quite clear that no link between dialysis mode and response to HB vaccine exists.

This meta-analysis is potentially limited in a number of ways. First, it has been reported that the response rate to HB vaccine in dialysis patients is related to several demographic, or clinical factors. As an example, there was in our studies incomplete information about nutritional status, HIV/HCV infection, serum haemoglobin concentration, DM rate and adequacy of dialysis. However, the link between these parameters and seroresponse to HB vaccine is still controversial in dialysis population.39 Secondly, this review has the potential limitation of publication bias, as with all meta-analyses. Negative trials are less likely to be published – we postulated that the authors who found a statistical association between dialysis mode and response rate to HB vaccine would likely be to comment on such a finding in published manuscripts, whereas investigators who failed to find such an association would be less likely to give any comment. This is of particular concern, given that evaluation of vaccine response was not a primary objective of many studies (eight of 14, 57%) included in our analysis. On the other hand, the pooled RR did not change in the subset of patients that formally compared HD vs. PD groups. To limit the possible effect of publication bias, we used several strategies for identifying studies to include published and unpublished studies. Inclusion criteria, established a priori, were chosen to increase the likelihood that high-quality studies would be included.

Our findings are consistent with data from other sources. A recent US survey using data obtained from the FMCNA database (14 546 patients with end-stage renal disease who received HBV recombinant DNA vaccine) revealed that dialysis modality did not have significant impact on protective antibody response within 365 days.40 The rate of ESRD patients undergoing maintenance HD ranged between 91% and 94%. The OR (95% CI) for dialysis modality in univariate analysis determining protective antibody response was 0.86 (0.75–0.99; P = 0.03). However, the OR (95% CI) for dialysis modality in multivariable logistic regression model was 1.1 (95% CI: 0.85–1.4; P = 0.5).

The Centers for Disease Control (CDC) currently recommend that healthy adults receive a hepatitis B vaccine in the form of Engerix-B 20 mcg at 0, 1 and 6 months,41 and that HD patients receive double doses (20 × 2 mcg) at 0, 1, 2 and 6 months with regular monitoring of antibody levels to ensure that antibody concentrations remain above the protective level of 10 mIU/mL. No recommended dosage schedule for PD patients exists. Our study shows that no significant difference in response to hepatitis B vaccination between HD and PD groups occurs. PD patients should receive the same vaccine schedule as chronic HD patients.

Acknowledgement

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

This study was supported in part by the grant ‘Project Glomerulonephritis’ in memory of Pippo Neglia.

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