A Randomized Clinical Trial of Immunization With Combined Hepatitis A

and B Versus Hepatitis B Alone for Hepatitis B Seroprotection in

Hemodialysis Patients
Jennifer Tung, BScPhm,1 Euan Carlisle, MD,2 Marek Smieja, MD, PhD,2 Peter T. Kim, PhD,3 and
Christine H. Lee, MD2

Background: The Centers for Disease Control and Prevention recommend immunizing susceptible
high-risk groups, such as hemodialysis patients, against hepatitis B virus. However, hemodialysis
patients may not develop seroprotective antibodies despite receiving high doses of the vaccine. Recent
reports indicate that combined vaccination against hepatitis B and hepatitis A viruses may improve the
immunogenicity of hepatitis B vaccine in healthy individuals, but the effectiveness of this strategy in
hemodialysis patients is unknown.
Study Design: Prospective randomized controlled trial.
Setting & Participants: Hepatitis B virus–seronegative hemodialysis patients with undetectable
antibody levels at baseline.
Intervention: Intramuscular administration of Twinrix (inactivated hepatitis A virus [720 ELISA units]
and purified hepatitis B virus surface antigen [20 ␮g]; GlaxoSmithKline) and Engerix-B (purified hepatitis
B virus surface antigen [20 ␮g]) at 0, 1, and 6 months plus Engerix-B, 40 ␮g, at month 2 (intervention
arm) or Engerix-B, 40 ␮g, at 0, 1, 2, and 6 months (control arm). Both groups received a total dose of 160
␮g of hepatitis B antigen.
Outcomes: The primary outcome was the difference in seroprotection rates at 7 months, defined by
antibody titers ⬎10 mIU/mL. The secondary outcome was frequency of adverse events.
Measurements: Antibody response at months 3 and 7.
Results: 96 patients were enrolled, and 73 completed the investigation. At 3 months, there was no
difference in the groups’ seroprotection rates (25% vs 27%; P ⫽ 0.4). At the completion of the vaccination
series, using per-protocol analysis, 27 of 40 (68%) and 16 of 33 (49%) had antibody titers ⬎10 mIU/mL in the
treatment and control groups, respectively (P ⫽ 0.05; RR, 1.4; absolute abatement, 19%). Intention-to-treat
analysis showed 58% and 38% seroprotection rates in the treatment and control groups, respectively (P ⫽
0.02; RR, 1.5; absolute abatement, 20%). There was no difference in adverse events.
Limitations: Lack of evidence of long-term protection.
Conclusion: Vaccination of hemodialysis patients with a combined hepatitis A and hepatitis B
regimen resulted in a statistically significant and clinically important improvement in seroprotection
against hepatitis B virus compared with hepatitis B monovalent vaccine.
Am J Kidney Dis 56:713-719. © 2010 by the National Kidney Foundation, Inc.

INDEX WORDS: Hepatitis B vaccine; hemodialysis; hepatitis B seroprotection.

acute infections.6 However, many hemodialysis

H epatitis B is a human viral pathogen that is
a major cause of mortality and morbidity.
With approximately 20 million new cases re-
ported annually, the World Health Organization
estimates that 350 million people are chronically
infected worldwide.1 In Canada, there are an
estimated 250,000 cases of hepatitis B infec-
tion.2 According to the Canada Communicable
Disease Report, the incidence rate of clinically
recognized acute hepatitis B infection is 2.3
cases/100,000, or approximately 700 cases per
year,3 and in the United States, the reported
incidence is similar at 1.5 cases/100,000.4 Since
1990, the rate of incidence in both countries has
decreased significantly with the introduction of
immunization programs.4,5
In contrast to healthy adults, hemodialysis
patients usually experience mild asymptomatic
patients progress to chronic infection and remain
highly contagious.7 These factors contributed to
the large-scale outbreaks in dialysis centers in
the 1970s. The routes of transmission of the virus
From 1St. Joseph’s Healthcare; 2McMaster University,
Hamilton; and 3Department of Math and Statistics, Univer-
sity of Guelph, Guelph, Ontario, Canada.
Received November 30, 2009. Accepted in revised form
April 15, 2010. Originally published online as doi:10.1053/
j.ajkd.2010.04.015 on July 14, 2010.
Trial registration: www.ClinicalTrials.gov; study num-
ber: NCT00186836
Address correspondence to Christine H Lee, McMaster Uni-
versity, Hamilton, ON, Canada. E-mail: clee@mcmaster.ca
© 2010 by the National Kidney Foundation, Inc.
0272-6386/10/5604-0015$36.00/0
doi:10.1053/j.ajkd.2010.04.015

American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp 713-719 713
714
are well established: direct percutaneous inocula-
tion of virus through exchange of contaminated
blood, blood products, body fluids, and hemodi-
alysis.
The current recommendation by the Centers
for Disease Control and Prevention is to immu-
nize susceptible high-risk groups, which in-
cludes patients undergoing hemodialysis. After a
primary series of hepatitis B vaccination, 90%-
95% of healthy immunocompetent adults de-
velop protective anti–hepatitis B surface antigen
(HBsAg) antibodies, defined as ⬎10 mIU/mL.
However, the overall efficacy of the vaccine in
hemodialysis patients is found to be much lower,
with a median of 64% (range, 34%-88%) and
86% (range, 40%-98%) developing seroprotec-
tive antibody even after receiving higher doses
of the monovalent vaccine with 3- or 4-dose
regimens, respectively.8
As a result, numerous approaches to improve
immunization have been attempted, including varia-
tions in dose and frequency,9,10 use of novel adju-
vants,11,12 and coadministration of immunomodula-
tors, such as interleukin 2,13 interferons,14,15
levamisole,16 glycophosphopeptical (AM3; mar-
keted as Inmunoferon),17 and thymopentin,8 all
with varying results. Intradermal administration
also has been studied, and a recent study using
smaller more frequent doses of intradermal vaccina-
tion has proved to be successful.18
To date, there are limited data about hepatitis
A vaccine immunogenicity in hemodialysis pa-
tients, although findings have indicated that vac-
cination is feasible, well tolerated, and as effec-
tive as in healthy individuals, with seroconversion
rates of up to 100% in hemodialysis patients with
intramuscular vaccination.19
Recent reports suggest that combined vaccina-
tion of hepatitis B and hepatitis A may improve
immunogenicity to hepatitis B in healthy indi-
viduals. In 1 study that compared the geometric
mean of anti-HBsAg titers at month 6, patients
receiving the combined vaccine showed a statis-
tically significant higher response than with
monovalent vaccines.20 Other studies also reflect
the same trend at varying points in the vaccina-
tion series.21-24
There currently are 2 monovalent recombinant
hepatitis B vaccines on the market in Canada:
Recombivax HB (Merck Frosst, www.merckfrosst.ca)
and Engerix-B (GlaxoSmithKline; www.gsk.com).25
Tung et al
Twinrix (GlaxoSmithKline) is the only combined
hepatitis A and hepatitis B vaccine available (the
hepatitis B components are the same as used in
the Engerix-B vaccine). Both monovalent and
combined hepatitis A and B vaccines have simi-
lar adverse-event profiles.
Although promising results of combined hepa-
titis A and B vaccine have been shown in healthy
adults, the effect of combined vaccination on
anti-HBsAg antibody response in hemodialysis
patients is unknown. The hemodialysis program
at St. Joseph’s Healthcare in Hamilton, Ontario,
Canada, has a current enrollment of approxi-
mately 500 patients, most of whom are suscep-
tible to hepatitis B virus infection. We designed
this randomized controlled trial to investigate the
difference in efficacy in developing protective
antibody response and adverse reactions be-
tween the combination hepatitis A and B vaccine
versus monovalent hepatitis B vaccine alone in
hemodialysis patients attending the hemodialysis
clinic.
The primary objective is to determine whether
vaccinating hemodialysis patients with com-
bined hepatitis A and B vaccine resulted in a
statistically significant difference in anti-HBsAg
antibody response compared with monovalent
hepatitis B vaccine. (Clinically important anti-
body response is defined as the development of
at least a 10-mIU/mL concentration of anti-
HBsAg antibodies.) The secondary objective is
to determine the frequency of adverse events
associated with the vaccine administration.
METHODS
Setting and Participants
This was a prospective randomized controlled trial in
outpatient hemodialysis patients. Patients were identified
through the Infection Prevention and Control Department at
St. Joseph’s Healthcare. There was a program-wide screen-
ing for hepatitis B virus infection susceptibility and immu-
nity at the time of this study. Hepatitis B virus–susceptible
patients were given an option of participating in the study.
Hemodialysis patients presenting to the St. Joseph’s
Healthcare Centre hemodialysis outpatient department were
eligible provided they met the following inclusion and
exclusion criteria. Inclusion criteria were receiving hemodi-
alysis treatment, 18 years or older, undetectable antibody to
HBsAg, and able and willing to give informed consent.
Exclusion criteria were the presence of HBsAg and antibody
to hepatitis B core antigen, treatment with intravenous
immune globulin within the last 6 months, hypersensitivity
to components of either vaccine, and contraindication to
Hepatitis A and B Versus Hepatitis B for Hepatitis B Seroprotection in Hemodialysis Patients
intramuscular injections. Patients were not excluded based
on pre-existing antibodies to hepatitis A.
Consents were obtained and patients were randomly as-
signed starting in February 2005. Vaccination began in
March 2005, and the vaccination schedules were completed
by November 2005. Ethics approval was obtained from the
St. Joseph’s Healthcare Research Ethics Board. Consent was
obtained initially by the nephrology research nurse, then
later in the study by a physician and study coordinator.
Study Design
Patients were given 4 doses at 0, 1, 2, and 6 months
according to the vaccine schedule and were randomly as-
signed to receive one of the following regimens (Fig 1):
Engerix-B, 20 ␮g (1 mL), and Twinrix (720 ELISA units of
inactivated hepatitis A virus and 20 ␮g of recombinant
HBsAg protein) at 0, 1, and 6 months plus Engerix-B, 40 ␮g,
at month 2 or Engerix-B, 40 ␮g (2 mL), at 0, 1, 2, and 6
months. Both groups received a total dose of 160 ␮g of
hepatitis B vaccine. The route of administration was intramus-
cular injection.
The primary outcome was the difference in proportion of
patients achieving seroprotection against hepatitis B virus
between the 2 arms, with seroprotection defined as an
anti-HBsAg antibody titer ⬎10 mIU/mL at month 7. The
secondary end point was the frequency of adverse events
associated with vaccine administration.
Consents were obtained by a research nurse, and partici-
pants were randomly assigned to receive either the combina-
tion vaccination (ie, Twinrix and Engerix-B) or monovalent
hepatitis B vaccination (ie, Engerix-B). Blood samples were
drawn at baseline and months 3 and 7 to determine antibod-
ies to HBsAg.
For practical reasons, neither patients nor clinical study
personnel were blinded with respect to the vaccine adminis-
Figure 1. Vaccination and blood work regimen.
715
tered. The laboratory personnel performing tests for anti-
body levels and the independent statistician assessing clini-
cal outcomes were blinded.
Adverse events were recorded after each dose. Patients
were interviewed to obtain ratings for pain and swelling,
which were evaluated using a visual analogue scale. Tempera-
tures were measured 1 hour after vaccination and on days 2
and 4. Fever was defined as temperature ⬎37.5°C. Adverse
events also were documented in the patient chart by the
hemodialysis nurses. When there was a language barrier and
no translators were available, the chart was consulted.
Statistical Analysis
In planning this study, calculations were based on a 50%
seroconversion rate with attrition of about 20% due to age
and other considerations in the population base. A 30%
difference in seroconversion rates between treatment groups
was considered effective. This determined a sample size of
48 per group, yielding 80% power and 5% effect size.
Descriptive statistics are expressed in terms of mean ⫾
standard deviation for continuous variables and percentages
for categorical variables. Standard statistical tests for com-
paring mean values, unpaired t test, and unpaired proportion
tests were used to assess treatment differences.
RESULTS
Patient Characteristics
The flow diagram (Fig 2) outlines the events
of this study. In particular, 454 patients were
screened for eligibility. Three hundred fifty-eight
patients were excluded based on the following:
226 did not meet inclusion criteria, and others
did not wish to participate, already received a
dose of hepatitis B vaccine, or needed time to
discuss with family member/own nephrologist.
A total of 96 hemodialysis patients were en-
rolled. Twelve patients died (including 1 who
died before the first dose), 3 withdrew from the
study, 6 were lost to follow-up, and 2 were
excluded for protocol deviation. Of 96 patients
originally enrolled, 73 completed the study, for
which per-protocol analysis was performed. For
robustness, we also performed an intention-to-
treat (ITT) analysis. As mentioned, several pa-
tients had incomplete data, with some having no
seroprotection measurements performed, and oth-
ers having only a month-3 seroprotection mea-
surement recorded. In the first case (no measure-
ments), we assumed that the patient did not reach
seroconversion at the end of month 3 and month
7. For patients obtaining seroprotection measure-
ment at the end of month 3 only, we assumed that
value for the month-7 measurement as well.
716
Table 1 summarizes the patient population in
terms of the per-protocol and ITT analyses. Over-
all, mean age was 67 years (range, 34-91 years),
and 63% were men. Duration of dialysis therapy
ranged from 10 days to 9 years, with a mean of 3
years. Patient characteristics in both study groups,
as well as in the per-protocol and ITT analyses,
were similar with regard to mean years on dialysis
therapy, rate of diabetes mellitus, and cardiovascu-
lar disease. More patients in the treatment group
were receiving immunosuppressants at the begin-
ning of the vaccination series, including prednisone
and sirolimus. In terms of age, for the per-protocol
analysis, there was no statistically significant differ-
ence. However, for the ITT analysis, one notices a
statistical difference in that the control group was
older. Although we believe this factor does not
affect the outcome, it is interesting to remark that
this perhaps explains why fewer patients in the
control group completed this study.
Tung et al
Figure 2. Flow diagram of
hepatitis B vaccination of he-
modialysis patients.
Month-7 Blood Work
After completion of the vaccination series,
there was a statistically significant difference in
anti-HBsAg antibody response between the 2
groups using either per-protocol or ITT analyses.
At month 7, using per-protocol analysis, 68%
and 49% of patients had experienced seroconver-
sion in the treatment and control groups, respec-
tively (P ⫽ 0.05; relative risk, 1.4; absolute
abatement, 19%). Using ITT analysis, 58% and
38% of patients had experienced seroconversion
in the treatment and control groups, respectively
(P ⫽ 0.02; relative risk, 1.5; absolute abatement,
20%).
Month-3 Blood Work
There was no statistically significant differ-
ence in seroprotection rates for hepatitis B be-
tween the 2 groups. At month 3, using per-
Hepatitis A and B Versus Hepatitis B for Hepatitis B Seroprotection in Hemodialysis Patients 717

Table 1. Patient Characteristics Between Study Groups Adverse Events

Treatment Control P There were no significant differences between
groups in pain scores or swelling scores (Table
Entire population 2). Two patients experienced fever within 4 days
PP 40 33 of receiving the vaccine; 4 patients experienced
ITT 48 48
systemic side effects, such as lethargy, aches, or
Men other flu-like symptoms; 1 patient had nausea;
PP 23 (58) 24 (72) 0.2 and 1 patient experienced severe bruising at the
ITT 27 (56) 33 (69) 0.2 vaccine site.
Mean years on dialysis DISCUSSION
PP 2.7 ⫾ 2.3 2.6 ⫾ 1.9 0.6
ITT 2.7 ⫾ 2.3 2.7 ⫾ 1.9 0.2 This was a randomized controlled study to
examine the effects of adding hepatitis A vaccina-
Age (y)
PP 65.1 ⫾ 13.3 68.3 ⫾ 13.7 0.3 tion to the standard hepatitis B vaccination series
ITT 69.4 ⫾ 13.6 70.1 ⫾ 13.1 0.04 in hemodialysis patients. The study’s main out-
come, hepatitis B seroconversion at 7 months,
Diabetes mellitus
showed a statistically significant and clinically
PP 19 (48) 14 (42) 0.6
ITT 24 (50) 25 (52) 0.8 important improvement in the combined-vaccina-
tion arm. Preliminary blood work was drawn at
Cardiovascular disease month 3 to determine whether the combined
PP 31 (78) 30 (91) 0.1
regimen would induce seroprotection at a faster
ITT 38 (80) 43 (90) 0.2
rate; however, results did not support this hypoth-
Immunosuppressant esis.
use Adverse events were similar to those previ-
PP 5 (13) 3 (9) 0.6
ously reported.1 Of interest, there is no statistical
ITT 8 (17) 4 (8) 0.2
difference in pain scores, although patients in the
Note: Values expressed as mean ⫾ standard deviation
combined-regimen group received 2 injections
or number (percentage). Treatment consists of administra-
tion of Twinrix and Engerix-B; control is administration of per dose. Reporting of adverse events was lim-
Engerix-B only. ited by recall bias and translation bias if the
Abbreviations: PP, per-protocol; ITT, intention-to-treat. patient was not English speaking.
In comparison to healthy persons, who have a
protocol analysis, 25% and 27% of patients reported 89% seroprotection rate at month 3 and
achieved seroprotection in the combined-regi- 90%-95% at month 7 with standard dosing, sero-
men and control groups, respectively (P ⫽ 0.4). protection rates in this study population were
Using ITT analysis, 23% and 21% of patients much lower.26 This is not surprising because
achieved seroprotection in the combined-regi- chronic renal failure often is associated with
men and control groups, respectively (P ⫽ 0.4). compromised immune function.27 However, in

Table 2. Pain and Swelling Ratings

Treatment Control P

Pain ratings
Dose 1 0.65 ⫾ 1.40 (n⫽34) 0.31 ⫾ 0.82 (n⫽34) 0.2
Dose 2 1.00 ⫾ 2.53 (n⫽38) 0.47 ⫾ 1.34 (n⫽34) 0.3
Dose 3 0.35 ⫾ 1.53 (n⫽39) 0.39 ⫾ 1.84 (n⫽33) 0.9

Swelling ratings
Dose 1 0.13 ⫾ 0.65 (n⫽33) 0.04 ⫾ 0.18 (n⫽35) 0.5
Dose 2 0.13 ⫾ 0.84 (n⫽39) 0.00 ⫾ 0.00 (n⫽35) 0.4
Dose 3 0.00 ⫾ 0.00 (n⫽41) 0.29 ⫾ 1.69 (n⫽35) 0.3
Note: Treatment consists of administration of Twinrix and Engerix-B; control is administration of Engerix-B only. Ratings
are from a 12-point (cm) scale.
718
our population, the seroprotection rate in our
control group also was lower compared with
previous studies of hemodialysis patients, in
which median seroprotection rates of 64%-86%
were reported.8 There are a number of factors
that decrease response to hepatitis B vaccination,
including sex, age, HLA type, and nutritional
status.28 Of these, older age and male sex may
have had a significant impact in decreasing sero-
conversion rates in this study.28 We have not had
the opportunity to examine other possible factors
that led to low seroprotection rates in our study.
At the beginning of the study, there were 454
patients in St. Joseph’s hemodialysis program, of
whom 131 were immune to hepatitis B virus by
vaccination or past infection. There may be a
potential benefit in providing this regimen in
place of the monovalent vaccine, especially for
patients who do not respond to revaccination
after failure with a primary series.
Identifying a vaccine regimen that is most effec-
tive in preventing hepatitis B virus infection in
patients undergoing hemodialysis will be important
in reducing the risk of morbidity and mortality
secondary to this infection. Furthermore, this will
have a positive impact on health care costs by
reducing additional laboratory investigations and
treatment and shorten the number of inpatient hos-
pital days. Nevertheless, the benefit of adding Twin-
rix to the hepatitis B immunization regimen must
be weighed against the added costs of the drug.
Using average wholesale prices, the combined vac-
cination regimen costs US $488.90, whereas the
monovalent vaccine regimen costs US $292.64.29
However, at our institution, a patient who has not
achieved seroprotection at month 7 will receive a
second vaccination series; thus, successful vaccina-
tion with the combined regimen may result in drug
cost savings compared with 2 consecutive monova-
lent vaccination series (which would cost $585.28).
Limitations in this study include its small sample
size. Recruitment was limited by the short duration
of the study. In addition, at the time of the study, a
program-wide hepatitis B immunization was initi-
ated in hemodialysis patients at the hospital. Be-
cause of the delay in initiating the study, many
originally susceptible patients were already in the
process of receiving the vaccine within this pro-
gram before the study had begun. The short study
period also did not allow for evaluation of the
Tung et al
duration of a patient’s seroprotection or determine
the need for future booster shots or revaccination.
Concurrent to the study was an initiative for
program-wide hepatitis B vaccination. Initially, there
was a designated registered nurse to administer all
hepatitis vaccines. Midway through the study, there
was a change in policy for bedside nurses to admin-
ister vaccines and during the period when nurses
were trained, some doses in the vaccination sched-
ule were delayed. It is unclear whether this would
have an impact on results.
Laboratory personnel were blinded. Because
the primary outcome is objective, not blinding
the patients and clinical study personnel would
not be expected to bias the outcome.
Vaccination against hepatitis A virus in dialy-
sis patients is not routinely performed because it
is neither associated with hemodialysis therapy
nor transmitted through parenteral mechanisms.30
There also is no documented evidence for ad-
verse events associated with vaccination of pa-
tients previously immune to hepatitis A virus,
although these patients may experience a postvac-
cination increase in the geometric mean titer of
anti–hepatitis A virus antibody. We therefore did
not assess pre-existing antibodies for hepatitis A
virus at the beginning of the study.19
Since the start of this study, there have been
new strategies to improve immunization re-
sponse. Although not yet approved in Canada
and the United States, HBV-AS04 (Fendrix;
GlaxoSmithKline) has been widely used. This
new hepatitis B vaccine uses an adjuvant system
consisting of an aluminum salt and MPL (3-O-
desacyl-4=-monophosphoryl lipid A) that has been
shown to elicit an earlier immunogenic response,
higher antibody titers, and higher persistence of
seroprotection at 42 months compared with the
standard hepatitis B vaccine (Engerix), which
uses aluminum hydroxide.11,12 Because HBV-
AS04 may become standard therapy, future stud-
ies comparing combination vaccination with this
new formulation should be considered.
In conclusion, there was a statistically significant
difference in seroprotection between the 2 groups
at the completion of the vaccination series. Vaccina-
tion of hemodialysis patients with a combined
hepatitis A and hepatitis B regimen may be more
effective than hepatitis B monovalent vaccine in
providing seroprotection against hepatitis B virus.
Hepatitis A and B Versus Hepatitis B for Hepatitis B Seroprotection in Hemodialysis Patients
ACKNOWLEDGEMENTS
The authors acknowledge the assistance of Stephanie
Trowbridge and Anna Lisa Athaide for providing back-
ground information related to the hepatitis B immunization
program for St. Joseph’s Healthcare Hemodialysis Unit,
Santina Castriociano for coordinating specimen collection,
and the Virology Laboratory in Hamilton Regional Labora-
tory Medicine Program for serologic testing.
Support: Vaccines used in the trial were provided by St.
Joseph’s Healthcare Pharmacy Department. This study did
not have industry funding.
Financial disclosure: The authors declare that they have
no relevant financial interests.
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