Hepatitis B vaccination for patients with chronic renal failure
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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To identify the effectiveness and safety of hepatitis B vaccine in CRF patients for seroconversion and prevention of HBV infection.
To identify the effectiveness and safety of a reinforced vaccination series (three inoculations plus one or more booster inoculations) against a vaccination series of three inoculations using recombinant hepatitis B vaccine for seroconversion and prevention of HBV infection.
Background
Hepatitis B virus (HBV) is one of the most frequent viral infections in humans with estimates of 200 to 500 million infected people worldwide (Specter 1999; Fabrizi 2000). Infection can occur either through perinatal transmission, which is the cause of 35 to 40 per cent of new infections worldwide (Fabrizi 2000) or horizontally through exposure to infected blood or other body fluids. While the perinatal (vertical) mode of transmission is of increasing concern in specific geographic regions of the world (Fabrizi 2000) much more attention has been focused on the horizontal transmission of the HBV among high‐risk populations. The high‐risk population for horizontal transmission include health‐care workers and chronic renal failure patients (Jefferson 2000; Torres 1996).
Chronic renal failure (CRF) patients are at particular risk of HBV infection due to their increased exposure to blood products, hemodialysis (Desmyter 1983; Crosnier 1981; El‐Reshaid 1994; Dukes 1993; Seaworth 1988; Jilg 1986; Jungers 1994), and an impaired immune response (Johnson 1992; reviewed in Chatenoud 1990; Revillard 1979; reviewed in Chatenoud 1986) that affects hepatitis B vaccine efficacy. Cases of infections among renal patients undergoing dialysis are generally mild, but up to 80 per cent may progress into chronic carriers; which poses risk to other hemodialysis recipients in the same clinical treatment facility (Stevens 1984; Desmyter 1983; Huang 1997). Occurrences of chronic hepatitis in the hemodialyzed populace have ranged from three per cent to 29 per cent (Huang 1997) and the estimated prevalence of HBV infection has previously been reported to be 1.1 to 6.1 per cent in dialysis patients worldwide (Tokars 1998; Petrosillo 1993; Geerlings 1991). Current data from the United States indicate that the prevalence of HBV infections among those receiving maintenance hemodialysis is 0.9 per cent (Tokars 2000) while the prevalence of HBV infections among dialysis patients in the developing world range from 12 to 21.6 per cent (Fabrizi 2001).
Transmission of hepatitis B may be prevented through the administration of hepatitis B vaccine to persons at risk. The first hepatitis vaccine was derived from pooled hepatitis B surface antigen positive plasma and was licensed in the United States of America in 1981(Fabrizi 2000). Today, recombinant vaccines have largely replaced it (El‐Reshaid 1994; Jilg 1986; Zannolli 1997).
Vaccination efficacy of hepatitis B vaccine is determined by measuring the serum titres of antibody to the hepatitis B surface antigen (HBsAg), and seroconversion can be used as surrogate marker for protection against hepatitis B (Popper 1990). Titres greater than 10 milli international units per millilitre (mIU/mL) or greater than 10 Sample Ratio Units (SRU) are generally considered protective (Popper 1990). A systematic Review of effectiveness of these vaccines in health‐care workers (Jefferson 2000) has shown benefits. Early studies have demonstrated that renal‐failure patients benefit from vaccination; however, many have incomplete seroconversion with rates ranging from 32 to 80 per cent, and not all studies have consistently shown benefit (reviewed in Fabrizi 2000). The Advisory Committee on Immunization Practices recommends a four doses schedule of recombinant Engerix B (40 µg) vaccine in renal patients over 20 years of age (Rangel 2000). The current Center for Disease Control (CDC) recommendations for vaccination of renal patients over 20 years of age also specifies a four dose recombinant vaccine schedule of 40 µg Engerix B at 0, 1, 2, and 6 months (CDC 2001). Various strategies employed in HBV vaccination in this population include increased doses of vaccine, reinforced vaccination strategies, and different schedules of vaccine administration (Jilg 1986; Seaworth 1988; El‐Reshaid 1994). Trials which have investigated variations in vaccine dose, dose scheduling, and the use of adjuvants to enhance seroconversion rates have had variable results (reviewed in Fabrizi 2000). Thus the optimum strategy for immunizing CRF patients is not clear.
This systematic Review investigates the effectiveness and safety of hepatitis B vaccination in preventing hepatitis B infections and providing adequate seroconversion in CRF patients.
Objectives
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To identify the effectiveness and safety of hepatitis B vaccine in CRF patients for seroconversion and prevention of HBV infection.
To identify the effectiveness and safety of a reinforced vaccination series (three inoculations plus one or more booster inoculations) against a vaccination series of three inoculations using recombinant hepatitis B vaccine for seroconversion and prevention of HBV infection.
Methods
Criteria for considering studies for this review
Types of studies
Inclusion criteria
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randomised clinical trials comparing the administration of hepatitis B vaccine to CRF patients, with or without dialysis.
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No language, publication date, or publication status restrictions will be imposed.
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Hepatitis B vaccines of all types, dose, and regimen will be considered.
Exclusion criteria
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Trials comparing the beneficial and harmful effects of immunoglobulin prophylaxis. This review will be limited to studies looking at active, not passive immunization.
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Trials comparing the beneficial and harmful effects of hepatitis B vaccines with adjuvant or cytokine co‐interventions.
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Trials involving renal transplant patients.
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Quasi‐randomised trials.
Types of participants
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Participants of any age with CRF or receiving dialysis (hemodialysis or peritoneal dialysis) will be considered. CRF will be defined as serum creatinine greater than 200 µmol/l for a period of more than six months or individuals receiving dialysis (hemodialysis or peritoneal dialysis).
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Current renal transplant patients will be excluded from this Review as these individuals are immunosuppressed and are receiving immunosuppressant agents to prevent the rejection of their transplanted organs (Fivush 1998; Huang 1997; Johnson 1992; Lefebure 1993), and they have essentially normal renal function (Feuerhake 1984).
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Participants must be seronegative for HBsAg and seronegative for anti‐HBsAg antibodies or unsuccessfully vaccinated against HBV (< 10 SRU, < 10 mIU/ml, < 10 IU/L, or equivalent) (Popper 1990; Alexander 1998) prior to vaccine administration. (See 'Additional tables' 01 and 02.)
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Participants infected with the HBV, or with evidence of potential infection (elevated transaminases) will be excluded.
Types of interventions
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Hepatitis B vaccines (plasma or recombinant (yeast) derived) versus placebo, control vaccine, or no vaccine.
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A primary vaccination series of three inoculations of vaccine versus reinforced schedules of vaccine of three inoculations plus one or more booster inoculations.
Types of outcome measures
Primary outcome measures:
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Rate of seroconversion, with adequate anti‐HBs responses (> 10mIU/mL or > 10 SRU).
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Hepatitis B infections (as measured by hepatitis B core antigen (HBcAg) positivity or persistent of HBsAg positivity), both acute and chronic. Acute (primary) HBV infections will be defined as seroconversion to HBsAg positivity or development of IgM anti‐HBc. Chronic HBV infections will be defined as the persistence of HBsAg for more than six months or HBsAg positivity and liver biopsy compatible with a diagnosis or chronic hepatitis B.
Secondary outcome measures:
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Adverse events of hepatitis B vaccines will be recorded where mentioned and will be categorized as:
i) Local injection‐site reactions
ii) Systemic reactions.
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Liver related morbidity (elevated transaminases, cirrhosis, hepato‐cellular carcinoma)
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Mortality
Where outcomes are reported at various intervals during the randomised trials, the outcomes reported at the longest period following vaccinations will be analysed.
Search methods for identification of studies
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The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Renal Group Controlled Trials Register, and The Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2002) will be searched.
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Electronic searches will be conducted utilizing PubMed/MEDLINE (1966 ‐ 2001) and EMBASE (Excerpta Medica Database) (1985 ‐ 2001) databases (see 'Additional table' 03 for the search strategies and MESH terms to be utilized).
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Science Citation Index (Web of Science) will be searched utilizing search terms similar to those used for the PubMed/MEDLINE and EMBASE searches.
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Published abstracts and proceedings from key scientific conferences of renal, hepatologic, and immunology societies will be searched to identify any trials not published in journal format. This will include the Journal American Society of Nephrology, Nephrology Dialysis Transplant ‐ European Dialysis Transplant Association, Hepatology, Journal of Hepatology, American Association of Liver Diseases, and Vaccine from 1980 to 2002.
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Current clinical practice guidelines (Canadian Immunization Guide and Vaccine Preventable Diseases Surveillance Manual) will be searched for relevant randomised clinical trials.
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Reference lists from review articles retrieved from PubMed/MEDLINE and reference lists from randomised clinical trials will be hand searched to identify additional trials.
Data collection and analysis
Application of inclusion criteria
This meta‐analytic Review will be conducted and will report findings according to the 'Quality of reporting of meta‐analysis guidelines' (QUORUM) (Moher 1999; Walker 1999) and according to the recommendations of The Cochrane Collaboration in The Cochrane Reviewer's Handbook (Clarke 2001).
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Titles of research articles retrieved from the electronic database and hand searches will be assessed by the reviewers to determine which abstracts should be reviewed for possible inclusion as per the reviewers defined eligibility criteria described under 'Types of studies', 'Types of participants', 'Types of interventions', and 'Types of outcome measures'.
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All abstracts will be assessed using the eligibility criteria proposed by the reviewers for selecting papers.
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Excluded trials will be listed with the reasons for exclusion.
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Discrepancies between individual reviewers will be resolved through consensus.
Data extraction
Data extraction will be performed on all randomised clinical trials meeting eligibility criteria and review objectives. To ensure accuracy, a minimum of three reviewers will independently extract data from each trial.
Data extraction will include:
1. Number of participants in each randomised controlled trial (N) and the number enrolled to receive each intervention (n).
2. Demographic composition and baseline clinical information for each intervention group. This will include, when specified, age, gender, stage of renal disease, dialysis status (hemodialysis, peritoneal dialysis, and average number of years on dialysis), previous vaccination status (previous vaccination attempts, previously unvaccinated, or unknown), previous antigen status before receiving trial intervention (negative surface antigen, anti HBsAg negative) and participant withdrawals or drop‐outs.
3. Types of interventions employed (plasma versus placebo, plasma versus recombinant vaccine, primary vaccination series (three inoculations) versus reinforced series (three inoculations plus one or more booster inoculations)).
4. Information relating to the vaccines (or placebo), the trade name, dose, number of doses utilized in the trial, the immunization schedules utilized (in months, with first inoculation = 0 months), and route of vaccination if indicated.
5. Information concerning the primary outcomes utilized in each included randomised clinical trial, the type of immunoassay employed, and the time of assessment of outcomes.
6. Primary outcomes collected will include the definition of seroconversion in each trial (SRU, mIU/ml, or IU/L) and the number seroconverted in each group, the definition of partial seroconversion, and the number partially seroconverted if given, and the number of active hepatitis B infections in each group (both acute and chronic).
7. Secondary outcomes collected will include the number of adverse events, deaths, and liver related morbidity.
Methodological quality
The methodological quality, defined as the confidence that the design and report will restrict bias in the intervention comparison (Moher 1998), will be evaluated independently and unblinded by a minimum of two reviewers. According to empirical evidence (Schulz 1995; Jadad 1996; Kjaergard 2001; Jüni 2001), we will assess the methodological quality of all randomised controlled trials meeting the criteria and objectives of this Review by using separate components, that is, generation of the allocation sequence, allocation concealment, double blinding, follow‐up, and use of intention‐to‐treat analyses. Components will be assessed as adequate or inadequate:
‐ Generation of the allocation sequence: adequate (computer generated random numbers or similar) or inadequate (other methods, or not described);
‐ Allocation concealment: adequate (central independent unit, sealed envelopes, or similar) or inadequate (not described, or open table of random numbers, or similar);
‐ Double‐blinding: adequate (identical placebo tablets, or similar, blinding of both participants and investigators) or inadequate (not performed, or tablets versus injections, or similar, blinding of participants only, blinding of investigators only);
‐ Follow‐up: adequate (number and reasons for drop‐outs and withdrawals described) or inadequate (number or reasons for drop‐outs and withdrawals not described).
Statistical analysis
Data extracted from included randomised controlled trials will be entered into Review Manager 4.1 software for statistical analysis. The random effects model will be used. Data synthesis will be carried out as follows:
‐ Relative risk and 95% confidence limits will be computed.
‐ Chi‐squared testing for heterogeneity and homogeneity outcome comparisons will be performed. A P value of 0.1 will be selected (Engels 2000).
‐ Homogeneity of interventions, participants, and outcomes will be assessed prior to combining extracted data from different included randomised clinical trials being compared.
‐ Variability among trial results are expected, and possibilities include dose, route, frequency, and timing of vaccine administration, along with the populations reported,and the length of follow‐up.
‐ Significant heterogeneity encountered will require explanation by the reviewers.
‐ The reviewers will exercise caution when facing the dilemma of low quality scores for significant number of included trials.
‐ The results will be analysed with intention‐to‐treat analyses.
‐ Where comparisons involve less than three included trials, only commentaries will be given as meta‐analysis is inappropriate.
‐'Subgroup Analysis' will be performed in cases where comparisons between interventions being considered demonstrate significant heterogeneity.
