Extra-high-dose intramuscular hepatitis B vaccine
46. Fernandez-Reyes MJ, Bajo MA, Hevia C et al. Inherent
high peritoneal transport and ultrafiltration deficiency: their
mid-term clinical relevance. Nephrol Dial Transplant 2007; 22:
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2303
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Received for publication: 24.9.09; Accepted in revised form: 13.1.10
Nephrol Dial Transplant (2010) 25: 2303–2309
doi: 10.1093/ndt/gfq094
Advance Access publication 24 February 2010
Extra-high-dose hepatitis B vaccination does not confer longer
serological protection in peritoneal dialysis patients: a randomized
controlled trial
Kai Ming Chow1, Stanley Hok King Lo2, Cheuk Chun Szeto1, Sze Kit Yuen3, Kin Shing Wong2,
Bonnie Ching Ha Kwan1, Chi Bon Leung1 and Philip Kam-Tao Li1
1
Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong,
China, 2Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China and 3Department of
Medicine and Geriatrics, Caritas Medical Centre, Kowloon, Hong Kong, China
Correspondence and offprint requests to: Kai Ming Chow; E-mail: [email protected]
Abstract
Background. The response to recombinant hepatitis B
vaccine remains suboptimal among the dialysis population.
Methods. In this multi-centre randomized controlled trial,
we studied the factors that modify the response to intramuscular Engerix-B vaccination in patients on peritoneal
dialysis. The primary aim was to study if a three-dose
schedule of extra-high dose (80 μg) of Engerix-B would
offer better primary seroconversion and more persistent serological protection than the conventional 40-μg dose.
Results. Forty-two peritoneal dialysis patients were randomized to receive the conventional 40-μg Engerix-B dose
and 45 patients to 80-μg dose. Seroconversion [hepatitis B
surface antibody (anti-HBs) level ≥10 IU/l 3 months after
completion of the third dose] occurred in 78.6% of patients
after 40-μg Engerix-B dosage treatment versus 62.2% for
those receiving 80-μg Engerix-B treatment (P = 0.11). After 12 months, the persistence of protective anti-HBs also
did not differ between 40- (45.2%) and 80-μg (51.1%)
treatment groups (P = 0.67). In contrast, patients with seroconversion 3 months after the third dose of Engerix-B
had a higher normalized protein nitrogen appearance
(nPNA) than patients without seroconversion (1.16 ±
0.25 versus 0.96 ± 0.23 g/kg/day, P = 0.001).
Conclusions. We found no evidence of a worthwhile clinical benefit from increasing the three-dose intramuscular
Engerix-B vaccine from 40- to 80-μg dose. An unplanned
analysis suggested a role of improved protein intake to improve the immune response to hepatitis B vaccine in peritoneal dialysis patients.
Keywords: end-stage renal disease; Engerix-B; hepatitis B; peritoneal
dialysis; protein nitrogen appearance
Introduction
Viral hepatitis B infection remains a major health hazard
for end-stage renal disease patients on dialysis. The direct
costs of hepatitis B infection and their long-term impact on
patient morbidity and mortality are substantial among patients receiving dialysis [1] as well as subsequent renal
transplantation [2]. Ten-year graft and patient survival
was observed to be significantly lower in hepatitis B surface antigen positive than seronegative renal transplant recipients [3], and further confirmed in a meta-analysis [4].
Apart from the devastating consequences of hepatitis B infection on end-stage renal disease patients on dialysis or
after transplantation, the infected patients are potential reservoirs for outbreaks in health-care setting, infecting other
patients and staff [5,6].
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
2304
Despite the availability of hepatitis B vaccination programmes as recommended in most dialysis centres and
the Centers for Disease Control and Prevention (CDC)
[7,8], antibody production achieved in patients with chronic renal disease is suboptimal. The traditional administration of three doses of intramuscular recombinant vaccine
(40 μg at months 0, 1, and 6) leads to a seroconversion rate
of 44–76% in patients on dialysis [9–11].
To improve the relatively low immunogenicity of hepatitis B virus vaccine (regarding seroconversion and maintenance rate of protective hepatitis antibody levels), the
treatment strategy using various doses of recombinant hepatitis B vaccine (Engerix-B, GlaxoSmithKline) has been
explored in an observational study [12]. We previously
demonstrated no statistically significant difference in response rate between patients receiving three recommended
doses of Engerix-B intramuscularly (40 μg each dose) and
those with four times the normal adult dose (80 μg each
dose). On the other hand, there was an absolute risk reduction of 18% for losing the antibody response with a threedose schedule of 80-μg Engerix-B vaccination programme.
Based on this preliminary retrospective study using historical controls, it was estimated that giving 80-μg Engerix-B
dose would lead to one extra end-stage renal disease subject with persistent seroprotective antibodies to hepatitis B
surface antigen (anti-HBs) level at 1 year for every 5.6 patients treated [number needed to treat to benefit (NNT),
5.6; 95% confidence interval, 5.4–5.8] [12]. Furthermore,
similar benefit of extra-high-dose (80 μg) hepatitis B vaccine had been shown in chronic liver disease patient groups
without adverse events [13].
To test the hypothesis that extra-high-dose (80 μg) Engerix-B vaccine leads to longer serological protection
among dialysis patients, we conducted this randomized
controlled study comparing 40- and 80-μg dose in peritoneal dialysis patients, focusing on primary seroconversion
and long-term serological protection.
Materials and methods
This is a multi-centre, randomized, unblended clinical trial conducted from
May 2005 through May 2009 at three dialysis units. This study was designed to evaluate the optimum strategy of recombinant hepatitis B vaccination in the maintenance of protective anti-HBs antibody among end-stage
renal disease patients on peritoneal dialysis. Our primary objective was to
determine whether a three-dose schedule of 80-μg Engerix-B vaccine could
better maintain protective antibody response among dialysis patients. Our
secondary aim is to identify the effects of other parameters on Engerix-B
vaccine response among peritoneal dialysis patients.
The study was approved by the local Clinical Research Ethics Committee of the individual centres. All patients provided written informed
consent, and the study was conducted in accordance with Good Clinical
Practice Guidelines and the Declaration of Helsinki.
Patients
Patients who were undergoing peritoneal dialysis were screened for enrolment. Inclusion criteria were end-stage renal disease patients on maintenance peritoneal dialysis and serologically negative for hepatitis B surface
antigen (HBsAg) and antibody to hepatitis core antigen (anti-HBc), in the
absence of previous hepatitis B vaccination history. Additional criteria for
eligibility were age above 18 years and willingness to give written informed consent and comply with the study protocol.
Exclusion criteria applied before randomization were a diagnosis of active malignancy, alcoholic liver disease, chronic hepatitis C and/or human
K.M. Chow
immunodeficiency virus infection; an expected survival of <6 months; a
patient refusal of vaccination; and an ongoing patient medication of immunosuppressive drugs.
Randomization
After informed consent, eligible patients were randomly assigned to treatment at enrolment site by drawing a consecutively numbered, sealed,
opaque envelope containing a form indicating which dose of Engerix-B
should be administered. Patients were randomly assigned to receive Engerix-B at two dosages: 40 μg each dose or 80 μg each dose.
Vaccination schedule
The vaccine Engerix-B was administered intramuscularly in the deltoid
muscle. Patients allocated to the 80-μg regimen received 80-μg EngerixB in a three-dose schedule at 0, 1 and 6 months. Patients in the 40-μg treatment group were assigned to 40 μg each in an otherwise identical manner.
Administration of a single booster dose (40 μg), according to the current recommendation [8], was given to those subjects with negative antibody response 3 months after completion of the immunization.
Clinical data
Demographic and clinical data were collected for all patients in the study.
Medications were tabulated and recorded at the start of the immunization
schedule. The modified Charlson’s Co-morbidity Index, which was validated in continuous ambulatory peritoneal dialysis (CAPD) patients [14],
was used to calculate a co-morbidity score. Adequacy of peritoneal dialysis was determined by measurement of Kt/V using a standard method. Serum albumin was measured by bromocresol purple method, and
normalized protein nitrogen appearance (nPNA) was calculated by the
modified Bergström formula and normalized to ideal body weight [15].
The residual glomerular filtration rate was calculated as an average of
24-h urinary urea and creatinine clearance by standard method as described previously [16].
Serological assay
After completion of vaccination, blood samples were collected and measured for anti-HBs at 3, 6 and 12 months after the third dose of Engerix-B,
using a commercial kit with enzyme immunoassay (Cobras Core Anti-HBs
Quant EIA II; Roche Diagnostics GmbH, Mannheim). Antibody concentrations ≥10 IU/l were considered seroprotective. All laboratory personnel
were masked to the group assignment of the analysed sera.
Outcome measures
The primary outcome of interest is seroconversion, defined as hepatitis B
surface antibody (anti-HBs) level ≥10 IU/l 3 months after completion of the
third dose [8,17,18], and the persistence of protective anti-HBs 12 months
after completion of the third dose.
Secondary outcomes included the response to hepatitis B vaccine with
relevant factors including diabetes mellitus, Charlson’s Co-morbidity Index, age, dialysis adequacy, nutritional status and residual renal function.
Statistical analysis
Data were expressed as mean ± SD unless otherwise specified. We calculated geometric mean titres by taking the antilog of the mean of the log
transformation of anti-HBs antibody titres. To identify differences between the two groups, Wilcoxon’s signed rank test for non-parametric data
was used. The parametric and non-parametric variables were compared by
chi-square test, Student’s t-test and Mann–Whitney test where appropriate, between treatment groups. Proportions of seroconverted subjects at
`3 months after completion of immunization and the proportions of seroconverted subjects who lose the antibody by 12 months were compared.
Statistical analysis was performed by SPSS for Windows software version
16.0 (SPSS Inc., Chicago, IL). We considered a P-value <0.05 to be statistically significant. All probabilities were two-tailed. Sample size estimation was based on the primary hypothesis generated from our pilot
study showing that the conventional 40-μg dose of Engerix-B conferred
a 78% protection rate versus 96% in the 80-μg dose group [12], as mea-
Extra-high-dose intramuscular hepatitis B vaccine
2305
Patients consented to participate
(n = 109)
Randomly assigned
(n = 109)
40 microgram Engerix-B dose
80 microgram Engerix-B dose
(n = 50)
(n = 59)
Died (n = 3)
Died (n = 5)
Excluded (n = 2) *
Excluded (n = 1) *
Incomplete vaccination (n = 1)
Incomplete vaccination (n = 1)
Transplanted (n = 2)
Transplanted (n = 1)
Haemodialysis (n = 1)
Withdrew (n = 1) †
Recovery of renal function (n = 1)
Withdrew (n = 2) †
Lost to follow-up (n = 1)
Included in analysis
Included in analysis
40 microgram Engerix-B dose
80 microgram Engerix-B dose
(n = 42)
(n = 45)
* Had missing laboratory data about anti-HBs titres
† Had protocol violation because of occult hepatitis B
Fig. 1. Trial profile: enrolment, random assignment and follow-up of the study participants.
sured by the persistence of the seroprotective levels of anti-HBs at 12
months. The planned sample size and power estimation were generated
using the Power Analysis and Sample Size for Windows software (PASS
2000, NCSS, Kaysville, Utah). Sample sizes of 65 in each treatment arm,
allowing a 10% dropout rate, would therefore achieve 80% (1 − β = 0.80)
power to detect the expected difference between the groups with a significance level (alpha α = 0.05) of 0.05 using chi-square test.
Role of the funding source
The study was funded by the Research Fund for the Control of Infectious
Diseases (RFCID), Food and Health Bureau, Hong Kong Special Administrative Region. The funding source had no role in the study design, data
collection, administration of the interventions, analysis or decision to submit the findings for publication.
Results
Among the 109 patients who were enrolled and vaccinated,
87 completed the study and were included in the final
analysis. Figure 1 shows the flow of participants in the
study. The dropout over the course of the study was linked
to the physical condition of the patients (death, renal recovery, transplantation or switch to haemodialysis), protocol violation or inability to contact the study participants.
None of these events were determined by investigators to
be vaccine or study procedure related.
Of the 87 study subjects, 41% were female, and 52%
had diabetes mellitus; the mean age at the time of the first
dose was 60 years (Table 1). Forty-two patients received
the conventional 40-μg Engerix-B dose, and 45 were assigned to the 80-μg dose. Baseline characteristics did not
differ meaningfully by treatment group, except a higher
percentage of human recombinant erythropoietin use in
the 80-μg Engerix-B group.
No study-related adverse events occurred in any intervention group. None of the patients developed acute hepatitis B infection.
2306
K.M. Chow
Table 1. Comparison of baseline characteristics between the two treatment groups
Number of study subjects
Gender (male: female)
Patient age (years)
Median duration of dialysis (years)
Body mass index (kg/m2)
Percentage of patients with diabetes mellitus
Serum albumin at baseline (g/l)
Charlson’s Co-morbidity Index
Median number of antihypertension medications
Mean arterial blood pressure (mmHg)
Percentage of patients receiving human recombinant erythropoietin
Haemoglobin level at baseline (g/dl)
Median parathyroid hormone at baseline (pmol/l)
Residual GFR (ml/min/1.73 m2)
Total Kt/V
nPNA (g/kg/day)
Vaccination with standard
40-μg Engerix-B
Vaccination with extra-high-dose
80-μg Engerix-B
P-value
42
23:19
59.7 ± 11.1
0.48 (IQR 0.11–1.29)
25.4 ± 6.3
45.2%
35.5 ± 4.9
4.9 ± 2.1
2
92.6 ± 12.4
7.1%
9.2 ± 1.6
30.6 (IQR 18.4–56.4)
3.07 ± 1.87
2.2 ± 0.6
1.14 ± 0.27
45
28:17
59.3 ± 10.6
0.28 (IQR 0.11–2.50)
25.7 ± 4.1
57.8%
35.1 ± 6.2
5.4 ± 1.8
2
96.4 ± 16.8
24.4%
8.8 ± 1.3
40.4 (IQR 19.4–54.1)
3.54 ± 3.37
2.1 ± 0.5
1.07 ± 0.24
0.52
0.86
0.21
0.80
0.29
0.78
0.18
0.33
0.25
0.04
0.23
0.37
0.52
0.34
0.22
GFR, glomerular filtration rate; IQR, interquartile range; nPNA, normalized protein nitrogen appearance.
Primary outcome
The immune response was assessed by anti-HBs antibody
titre at 3 and 12 months after the third dose of Engerix-B.
Overall, 70.1% of patients experienced seroconversion after three doses of Engerix-B. As expected, seroprotection
rates decreased over time in both groups (Figures 2 and 3).
No differences, however, were observed in seroprotection
rates in the 40- and 80-μg Engerix-B treatment groups at
the two predefined time points, including 3 and 12 months
after completing the immunization. The primary end point
of seroconversion (anti-HBs level ≥10 IU/l 3 months after
completion of the third dose) occurred in 78.6% of patients
after 40-μg Engerix-B dosage treatment versus 62.2% for
those receiving 80-μg Engerix-B treatment (P = 0.11). After 12 months, the persistence of protective anti-HBs, another primary end point in this trial, also did not differ
80
Secondary outcomes
The geometric mean antibody titres were estimated longitudinally. The anti-HBs geometric mean titres elicited 3, 6 and
12 months after the third dose of vaccination did not differ
significantly (P > 0.50 at all time points) between the patients assigned to 40- and 80-μg dose (Figure 4). Twelve
months after the third dose of Engerix-B, the anti-HBs geometric mean titres in the two groups were 18.1 IU/l [95%
confidence interval (CI) 15.1–21.2] and 18.2 IU/l (95%
CI 15.2–21.1), respectively (P = 1.00). Repeated measures
analysis of variance (ANOVA) confirmed no difference in
100
79%
P = 0.67
62%
60
45%
51%
40
20
0
3 months after
third dose of
Engerix-B vaccine
12 months after
third dose of
Engerix-B vaccine
Percentage of patients maintaining
anti-HBs levels more than 10 IU/l
Patients with anti-HBs
levels more than 10 IU/l (%)
100
40 mcg dose
80 mcg dose
P = 0.11
between 40- (45.2%) and 80-μg (51.1%) treatment groups
(P = 0.67). A stricter criterion for assessing adequate antiHBs response is sometimes defined as >100 IU/l instead
of ≥10 IU/l in Europe [1]; the percentage of patients with
anti-HBs >100 IU/l after 12 months did not differ between
40- and 80-μg treatment groups (28.6% versus 24.4%,
respectively).
40 mcg dose
80
60
80 mcg dose
40
20
0
0
3
6
9
12
15
Time after the third dose of vaccination (months)
Fig. 2. Percentage of randomized patients who had a seroprotective
hepatitis B virus surface antibody (anti-HBs) titre at 3 and 12 months
after completion of the three-dose Engerix-B vaccination schedule.
Fig. 3. Time to loss of protective hepatitis B virus surface antibody (antiHBs) titre >10 IU/l.
Extra-high-dose intramuscular hepatitis B vaccine
2307
Table 2. Univariate comparison of clinical and laboratory characteristics of hepatitis B vaccine responders and non-responders according to the
anti-HBs titres 3 months after completion of the three-dose Engerix-B vaccination schedule
Number of study subjects
Gender (male: female)
Patient age (years)
Median duration of dialysis (years)
Body mass index (kg/m2)
Percentage of patients with
diabetes mellitus
Serum albumin at baseline (g/l)
Charlson’s Co-morbidity Index
Percentage of patients receiving human
recombinant erythropoietin
Haemoglobin level at baseline (g/dl)
Residual GFR (ml/min/1.73 m2)
Total Kt/V
nPNA (g/kg/day)
Primary responders (anti-HBs
≥10 IU/l 3 months after the
third dose of Engerix-B)
Non-responders (anti-HBs
<10 IU/l 3 months after the
third dose of Engerix-B)
P-value
61
33:28
59.1 ± 9.5
0.46 (IQR 0.11–1.74)
25.4 ± 6.3
47.5%
26
18:8
60.6 ± 13.4
0.32 (IQR 0.09–1.75)
25.7 ± 4.1
61.5%
0.24
0.61
0.65
0.80
0.25
35.8 ± 5.2
4.9 ± 1.9
16.4%
34.0 ± 6.3
5.7 ± 2.0
15.4%
0.16
0.07
1.00
9.0 ± 1.4
3.02 ± 2.37
2.2 ± 0.5
1.16 ± 0.25
8.9 ± 1.8
4.17 ± 3.46
2.1 ± 0.8
0.96 ± 0.23
0.82
0.28
0.79
0.001
GFR, glomerular filtration rate; IQR, interquartile range; nPNA, normalized protein nitrogen appearance.
months after the third dose of Engerix-B also correlated
with the persistence of anti-HBs protection 12 months later
(Table 3). There was a large difference in the geometric
mean titres of anti-HBs at 3 months between patients with
and without persistent seroprotective anti-HBs level 12
months after the last dose, 357 versus 9 IU/l, respectively
(P < 0.00001).
Discussion
Despite early evidence suggesting beneficial effect of extra-high-dose recombinant hepatitis B vaccination [12],
our data from this randomized controlled trial do not support that 80-μg Engerix-B dose results in extra clinical
benefit compared with the standard 40-μg dose. No seroprotective improvements in terms of primary seroconversion or longevity of seroprotective anti-HBs antibody
titres were seen. On the other hand, a post hoc analysis
Hepatitis B antibody geometric mean titre
the antibody titres between the groups throughout the study
period.
Analyses were performed to determine whether the ability to achieve primary anti-HBs seroconversion differed according to the baseline clinical characteristics and dialysis
dose. Table 2 compared the characteristic of patients who
exhibited an antibody to the anti-HBs level ≥10 IU/l (seroconversion) and <10 IU/l 3 months after the last dose of
Engerix-B. Patients who had higher baseline nPNA were
more likely to develop anti-HBs ≥10 IU/l at 3 months
(Table 2). The mean nPNA values were significantly higher
for patients who developed seroconversion versus patients
without seroconversion (1.16 ± 0.25 versus 0.96 ± 0.23 g/
kg/day, P = 0.001). The odds for developing seroconversion were four times (odds ratio 4.01, 95% CI 1.48–
11.00, P = 0.006) greater for patients with nPNA at least
1 g/kg/day. Conversely, the higher total Kt/V and residual
renal function did not improve the chance of developing
seroprotective anti-HBs titre. We also found no significant
correlation between primary seroconversion rate and patient age. Although patients with primary seroconversion
had a tendency of lower Charlson’s Co-morbidity Index
(4.9 ± 1.9 versus 5.7 ± 2.0), it did not reach statistical significance (P = 0.07). An additional analysis was performed
using the anti-HBs level > 100 IU/l (data not shown);
nPNA values remained to have significant association with
this criterion of immunogenicity.
When we divided patients into two groups on the basis
of persistent anti-HBs level 12 months after the last dose
of Engerix-B treatment (Table 3), we again found a higher
baseline nPNA values in those with persistent seroprotective anti-HBs level (1.18 ± 0.24 versus 1.03 ± 0.25 g/kg/
day, P = 0.007). In contrast, there were no significant differences in persistence of anti-HBs serological protection
between patients with and without diabetes. Baseline serum albumin concentration, haemoglobin level, Charlson’s Co-morbidity Index, total Kt/V and residual renal
function did not influence the persistence of anti-HBs seroprotection. The geometric mean titres of anti-HBs 3
80
P = 0.65
60
40 mcg dose
80 mcg dose
P = 0.67
40
P = 1.00
20
0
0
3
6
9
12
Months after the third dose of Engerix-B vaccine
Fig. 4. Changes from baseline to 12 months in geometric mean titre of
hepatitis B virus surface antibody (anti-HBs). I bars indicate the 95%
confidence intervals.
2308
K.M. Chow
Table 3. Univariate predictors of long-term seroprotection as defined by the anti-HBs titres 12 months after completion of the three-dose Engerix-B
vaccination schedule
Number of study subjects
Gender (male: female)
Patient age (years)
Median duration of dialysis (years)
Body mass index (kg/m2)
Percentage of patients with diabetes mellitus
Serum albumin at baseline (g/l)
Charlson’s Co-morbidity Index
Percentage of patients receiving human
recombinant erythropoietin
Haemoglobin level at baseline (g/dl)
Residual GFR (ml/min/1.73 m2)
Total Kt/V
nPNA (g/kg/day)
Anti-HBs geometric mean titres (GMT) 3 months
after the third dose of Engerix-B (IU/l)
Patients with anti-HBs ≥10 IU/l
12 months after the third dose
of Engerix-B
Patients with anti-HBs <10 IU/l
12 months after the third dose
of Engerix-B
P-value
42
21:21
58.3 ± 10.8
0.36 (IQR 0.11–1.59)
25.5 ± 4.1
47.6%
35.7 ± 4.8
4.9 ± 2.0
21.4%
45
30:15
60.6 ± 10.7
0.36 (IQR 0.11–2.08)
25.5 ± 6.2
55.6%
34.9 ± 6.2
5.4 ± 1.9
11.1%
0.13
0.32
0.92
0.99
0.52
0.50
0.22
0.25
8.9 ± 1.5
3.23 ± 2.50
2.3 ± 0.5
1.18 ± 0.24
357 (95% CI 356–359)
9.0 ± 1.5
3.38 ± 2.95
2.1 ± 0.6
1.03 ± 0.25
9 (95% CI 7–11)
0.71
0.84
0.12
0.007
<0.00001
Anti-HBs, anti-hepatitis B surface antibody; CI, confidence interval; GFR, glomerular filtration rate; IQR, interquartile range; nPNA, normalized
protein nitrogen appearance.
showed that the amount of dietary protein intake, as measured by normalized protein nitrogen appearance, is predictive of the response to the recombinant hepatitis B
vaccine.
An important limitation of our trial concerns the issue of
patient selection. As noted, the mean age of patients was
60 years, much older than the cohort in our previous retrospective study having a mean age of 43 years [12]. It is
noteworthy that an inverse relationship between age and
response to hepatitis B vaccine had long been recognized
in numerous studies involving patients on dialysis [12,19–
21]. A clear relationship between old age and impaired immunological response to hepatitis B vaccine among endstage renal disease patients is further supported by a
meta-analysis [22]. This also explains a lower primary seroconversion rate (70.1%) and less impressive long-term
immunogenicity (48.3% at 1 year) in the current study. Although our result leaves unresolved the question of whether
younger patients with end-stage renal disease might have
benefited from extra-high-dose recombinant hepatitis B
vaccination, our trial population was nonetheless intended
to be representative of ‘real-world’ practice. Recognizing
the preferred strategy of vaccination at an earlier stage of
chronic kidney disease [23,24], an accumulating number
of the younger generation patients have received hepatitis
B vaccination before the start of dialysis therapy. Increasing
attention to or better awareness of early vaccination explains why we included patients with relatively older age
in this randomized trial than those in past studies.
Another unavoidable limitation of our study is that, with
the number of recruited cases falling short of the planned
sample size (109 instead of 130), we cannot fully exclude a
type II error. A third limitation of our study relates to our
inability to distinguish whether the seroprotective efficacy
of extra-high-dose Engerix-B can be improved by a different four-dose schedule (0, 1, 2, and 6 months) [25]. This
regime was not commonly practised at the time of our
planning the trial; a Cochrane review did not support the
administration of more than three doses of recombinant
vaccine for patients with chronic renal failure [1]. Furthermore, the role of intradermal recombinant hepatitis B vaccine [26] and adjuvant-enhanced vaccine formulations
[27], recently tested promising strategies, was not tested
in the current study.
In our study, an increase in the estimated protein intake
was associated with a statistically significant improvement
in primary seroprotective response 3 months after intramuscular Engerix-B vaccination. The relationship between
the longevity of maintaining seroprotective anti-HBs titre
and a higher nPNA was persistently evident after 1 year.
Although this is an unplanned analysis, it is our view that
the observation is worth exploring. There are a very few
data on the relationship between protein–energy malnutrition and end-stage renal disease patients' antibody production response after hepatitis B vaccination. Reasons for the
impaired immunological response with protein–energy
malnutrition include lower granulocyte–macrophage–
colony-stimulating factor (GM–CSF), among other relevant cytokine responses. Data from animal and human
studies have indicated that protein–energy malnutrition
leads to deficiency or impaired response of GM–CSF
[28,29]. It is of clinical interest that GM–CSF administration to end-stage renal disease patients, as shown in numerous clinical trials [30–32] and two meta-analyses
[33,34], significantly improves the hepatitis B vaccine response rate and achieves an earlier seroconversion to the
vaccine. This seems to be in line with our data showing
the relationship between nPNA and hepatitis B vaccine
response.
In summary, evidence from this multi-centre randomized
controlled trial involving 87 peritoneal dialysis patients
with a mean age of 60 years demonstrated no overall significant differences in the hepatitis B vaccine response after 80-μg intramuscular Engerix-B doses. On the basis of
Extra-high-dose intramuscular hepatitis B vaccine
current data, the routine extra-high-dose intramuscular
hepatitis B vaccination seems premature.
Acknowledgements. This study was supported by the Research Fund for
the Control of Infectious Diseases (RFCID) (Project Reference 06060072),
Food and Health Bureau, Hong Kong Special Administrative Region. We
thank Ms. Shirley Sun Kiu Tsang for the clerical support.
Conflict of interest statement. None declared.
References
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Received for publication: 18.12.09; Accepted in revised form: 4.2.10