LIVER TRANSPLANTATION 14:435– 442, 2008

ORIGINAL ARTICLE

Antibody To Hepatitis B Surface Antigen Trough

Levels and Half-Lives Do Not Differ After
Intravenous and Intramuscular Hepatitis B
Immunoglobulin Administration After Liver
Transplantation
Nazanin Hooman,1 Kinan Rifai,1 Johannes Hadem,1 Bernhard Vaske,2 Gunnar Philipp,4 Andrea Priess,4
Juergen Klempnauer,3 Hans L. Tillmann,5 Michael P. Manns, and Jens Rosenau1
1
Departments of Gastroenterology, Hepatology, and Endocrinology, 2Biometry, and 3Visceral and
Transplant Surgery, Medizinische Hochschule Hannover, Hannover, Germany; 4CSL Behring, Marburg,
Germany; and 5Medical Department II, Universitätsklinikum Leipzig, Leipzig, Germany

Hepatitis B immunoglobulin (HBIG) administration remains an essential component of standard reinfection prophylaxis after liver
transplantation for hepatitis B virus–related liver disease. Previous studies have suggested that intramuscular (IM) HBIG
administration compared to intravenous (IV) HBIG administration may be cost-effective and dose-saving. To compare antibody
against hepatitis B surface antigen (anti-HBs) kinetics after IV HBIG administration versus IM HBIG administration, 24 patients
received 2000 IU of HBIG every 6 weeks over a study period of 48 weeks in a crossover design. HBIG was started intravenously
in 12 patients (group A) and intramuscularly in 12 patients (group B). After 4 doses, at week 24 HBIG administration was switched
from IM to IV and vice versa. Anti-HBs kinetics of 22 patients were evaluated. Mean anti-HBs levels measured 2, 4, and 6 weeks
after each HBIG administration did not differ significantly (480 ⫾ 166, 319 ⫾ 126, and 221 ⫾ 106 IU/L after IV administration versus
457 ⫾ 166, 310 ⫾ 147, and 218 ⫾ 112 IU/L after IM administration). Half-lives of anti-HBs decline (IV, 25.5 ⫾ 6.0 days, versus IM,
24.7 ⫾ 6.2 days) and area under the curve values from week 2 to 6 (IV, 9.4 ⫾ 3.6 IU*day/mL, versus IM, 9.0 ⫾ 3.9 IU*day/mL) also
showed no significant difference. Variation of anti-HBs levels after IV HBIG administration versus IM HBIG administration was neither
significantly different within patients (intraindividual variance) nor between patients (interindividual variance). However, intraindividual
variance was lower than interindividual variance after IV (P ⬍ 0.05) and IM (P ⬍ 0.05) HBIG administration at every time point (2,
4, and 6 weeks). In conclusion, IV HBIG administration and IM HBIG administration are equally effective with respect to the crucial
pharmacokinetic parameters. That is, IM HBIG is not dose-saving; however, it may be cost-effective if the price per unit is lower.
Individualized dosing intervals should be further evaluated as a cost-effective alternative to fixed dosing schemes. Liver Transpl
14:435– 442, 2008. © 2008 AASLD.

Received June 6, 2007; accepted August 28, 2007.

nucleotide analogues, remains the gold standard for

See Editorial on Page 423 hepatitis B reinfection prophylaxis after liver transplan-
tation.1-3 With the introduction of HBIG monoprophy-
Long-term administration of hepatitis B immunoglobu- laxis 2 decades ago, reinfection rates were reduced sig-
lin (HBIG), currently in combination with nucleoside or nificantly from about 80% to about 30%-50%, and the

Abbreviations: anti-HBs, antibody against hepatitis B surface antigen; AUC, area under the curve; BMI, body mass index; HBIG,
hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDV, hepatitis D virus; IM, intramuscular;
IV, intravenous; OLT, orthotopic liver transplantation; SC, subcutaneous; SD, standard deviation.
Supported by CSL-Behring (Marburg, Germany).
Address reprint requests to Jens Rosenau, M.D., Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hoch-
schule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Telephone: ⫹49-511-532-3305; FAX: ⫹49-511-532-4896;
E-mail: rosenau.jens@mh-hannover.de
DOI 10.1002/lt.21343
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2008 American Association for the Study of Liver Diseases.

436 ROSENAU ET AL.
beneficial effect of long-term immunoprophylaxis com-
pared to short-term prophylaxis was established.4,5
With combined treatment of HBIG and antiviral drugs,
currently lamivudine and adefovir, the risk of hepatitis
B virus (HBV) reinfection has been further reduced be-
low 10% during the first 2 years following transplanta-
tion.1-3 Combined long-term treatment is considered
the safest prophylactic strategy available, at least in
nonresponders to active vaccination.1-3 However, costs
for combined treatment, in particular for HBIG, are
tremendous.
As one strategy to reduce costs, conversion from
intravenous (IV) to intramuscular (IM) HBIG admin-
istration has been proposed and evaluated. The au-
thors of those studies concluded that IM HBIG
administration may be cost-effective and even dose-
sparing.6-8 Many transplant centers use HBIG prep-
arations for IM use as standard treatment with good
success9-18 because of the unavailability of IV HBIG
preparations or potential cost effectiveness. However,
pharmacokinetic data on IM HBIG use are rare,19
especially comparative data with IV administra-
tion.6,7
Our study provides comparative pharmacokinetic
data for IV and IM HBIG use derived from a high num-
ber of measured antibody against hepatitis B surface
antigen (anti-HBs) levels in a fairly large number of
patients as a basis for rationally deciding whether or
not to use IM HBIG.
PATIENTS AND METHODS
Patients
Twenty-four patients receiving long-term hepatitis B
reinfection prophylaxis for at least 12 months after liver
transplantation for HBV-related liver failure were en-
rolled between December 2003 and June 2004. All pa-
tients had received high-dose HBIG in the initial phase
after orthotopic liver transplantation [OLT; 10,000 IU
daily until hepatitis B surface antigen (HBsAg) became
negative] followed by low-dose, long-term HBIG treat-
ment (2000 IU in irregular intervals with an anti-HBs
maintenance level intended to be kept above 100 IU/
L).20 Prophylaxis was combined with lamivudine or ad-
efovir in all except 2 patients. In the 3 patients receiving
adefovir, antiviral therapy had been switched from
lamivudine to adefovir because of viral resistance pre-
OLT. At time of enrolment, all patients showed normal
liver function, negative HBsAg, and negative HBV poly-
merase chain reaction. Further baseline characteristics
for patients are shown in Table 1. Two responders to
active vaccination (discussed later) were excluded from
evaluation in this study. However, 22 patients (11 in
each group) did not respond to active vaccination, and
anti-HBs levels of these nonresponders were evaluated.
In all, 18 anti-HBs values were missing, with a maxi-
mum of 3 values in a single patient.
The immunosuppressive regimen consisted of cyclo-
sporine monotherapy in 12 patients, tacrolimus mono-
therapy in 3 patients, mycophenolate mofetil mono-
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
therapy in 1 patient, cyclosporine plus mycophenolate
mofetil in 3 patients, tacrolimus plus prednisolone in 2
patients, and cyclosporine plus prednisolone plus rapa-
mycin in 1 patient.
Study Protocol
During the study period, 2000 IU of HBIG was admin-
istered in regular 6-week intervals ⫾ 2 days. IM HBIG
was administered in 2 portions of 1000 IU (5 mL) into
each gluteus muscle. HBIG administration was started
intravenously in 12 patients of group A and intramus-
cularly in 12 patients of group B. At week 24, HBIG
administration was switched from IM to IV and vice
versa (crossover study). Anti-HBs levels were measured
2, 4, and 6 weeks after each HBIG administration [for
example, 4 ⫻ 3 values during the 24-week IM period
and 4 ⫻ 3 values during the 24-week IV period (in all, 24
values per patient ⫻ 22 patients)].
Twenty-four patients were vaccinated with conven-
tional double-dose recombinant vaccine containing 40
␮g of HBsAg up to 12 times.
During the study period, each patient was vaccinated
12 times [at weeks 0, 2, and 4 (cycle 1), 12, 14, and 16
(cycle 2), 24, 26, and 28 (cycle 3), and 36, 38, and 40
(cycle 4)] with a double-dose HBsAg vaccine adminis-
tered to the left deltoid muscle (Engerix B, GlaxoSmith-
Kline; 2 ⫻ 20 ␮g).21 Response to active vaccination was
defined as a reconfirmed increase of anti-HBs unex-
plained by HBIG administration or a lack of anti-HBs
decrease below 100 IU/L after discontinuation of HBIG
treatment after week 48.
The study protocol conformed to the ethical guide-
lines of the 1975 Declaration of Helsinki as reflected in
a priori approval by the appropriate institutional review
committee. Written informed consent was obtained
from each patient.
HBIG Preparations
The intravenously administered HBIG preparation was
Hepatect CP, which was manufactured by Biotest
(Dreieich, Germany) and contained 50 mg of plasma
protein standardized to 50 IU of anti-HBs per milliliter
(package insert). The intramuscularly administered
HBIG preparation was Hepatitis B Immunoglobulin Be-
hring, which was manufactured by CSL Behring (Mar-
burg, Germany) and contained 100-170 mg of plasma
protein per milliliter standardized to 200 IU of anti-HBs
per milliliter (package insert). Costs per 2000 IU in the
year 2006 were €1719 for Hepatect CP versus €1362 for
Hepatitis B Immunoglobulin Behring. The anti-HBs
content of both preparations was measured with the
same assay (Axsym AUSAB microparticle enzyme im-
munoassay, Abbott Diagnostics, Delkenheim, Ger-
many).
Anti-HBs Level Measurements
During the study, blood samples were collected for se-
rum anti-HBs level measurement every 2 weeks ⫾ 2
 COMPARISON OF IV AND IM HBIG ADMINISTRATION 437

TABLE 1. Demographic Data

Group A Group B Total

Number of patients enrolled 12 12 24
Number of patients evaluated 11 11 22
Sex: male/female 9/2 9/2 18/4
Age (years): mean ⫾ SD, median
(range) 48 ⫾ 14, 49 (26-68) 43 ⫾ 12, 45 (22-57) 46 ⫾ 13, 47 (22-68)
Weight (kg): mean ⫾ SD, median
(range) 83 ⫾ 19, 82 (60-125) 74 ⫾ 16, 75 (50-100) 79 ⫾ 18, 80 (50-125)
Height (cm): mean ⫾ SD, median
(range) 177 ⫾ 7, 175 (164-186) 174 ⫾ 8, 174 (159-186) 175 ⫾ 7, 175 (159-186)
BMI (kg/m2): mean ⫾ SD,
median (range) 26 ⫾ 5, 26 (20-37) 25 ⫾ 6, 22 (17-32) 26 ⫾ 5, 26 (17-37)
Plasma volume (L): mean ⫾ SD,
median (range) 3.1 ⫾ 0.4, 3.0 (2.4-3.8) 2.9 ⫾ 0.4, 2.9 (2.2-3.4) 3.0 ⫾ 0.4, 3.0 (2.2-3.8)
Race: white/black 11/0 10/1 21/1
Liver failure: acute/chronic 2/9 3/8 5/17
HBV DNA before antiviral
therapy (copies/mL) ⬍ 105 N ⫽ 5; ⬎ 105 N ⫽ 6 ⬍ 105 N ⫽ 6; ⬎ 105 N ⫽ 5 ⬍ 105 N ⫽11; ⬎ 105 N ⫽ 11
HBV DNA at time of OLT (copies/
mL)⬍ 105 N ⫽ 8; ⬎ 105 N ⫽ 3 ⬍ 105 N ⫽ 9; ⬎ 105 N ⫽ 2 ⬍ 105 N ⫽ 17; ⬎ 105 N ⫽ 5
HDV coinfection 2 3 5
Immunosuppression
(mono/combination) 8/3 8/3 16/6
Antiviral therapy during study
period (lamivudine/adefovir/
none) 8/2/1 9/1/1 19/3/2
Time of first study HBIG dose
post-OLT (months): median
(range) 42 (15-124) 42 (13-124) 42 (13-124)
Baseline anti-HBs levels at time
of first study HBIG
administration: mean ⫾ SD,
median (range) 214 ⫾ 77, 227 (107-342) 190 ⫾ 60, 182 (114-310) 202 ⫾ 69, 194 (107-342)

Abbreviations: anti-HBs, antibody against hepatitis B surface antigen; BMI, body mass index; HBIG, hepatitis B
immunoglobulin; HBV, hepatitis B virus; HDV, hepatitis D virus; OLT, orthotopic liver transplantation; SD, standard
deviation.

days, that is, 2, 4, and 6 weeks after HBIG administra-
tion. Directly after the 6-week measurement, another
HBIG dose was administered. Serum anti-HBs levels
were determined with the commercial Axsym AUSAB
microparticle enzyme immunoassay (Abbott Diagnos-
tics).
Calculation of Pharmacokinetic Parameters
Elimination rate constants for the calculation of elimi-
nation half-lives were determined from log-linear re-
gression of 3 anti-HBs serum concentration values.
AUC between week 2 and week 6 after HBIG adminis-
tration was estimated with the trapezoidal rule.
Statistics
The statistical evaluation was performed with SPSS 14.
Anti-HBs levels, half-lives, and AUC values after IV
HBIG administration versus IM HBIG administration
were compared pairwise with the t test for independent
samples (Table 2). Anti-HBs levels at consecutive time
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
points were compared pairwise by analysis of variance
for repeated measures (Table 2). Intraindividual and
interindividual mean variances of anti-HBs levels after
IV and IM HBIG administration was compared by the
nonparametric Mann-Whitney test (shown later in Fig.
4). Box plots were produced by means of SPSS 14.0
(shown later in Figs. 3 and 4).
RESULTS
Pairwise comparisons of anti-HBs levels at 3 different
time points, anti-HBs half-lives, and AUC values
showed no difference for IV administration mode versus
IM administration mode (Table 2). Kinetics of mean
anti-HBs levels of single patients 2, 4, and 6 weeks after
HBIG administration are given in Fig. 1. Figure 2 illus-
trates a direct comparison of anti-HBs trough levels
measured 6 weeks after IM HBIG administration versus
IV HBIG administration (mean of 4 values for each data
point). Figure 3 illustrates the similarity of the anti-HBs
concentrations, half-lives, and AUC values after IV and
IM HBIG administration.
438 ROSENAU ET AL.

TABLE 2. Anti-HBs Levels, Half-Lives, and AUC Values After IV and IM HBIG Administration

Group A P Group B P
IV IM IV IM
Anti-HBs level at week 2 518 ⫾ 175, 490 484 ⫾ 174, 513 0.66 442 ⫾ 154, 456 429 ⫾ 161, 406 0.85
Anti-HBs level at week 4 343 ⫾ 123, 360 336 ⫾ 164, 294 0.91 294 ⫾ 130, 281 284 ⫾ 130, 226 0.85
Anti-HBs level at week 6 251 ⫾ 115, 222 238 ⫾ 118, 207 0.84 190 ⫾ 91, 180 198 ⫾ 106, 174 0.85
Half-lives 26.7 ⫾ 7.0, 25.0 26.3 ⫾ 6.2, 24.7 0.91 22.7 ⫾ 4.9, 22.4 24.6 ⫾ 5.9, 23.0 0.42
AUC 10.2 ⫾ 3.7, 10.6 9.7 ⫾ 4.3, 8.4 0.77 8.5 ⫾ 3.5, 8.6 8.4 ⫾ 3.7, 7.2 0.91
Total
IV IM P P
Anti-HBs level at week 2 480 ⫾ 166, 471 (225-867) 457 ⫾ 166, 461 (179-833) 0.64 ⬍0.0005 (week 2 versus 4)
Anti-HBs level at week 4 319 ⫾ 126, 298 (129-599) 310 ⫾ 147, 269 (91-618) 0.83
⬍0.0005 (week 4 versus 6)
Anti-HBs level at week 6 221 ⫾ 106, 197 (67-484) 218 ⫾ 112, 187 (60-485) 0.93
Half-lives 24.7 ⫾ 6.2, 23.8 (16.1-39.6) 25.5 ⫾ 6.0, 23.6 (17.2-36.1) 0.67
AUC 9.4 ⫾ 3.6, 8.8 (3.8-16.8) 9.0 ⫾ 3.9, 8.1 (2.9-17.9) 0.77

NOTE: The mean ⫾ standard deviation, median, and range of single patients’ mean anti-HBs concentrations, half-lives, and
AUC values are given for separate groups and all patients together. P values far above 0.05 point out the absence of significant
differences between administration modes, whereas P values below 0.0005 demonstrate the highly significant decline of
anti-HBs levels at consecutive time points (2, 4, and 6 weeks after HBIG administration).
Abbreviations: anti-HBs, antibody against hepatitis B surface antigen; AUC, area under the curve; HBIG, hepatitis B
immunoglobulin; IM, intramuscular; IV, intravenous.

Figure 1. Mean anti-HBs levels of single patients 2, 4, and 6 weeks after HBIG administration. Each depicted anti-HBs level was
calculated as the mean of 4 measured anti-HBs concentrations. The crossover design is illustrated by the separation of groups
A and B.

In contrast, anti-HBs levels at consecutive time trough levels over time (from first to eighth HBIG ad-
points (2 versus 4 weeks and 4 versus 6 weeks after ministration) showed no significant trend of increasing
HBIG administration) declined continuously and signif- or decreasing values in any of the patients.
icantly (Table 2) without any difference between IV and To compare intraindividual and interindividual vari-
IM administration modes. ation of anti-HBs levels 2, 4, and 6 weeks after HBIG
Regression analysis of single patients’ anti-HBs administration, variances of single patients’ values at
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
 COMPARISON OF IV AND IM HBIG ADMINISTRATION 439

Figure 2. Mean anti-HBs trough levels of single patients. Mean anti-HBs levels (mean of 4 values for each data point) of single
patients measured 6 weeks after HBIG administration (trough levels) are compared directly (IV versus IM).

Figure 3. Variation of anti-HBs levels, half-lives, and AUC values. Anti-HBs levels measured 2, 4, and 6 weeks after HBIG
administrations, as well as half-lives and AUC values, are compared (IV versus IM).

different time points (4 IM and 4 IV values for each DISCUSSION

patient) were compared with variances of all patients’
values at defined time points (22 values per time point;
Fig. 4). After IV HBIG administration, the mean intra-
individual variance of anti-HBs levels (15,660, 6430,
and 5430 IU/L) was significantly lower than the inter-
individual variation (39,200, 20,590, and 15,260 IU/L)
at all 3 time points (P ⫽ 0.007, P ⫽ 0.002, and P ⫽
0.021, respectively), just as after IM HBIG administra-
tion (12,860, 4750, and 2590 IU/L for intraindividual
variation and 35,530, 24,620, and 14,340 IU/L for in-
terindividual variation with P ⫽ 0.004, P ⬍ 0.001, and
P ⫽ 0.001, respectively), as illustrated in Fig. 4.
In Table 3, the percentage of patients in whom anti-
HBs did not drop below predefined levels (for example,
100 IU/L) after administration of 2000 IU of HBIG in
6-week intervals is displayed.
During the study period, HBsAg remained negative in
all patients, and no laboratory or clinical signs of HBV
reinfection were seen in any patient.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
Our study demonstrates for the first time that crucial
pharmacokinetic parameters, including anti-HBs
trough levels at time of HBIG readministration, do not
differ significantly after IV and IM HBIG administra-
tion. All available previous trials on HBIG prophylaxis
after liver transplantation postulated a reduction of
HBIG costs of 50% or more by a switch from IV HBIG
administration to IM HBIG administration.6-8 How-
ever, these trials had substantial shortcomings: Ad-
equate comparative pharmacokinetic data measured
after IV and IM HBIG administration were not pre-
sented, the number of patients and measured data
points was to small, or the study protocol was too
confusing to draw meaningful conclusions. Our data
reveal that anti-HBs levels tend to differ between IV
and IM administration in single patients, underlining
the importance of a sufficient number of patients and
data points. However, our analysis of a large number
440 ROSENAU ET AL.

Figure 4. Intraindividual ver-

sus interindividual variation
of anti-HBs trough levels. To
compare intraindividual and
interindividual variation of an-
ti-HBs levels, variances of sin-
gle patients’ values at different
time points (4 IM and 4 IV val-
ues for each patient) are com-
pared with variances of all pa-
tients’ values at defined time
points (22 values per time
point).

TABLE 3. Anti-HBs Levels 2, 4, and 6 Weeks After IV and IM HBIG Administration

IV HBIG Administration
Anti-HBs Level ⬎50 IU/L ⬎100 IU/L ⬎200 IU/L ⬎500 IU/L
2 weeks 100%/100% 100%/100% 100%/95% 36%/9%
4 weeks 100%/100% 100%/100% 82%/68% 14%/0%
6 weeks 100%/100% 91%/82% 50%/18% 0%/0%
IM HBIG Administration
Anti-HBs Level ⬎50 IU/L ⬎100 IU/L ⬎200 IU/L ⬎500 IU/L
2 weeks 100%/100% 100%/100% 95%/86% 45%/9%
4 weeks 100%/100% 95%/95% 82%/50% 14%/5%
6 weeks 100%/100% 86%/82% 45%/32% 0%/0%

NOTE: The data are presented as percentage of patients with a mean anti-HBs concentration above the given level (mean of
4 values)/percentage of patients with repeated anti-HBs measurements above the given level (4 values each).
Abbreviations: anti-HBs, antibody against hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; IM, intramuscular;
IV, intravenous.

of anti-HBs levels, resulting half-lives, and AUC val-
ues measured in a high number of patients with a
crossover design does not show a pharmacokinetic
advantage of IM HBIG administration compared to IV
HBIG administration and unmasks trends in single
patients as coincidental.6,7 On the other hand, it is
important to stress that our analysis does not show a
pharmacokinetic disadvantage of IM HBIG adminis-
tration that may have been postulated because of
potentially lower bioavailability. Therefore, we con-
firm the cost-effectiveness of IM HBIG, which is easy
to calculate because it is restricted to the HBIG price:
IM HBIG is cost-effective if the price per unit of anti-
HBs is lower compared to IV HBIG (20% in our study)
or vice versa.
On the background of the additional repeated active
vaccination with conventional HBsAg vaccine in our
study, which failed to induce a significant anti-HBs
response in almost all patients as reported previous-
ly,21 it is important to note that this evaluation does not
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
even show a trend of increasing anti-HBs levels toward
the end of the study. The crossover design of the study
was performed for 2 reasons. First, we wanted to pre-
vent the difficulty of interpreting rising anti-HBs levels
toward the end of the study. However, such a trend did
not occur in either of the 2 groups. Second, the cross-
over design prevented an uneven distribution of pa-
tients with overall higher versus overall lower anti-HBs
levels in the IV versus the IM group, which is indeed
visible as a trend in groups A and B.
In principle, these data are consistent with published
pharmacokinetic data measured after IV infusion or IM
injection of antibodies. Previously published kinetics
clearly show an exponential antibody decrease well de-
scribed by a terminal elimination half-life. Indeed, the
measured half-lives of 25 ⫾ 6 and 26 ⫾ 6 days in the
present study perfectly fit the reported terminal elimi-
nation half-lives of 22 to 25 days.22-24
Kinetics measured after IM injection of antibodies (in
contrast to IV administration) are influenced not only

by distribution and elimination but also by absorption
processes. Systemic absorption of antibodies following
IM administration most likely occurs via the lymphatic
system. As lymph fluid drains slowly into the vascular
system, absorption of antibodies from the site of admin-
istration continues for a prolonged period.22 In animals
and in man, the time to maximal anti-HBs plasma con-
centrations for different monoclonal antibodies has
been reported to be 3, 5.5, and 7 to 8 days.22 Little
pharmacokinetic data about IM administration of HBIG
are available. Partovi et al.19 determined the time of
maximum anti-HBs levels to be between 4 and 20 days
(mean: 10.5 ⫾ 6.7) after HBIG administration.19 How-
ever, because of the variability of predose anti-HBs lev-
els, variable HBIG doses, and a small number of pa-
tients (6), the power of this study is limited. In principle,
prolonged absorption of drugs, as observed after IM or
subcutaneous (SC) injection, may result in increased
drug levels at later time points, if absorption is com-
plete, because AUC values after IV, IM, or SC drug
administration are equal if bioavailability is 100%.
However, after IM or SC administration, bioavailability
may be reduced because of local degradation of anti-
bodies by proteolytic enzymes. Indeed, most investiga-
tions of antibody absorption following IM injection have
reported incomplete absorption, with bioavailabilities
ranging from 50% to 100%.22
On this background, our pharmacokinetic data inter-
estingly do not show significantly lower AUC values
after IM HBIG administration versus IV HBIG adminis-
tration. Although AUC values during the first 2 weeks
after HBIG administration, which were not measured in
our study, presumably were lower after IM HBIG ad-
ministration because of incomplete absorption, this did
not influence anti-HBs levels after 2, 4, and 6 weeks
significantly. On the other hand, no effect of protracted
absorption was visible after IM HBIG administration, as
there was no trend to higher anti-HBs levels at any time
point.
Although a considerable number of studies have
shown that it is possible to maintain adequate postop-
erative anti-HBs levels in stable patients after liver
transplantation by IM HBIG administration,6-17 the
pros and cons of IM prophylaxis have to be weighed
carefully against IV prophylaxis on the background of
lacking pharmacokinetic benefits. On the one hand, IM
administration may be comfortable because the injec-
tion is performed quickly. On the other hand, this route
of administration can be painful because of the large
volumes injected, and local side effects of injections
affect some patients’ quality of life and bear a minimal
risk of infection and bleeding. On the basis of these pros
and cons, IM prophylaxis may be considered if IV HBIG
is unavailable or if a significantly lower price per HBIG
unit favors the use of an IM preparation.
Principles of anti-HBs pharmacokinetics after IM
HBIG administration can be expected to be applicable
to SC administration, which is currently under investi-
gation. Our study underlines that alternative routes of
HBIG administration have to be compared directly with
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
COMPARISON OF IV AND IM HBIG ADMINISTRATION 441
the gold standard of IV HBIG administration to assess
economic efficiency adequately.
Interindividual and intraindividual variations of anti-
HBs levels measured after administration of defined
HBIG doses in regular intervals have been observed in
previous studies.20,25 Besides intrarun and interrun
measurement inaccuracies, the interindividual varia-
tion in particular presumably mainly results from in-
terindividual differences in distribution and elimination
processes after IV administration. Differences in anti-
HBs levels may be additionally caused by variable ab-
sorption processes after IM injection. Thus, interindi-
vidual and intraindividual variations did not differ after
IV and IM HBIG administration and therefore do not
favor one of the two administration modes.
As a result of anti-HBs level variability, dosing
schemes with fixed HBIG doses and dosing intervals
appear to be inadequate for a cost-effective prophylaxis
with patient-independent defined anti-HBs trough lev-
els. Although anti-HBs levels were kept above 100 IU/L
in most patients at most time points by 6-week admin-
istration of 2000 IU of HBIG in the present study (Table
3), this could have been achieved by lower HBIG doses
or longer HBIG intervals in the majority of patients.
Individualized fixed dosing intervals would presumably
be more cost-effective, as intraindividual anti-HBs level
variability is significantly lower than interindividual
variability. However, an individualized anti-HBs level–
dependent HBIG administration can be expected to be
most cost-effective. If anti-HBs levels are measured at
regular intervals, for example, every 2 weeks, individual
anti-HBs levels and dynamics of anti-HBs decrease can
be assessed, and measurement intervals can be ad-
justed. If a defined trough level, such as 100 IU/L, is
sought, this strategy presumably not only is cost-effec-
tive because it prevents overdosing but also ensures a
high level of safety because it simultaneously prevents
underdosing.20 Finally, it is important to emphasize
that pharmacokinetic data in the present study were
measured in stable HBsAg-negative patients with at
least 12 months follow-up after OLT. HBIG doses re-
quired to decrease HBsAg levels and raise anti-HBs
levels in the initial posttransplant period strongly de-
pend on quantitative HBsAg levels at the time of liver
transplantation, as shown previously.26
In conclusion, pharmacokinetic data measured in the
present study favor neither IM nor IV HBIG administra-
tion. Therefore, the advantage of a quick and easy in-
jection of a usually cheaper IM HBIG preparation has to
be weighed against the disadvantage of potential dis-
comfort for patients and risk of complications after IM
HBIG administration. HBIG dosing intervals should be
individualized independently of the administration
mode.
REFERENCES
1. Lok AS. Prevention of recurrent hepatitis B post-liver
transplantation. Liver Transpl 2002;8:S67–S73.
2. Shouval D, Samuel D. Hepatitis B immune globulin to
prevent hepatitis B virus graft reinfection following liver
442 ROSENAU ET AL.
transplantation: a concise review. Hepatology 2000;32:
1189-1195.
3. Terrault N, Roche B, Samuel D. Management of the hep-
atitis B virus in the liver transplantation setting: a Euro-
pean and an American perspective. Liver Transpl 2005;11:
716-732.
4. Muller R, Gubernatis G, Farle M, Niehoff G, Klein H, Wit-
tekind C, et al. Liver transplantation in HBs antigen (HB-
sAg) carriers. Prevention of hepatitis B virus (HBV) recur-
rence by passive immunization. J Hepatol 1991;13:90-96.
5. Samuel D, Muller R, Alexander G, Fassati L, Ducot B,
Benhamou JP, et al. Liver transplantation in European
patients with the hepatitis B surface antigen. N Engl J Med
1993;329:1842-1847.
6. Burbach GJ, Bienzle U, Neuhaus R, Hopf U, Metzger WG,
Pratschke J, et al. Intravenous or intramuscular anti-HBs
immunoglobulin for the prevention of hepatitis B reinfec-
tion after orthotopic liver transplantation. Transplantation
1997;63:478-480.
7. Faust D, Rabenau HF, Allwinn R, Caspary WF, Zeuzem S.
Cost-effective and safe ambulatory long-term immunopro-
phylaxis with intramuscular instead of intravenous hepa-
titis B immunoglobulin to prevent reinfection after ortho-
topic liver transplantation. Clin Transplant 2003;17:254-
258.
8. Han SH, Martin P, Edelstein M, Hu R, Kunder G, Holt C, et
al. Conversion from intravenous to intramuscular hepati-
tis B immune globulin in combination with lamivudine is
safe and cost-effective in patients receiving long-term pro-
phylaxis to prevent hepatitis B recurrence after liver trans-
plantation. Liver Transpl 2003;9:182-187.
9. Alonso I, Herreros de Tejada A, Moreno JM, Rubio E, Lu-
cena JL, De la Revilla J, et al. Effectiveness of low-dose
intramuscular anti-VHB immune globulin in the prophy-
laxis of viral B hepatitis reinfection after liver transplan-
tation: preliminary report. Transplant Proc 2003;35:1850-
1851.
10. Angus PW, McCaughan GW, Gane EJ, Crawford DH, Har-
ley H. Combination low-dose hepatitis B immune globulin
and lamivudine therapy provides effective prophylaxis
against posttransplantation hepatitis B. Liver Transpl
2000;6:429-433.
11. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M,
et al. A randomized study comparing lamivudine mono-
therapy after a short course of hepatitis B immune glob-
ulin (HBIg) and lamivudine with long-term lamivudine
plus HBIg in the prevention of hepatitis B virus recurrence
after liver transplantation. J Hepatol 2003;38:811-817.
12. Ferretti G, Merli M, Ginanni Corradini S, Callejon V, Tan-
zilli P, Masini A, et al. Low-dose intramuscular hepatitis B
immune globulin and lamivudine for long-term prophy-
laxis of hepatitis B recurrence after liver transplantation.
Transplant Proc 2004;36:535-538.
13. Karademir S, Astarcioglu H, Akarsu M, Ozkardesler S,
Ozzeybek D, Sayiner A, et al. Prophylactic use of low-dose,
on-demand, intramuscular hepatitis B immunoglobulin
and lamivudine after liver transplantation. Transplant
Proc 2006;38:579-583.
14. Lerut JP, Donataccio M, Ciccarelli O, Roggen F, Jamart J,
Laterre PF, et al. Liver transplantation and HBsAg-positive
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
postnecrotic cirrhosis: adequate immunoprophylaxis and
delta virus co-infection as the significant determinants of
long-term prognosis. J Hepatol 1999;30:706-714.
15. Yao FY, Osorio RW, Roberts JP, Poordad FF, Briceno MN,
Garcia-Kennedy R, et al. Intramuscular hepatitis B im-
mune globulin combined with lamivudine for prophylaxis
against hepatitis B recurrence after liver transplantation.
Liver Transpl Surg 1999;5:491-496.
16. Yoshida EM, Erb SR, Partovi N, Scudamore CH, Chung
SW, Frighetto L, et al. Liver transplantation for chronic
hepatitis B infection with the use of combination lamivu-
dine and low-dose hepatitis B immune globulin. Liver
Transpl Surg 1999;5:520-525.
17. Zheng S, Chen Y, Liang T, Lu A, Wang W, Shen Y, et al.
Prevention of hepatitis B recurrence after liver transplan-
tation using lamivudine or lamivudine combined with
hepatitis B Immunoglobulin prophylaxis. Liver Transpl
2006;12:253-258.
18. Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jef-
frey GP, et al. Lamivudine plus low-dose hepatitis B immu-
noglobulin to prevent recurrent hepatitis B following liver
transplantation. Gastroenterology 2007;132:931-937.
19. Partovi N, Guy MW, Ensom MH, Noble MA, Yoshida EM. A
study of the pharmacokinetic profile of low-dose hepatitis
B immune globulin in long-term liver transplant recipi-
ents for chronic hepatitis B infection. Am J Transplant
2001;1:51-54.
20. Rosenau J, Bahr MJ, Tillmann HL, Trautwein C, Klemp-
nauer J, Manns MP, et al. Lamivudine and low-dose hep-
atitis B immune globulin for prophylaxis of hepatitis B
reinfection after liver transplantation possible role of mu-
tations in the YMDD motif prior to transplantation as a
risk factor for reinfection. J Hepatol 2001;34:895-902.
21. Rosenau J, Hooman N, Hadem J, Rifai K, Bahr MJ, Philipp
G, et al. Failure of hepatitis B vaccination with conven-
tional HBsAg vaccine in patients with continuous HBIG
prophylaxis after liver transplantation. Liver Transpl
2007;13:367-373.
22. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmaco-
kinetics and pharmacodynamics. J Pharm Sci 2004;93:
2645-2668.
23. Thurmann PA, Sonnenburg C, Valentova K, Gregora E,
Freischlager F, Lissner R. Pharmacokinetics of viral anti-
bodies after administration of intravenous immunoglobu-
lin in patients with chronic lymphocytic leukaemia or
multiple myeloma. Eur J Clin Pharmacol 2001;57:235-
241.
24. Thurmann PA, Sonnenburg-Chatzopoulos C, Lissner R.
Pharmacokinetic characteristics and tolerability of a novel
intravenous immunoglobulin preparation. Eur J Clin
Pharmacol 1995;49:237-242.
25. Terrault NA, Zhou S, Combs C, Hahn JA, Lake JR, Roberts
JP, et al. Prophylaxis in liver transplant recipients using a
fixed dosing schedule of hepatitis B immunoglobulin.
Hepatology 1996;24:1327-1333.
26. Rosenau J, Kreutz T, Kujawa M, Bahr MJ, Rifai K,
Hooman N, et al. HBsAg level at time of liver transplanta-
tion determines HBsAg decrease and anti-HBs increase
and affects HBV DNA decrease during early immunoglob-
ulin administration. J Hepatol 2007;46:635-644.