Beruflich Dokumente
Kultur Dokumente
Kazuharu Suzuki1*, Goki Suda1*, Yoshiya Yamamoto2, Ken Furuya3, Masaru Baba3, Megumi
Kimura1, Osamu Maehara², Tomoe Shimazaki¹, Koji Yamamoto¹, Taku Shigesawa1, Akihisa
Nakamura¹, Masatsugu Ohara1, Naoki Kawagishi1, Masato Nakai1, Takuya Sho1, Mitsuteru
Natsuizaka1, Kenichi Morikawa1, Koji Ogawa1, and Naoya Sakamoto1 for the NORTE Study
Group
1
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/hepr.13399
Acknowledgments
The authors would like to thank all patients and their families as well as the investigators and
staff of the participating institutions, NORTE study group a. The principal investigators of
the NORTE study sites are listed below: Junichi Yoshida (JCHO Sapporo Hokushin Hospital),
Atsushi Nagasaka (Sapporo City General Hospital), Akira Fuzinaga (Abashiri-Kosei General
Hospital), Hideaki Kikuchi, (Obihiro-Kosei General Hospital), Ken Furuya (JCHO Hokkaido
Hospital), Shuichi Muto (National Hospital Organization Hokkaido Medical Center), Takashi
Miyagishima (Kushiro Rosai Hospital), Jun Konno (Hakodate Central General Hospital),
Kenichi Kumagai (Mori city National Health Insurance Hospital), Manabu Onodera (NTT
EAST Sapporo Hospital), Tomoe Kobayashi (Tomakomai City Hospital), Minoru Uebayashi
(Japanese Red Cross Kitami Hospital), Kanji Katou (Iwamizawa Municipal General
Hospital), Yasuyuki Kunieda (Wakkanai City Hospital), Miki Tateyama (Tomakomai Nissho
hospital), Keisuke Shinada (Keiwakai Ebetsu Hospital), and Yoshiya Yamamoto (Hakodate
Municipal Hospital)
This study was supported in part by grants from the Japan Agency for Medical
Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and
Pharmaceutical K.K, grants and endowments from MSD K.K and Chugai Pharmaceutical
Co., Ltd, and a research grant from Gilead Sciences, Inc. Dr. Goki Suda received research
grants from Bristol Myers Squibb, MSD K.K, and Gilead Sciences. The other authors have
nothing to disclose.
and the safety and efficacy of TAF have not been established in severe renal dysfunction
patients, including hemodialysis patients. The efficacy and safety of ETV in these populations
has not been clarified. Thus, this study aimed to clarify this.
Methods: In this retrospective multicenter study, between 2006 and 2018, a total of 567
HBV-infected patients treated with ETV monotherapy were screened. Patients were included
if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical
information. The efficacy of ETV and changes in renal function were evaluated according to
renal function.
Results: A total of 273 patients were included; 9.2% (25/273), 1.8% (5/273), and 3.7%
(10/273) had chronic kidney disease (CKD) stage G3 and G4/5 and were on hemodialysis,
respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV-DNA
CKD stage G3/4/5, estimated glomerular filtration rate tended to restore with time, which
was in contrast to patients without renal dysfunction. The rate of disappearance in serum
between patients with or without renal dysfunction. ETV showed high efficacy for all 10
Conclusions: ETV for HBV-infected patients with severe renal dysfunction, including
hemodialysis patients, is highly effective and does not affect renal function.
HBV infection are crucial. So far, the available treatments for chronic HBV infection are
limited to nucleos(t)ide analogues (NAs) and interferon (IFN)-α. IFN-α therapy for HBV
patients has the following advantages: limited treatment duration, inhibition of HBV
response rate is low and severe adverse events are sometimes observed with IFN-α-based
therapy.5 On the contrary, NAs can suppress HBV replication efficacy and have a high safety
profile; however, consecutive administration is required.6 Until recently, entecavir (ETV) and
tenofovir disoproxil fumarate (TDF) were the first-line NAs for HBV-infected patients due to
the high efficacy and high genetic barrier. However, with TDF, consecutive administration
occasionally causes renal dysfunction.7 Thus, the use of TDF for HBV-infected patients with
chronic kidney disease (CKD) or patients at risk of renal dysfunction requires careful
In most phase 3 clinical trials of NAs for patients with HBV infection, patients with
severe renal dysfunction, including hemodialysis patients, were not included.8-10 Moreover,
evidence on the efficacy and safety of NAs for HBV-infected patients with severe renal
because all NAs are eliminated through the kidney, modified doses of NAs are often required
for patients with severe renal dysfunction.11 Thus, the safety and efficacy of the modified
administration dosage of NAs in HBV-infected patients with severe renal dysfunction should
it to have a similar effect but a safer profile regarding renal function in patients with chronic
HBV infection compared with TDF.9, 12 However, in a phase 3 clinical trial, HBV-infected
patients with severe renal dysfunction, including hemodialysis patients, were not included. In
addition, TAF is not recommended for patients with a creatinine clearance less than 15
mL/min. Thus, ETV might be the first choice for HBV-infected patients with severe renal
dysfunction. To the best of our knowledge, data on ETV administration for more than 1 year
in hemodialysis patients with HBV infection is limited to five cases.13 Additionally, in Japan,
with chronic kidney disease (CKD) are expected to increase due to age-related decline in
renal function.14 Thus, analyzing the safety and efficacy of ETV in HBV-infected patients
In this retrospective multicenter study, we aimed to evaluate the safety and efficacy of
ETV in HBV-infected patients with severe renal dysfunction, including hemodialysis patients.
This study was conducted by the NORTE Study Group, which have been conducting
clinical liver disease studies.15-20 In this retrospective, multicenter study, between 2006 and
2018, a total of 567 HBV-infected patients who were treated with entecavir monotherapy
were screened. Inclusion criteria were as follows: patients were >20 years old, were treated
with ETV monotherapy for >1 year, and had proper clinical information. Patients were
excluded if patients were co-infected with human immunodeficiency virus (HIV) or hepatitis
C virus, had other liver disease including autoimmune hepatitis, primary biliary cirrhosis and
Patients were assessed via physical examinations and blood tests at baseline and
every 3 months. In this retrospective study, data were collected at baseline and every year
In this study, baseline and changes in renal function was analyzed according to the
estimated glomerular filtration rate (eGFR), in the same manner as in previous reports.7, 21, 22
eGFR was calculated with the following equation: eGFR (mL/min/1.73 m2) = 194 × serum
creatinine−1.094 × Age−0.287 × 0.739 (if female).23 24 Renal function was classified according to
eGFR as follows: CKD stage G1, eGFR >90 mL/min/1.73 m2; CKD stage G2, eGFR = 60–89
mL/min/1.73 m2; CKD stage G3a, eGFR = 45–59 mL/min/1.73 m2; CKD stage G3b, 30–44
mL/min/1.73 m2; CKD stage G4, eGFR = 15–29 (mL/min/1.73 m2); and CKD stage G5,
eGFR < 15 mL/min/1.73 m2. Advanced liver fibrosis was defined as a FIB4 index >3.25.
This study protocol was approved by the ethics committee of each participating hospital
and conformed to the ethical guidelines of the Declaration of Helsinki. Participating patients
study was approved by the ethics committee of Hokkaido University Hospital (Clinical
ETV treatment
Eligible patients were orally administered with ETV as follows: 0.5 mg once daily in
patients with creatine clearance (Ccr) >50 ml/min, 0.5 mg once every 2 days in patients with
30<Ccr<50 ml/min, 0.5 mg once every 3 days in patients with 10<Ccr<30 ml/min, and 0.5
(Architect HBsAg-QT assay; Abbott Laboratory, Tokyo, Japan); the lower limit of detection
was 0.05 IU mL-1. The serum HBV-DNA level was measured using a real-time TaqMan PCR
assay (Cobas AmpliPrep/Cobas TaqMan HBV test, v2.0). The quantitative range was
20-170,000,000 IU/mL-1, 2.1-9.0 log10 IU/mL. Liver function tests, including levels of
serum alanine aminotransferase (ALT) (normal level, 5-40 U L-1), were performed at each
for the Study of Liver Diseases (AASLD) criteria (30 U/L for men and 19 U/L for women).9
The treatment outcome was evaluated based on the normalization of ALT and
rate of virological relapse, and the changes in eGFR according to renal function. Virological
breakthrough was defined as a 10-fold increase in serum HBV-DNA from nadir during
Statistical analysis
Changes in HBsAg and eGFR were analyzed using the paired T test. Other
continuous variables were analyzed using the Mann–Whitney U test and categorical variables
were analyzed using the χ2 test. All P-values were two-tailed, and the level of significance
was set at P < 0.05. All statistical analyses were performed using SPSS version 21.0 (IBM
Results
Patient characteristics
A total of 567 patients with HBV infection treated with ETV monotherapy
malignancy, 144 with insufficient clinical information and/or were observed for >1 year after
ETV initiation, and two patients with HBV/HIV co-infection were excluded from this study.
Finally, a total of 273 patients were included in the analysis (Supplemental Figure 1).
summarized in Table 1. Of 273 patients, 233 (85.3%), 25 (9.2%), 5 (1.8%), and 10 (3.7%)
patients were classified as CKD stage G1/2 (eGFR > 60 mL/min/1.73 m2), CKD stage G3
(eGFR = 30–59 mL/min/1.73 m2), CKD stage G4/5 (eGFR < 30mL/min/1.73 m2), and
hemodialysis patients, respectively. Overall, the patients aged 20–88 years (median, 57 years),
and 46.9% (128/273) were women. In total, 33.0% of patients had a FIB-4 index >3.25. Of
the 273 patients, a total of 15 and 19 patients were previously treated with IFN-α or
lamivudine.
Overall virological response and the rate of ALT normalization, and those in
subgroups stratified with HBe antigen status are summarized in Table 2 and Supplementary
Table 1. All included patients were evaluated at 1 year after ETV initiation, and the patients
who had adequate information were evaluated at 2, 3, and 5 years after ETV initiation. As
shown in Table 2, a total of 89.7% and 64.5% of included patients achieved normalization of
ALT (< 40U L-1) and matched the ASSLD criteria,9 respectively. As shown in Table 2, at 2
(n=234), 3 (n=211), and 5 (n=165) years after ETV initiation, the rate of normalization of
ALT increased with time. With regard to the virological response 1 year after ETV initiation,
84.2% of the patients achieved HBV-DNA >2.1 Log copies/mL. Similar to the normalization
of ALT, the rate of undetectable serum HBV-DNA increased accordingly with longer
response and HBV-DNA disappearance was worse in HBe antigen-positive patients. The rate
of disappearance of HBe antigen was similar between patients with or without renal
virological response during the treatment (5 (1.8%) and 2 (0.7%) with a virological
We analyzed changes in HBsAg between baseline and 1 year after ETV initiation
Comparison of ETV treatment outcome between patients with and without renal
dysfunction
patients with and without renal dysfunction (CKD G1/2 vs CKD G3/4/5/HD). As shown in
Table 3, baseline characteristics were significantly different between these two groups,
including age, platelet count, ALT level, and HBV-DNA level. The rate of HBV
shown in Figure 1, in patients with CKD stage G1 and G2, eGFR gradually declined and was
significantly worse 5 years after treatment initiation (P<0.001, Table 4). On the contrary, in
patients with CKD stage G3/4, the median eGFR tended to improve at 5 years after treatment
initiation compared with those at baseline (median eGFR; 48.8 and 56.0 mL/min/1.73 m2 at
Safety and efficacy of ETV for hemodialysis patients with HBV infection
shown in Table 5, 60% of included hemodialysis patients were men, three had liver cirrhosis
(LC), and three were positive for HBe antigen. The indication for ETV treatment were liver
cirrhosis (LC) (n=3), occurrence of HCC (n=2), acute flares in chronic HBV infection (n=1),
(n=1). All hemodialysis patients achieved undetectable serum HBV-DNA at 1 year after ETV
discontinuation due to adverse events. As shown in Supplementary Table 4, the rate of ALT
Discussion
However, during NA treatment for patients with HBV infection, HBsAg seroconversion is
rarely observed. Therefore, NA treatment for patients with HBV infection is required over a
long period of time, sometimes the patient’s entire life. Thus, information on the long-term
efficacy and safety of NAs is strongly required. In the latest Japan Society of Hepatology,
European Association for the Study of the Liver (EASL), and AASLD guidelines, ETV, TDF,
and TAF are recommended as a first-line anti-HBV therapy.6, 26, 27 However, previous reports
revealed that long-term TDF use can cause clinically significant nephrotoxicity,28, 29
especially in patients over 60 years old and with baseline renal impairment.21 Randomized
control trials revealed that nephrotoxicity is significantly decreased with the use of TAF
compared with TDF; however, the safety and efficacy for HBV-infected patients with severe
renal dysfunction (eGFR <15 mL/min/1.73 m2 and on hemodialysis) have still not been fully
clarified. In addition, data regarding the efficacy and safety of ETV for HBV-infected patients
Recently, several reports have shown a relationship between ETV treatment and
renal function. Trinh et al. compared the effect of TDF and ETV on renal function showing
that ETV treatment may recover the eGFR in patients with baseline eGFR <60 mL/min/1.73
m2.21 Similarly, in our study, as shown in Figure 1, patients with CKD stage G3/4/5 tended to
improve their eGFR. The observation period in the study by Trinh et al. was relatively long
(median: 44 months); however, it only included limited number of patients with moderate
renal dysfunction (n=34), the efficacy of ETV in patients with renal dysfunction was not
Similarly, Wong et al. conducted a study with a large number of patients, which
compared TDF, ETV, and untreated patients focusing on the effect on renal function.7 In the
from the untreated group. Although a large number of patients with CKD3/4 (n=170) was
included, the observation period was relatively short (median: 2.4 years), and the efficacy of
In our study, we focused on analyzing the efficacy and safety of ETV on patients with
renal dysfunction, including hemodialysis patients. As shown in Table 1, this study included
not only a small number of patients with moderate to severe renal dysfunction (n=40),
patients with moderate to severe renal dysfunction, the rates of disappearance of serum
HBV-DNA and ALT normalization were similar between patients with or without renal
dysfunction (Table 3). Additionally, the rate of insufficient virological response was also
similar between patients with or without renal dysfunction (Table 3). In addition, the rate of
disappearance of HBe antigen was also similar between patients with or without renal
dysfunction. Thus, dose modification for patients with renal dysfunction did not seem to
affect the treatment outcome over a long observation period in a real-world setting.
With regard to the effect of ETV on renal function, in patients without renal dysfunction,
eGFR significantly declined at 5 years after treatment initiation (Table 4, Figure 1). In
contrast, in patients with renal dysfunction, the eGFR tended to restore (median eGFR: 48.8
and 56.0 mL/min/1.73 m2, p=0.184, Table 4). In this study, the baseline age was older
7, 21
(baseline median age: 57 years old) than those in previous reports ; therefore, an
age-related decline in renal function14 might affect the renal function in patients with CKD
stage 1 and 2 over the 5-year observation period (Table 4). However, although the median
age was higher in patients with CKD 3/4 than in those with CKD stage G1/2, eGFR had the
tendency to restore. This result is consistent with a previous report (21). Therefore, ETV
of renal impairment. The reason why the eGFR in patients with CKD stage G3/4 tended to
improve during entecavir treatment was not clarified well. HBV-related nephritis might be
associated with this change. However, the number of patients with kidney biopsy was quite
limited in this study; thus, the association could not be analyzed. Therefore, further studies
with more patients, kidney biopsy, and a longer duration are required to assess them.
In hemodialysis patients with HBV infection without hepatitis, because there is no valid
evidence to suggest that HBV infection without hepatitis increases morbidity and mortality,26
the indication of NAs for such hemodialysis patients is not established.26 Thus, valid
indication of NAs for hemodialysis patients with HBV infection is limited to hemodialysis
patients waiting for renal transplantation, with LC, or have a history of HCC. In this study,
we included 10 hemodialysis patients who were treated with ETV more than 1 year; the most
common indications were history of HCC, LC, or waiting for renal transplantation. Reports
on the use of NAs for hemodialysis patients are quite limited, and most of them are regarding
lamivudine (LAM)30; however, current HBV treatment guidelines do not recommend LAM as
a first line therapy for patients with HBV infection.6, 26, 27 To best of our knowledge, data on
ETV administration for hemodialysis patients with HBV infection is quite limited. Ezequiel
et al. reported on seven hemodialysis patients with HBV infection who were treated with
ETV; however, two patients had a short observation period of <1 year; thus, only five
hemodialysis patients with HBV infection were treated with ETV >1 year.13 Similar to this
previous report, as shown in Table 2 and Supplemental Table 4, all hemodialysis patients in
the present study achieved undetectable serum HBV-DNA at 1 year after treatment initiation.
In addition, a total of 90% (9/10) and 100% (10/10) of patients achieved normalization of
ALT according to the AASLD criteria and laboratory normal range criteria, respectively, and
observation period. Thus, our results indicate that ETV for HBV infected hemodialysis
This study has some key strengths. The median observation period was relatively long,
at 5 years and up to 10 years. The evaluation of the efficacy and effect of ETV on renal
actively conduct many clinical studies regarding anti-hepatitis therapy for hemodialysis
However, this study has several limitations. First, this is a retrospective study; thus, there
is some missing data, including diagnosis of HBV-related nephritis and analysis of mutations
in HBV before entecavir treatment. Second, we could not follow all co-administered drugs,
including drugs that cause renal dysfunction. Third, when comparing patients with and
without renal dysfunction, several baseline factors, including age, ALT, and HBV-DNA levels
were significantly different; thus, this may have affected the comparison data. In addition,
although the median observation period was relatively long compared with previous reports,
NA treatment is usually required for a long time, almost life-long; therefore, a longer,
Baseline platelet count ( 104/µL) a 16.5 (0.9-45.2) 11.8 (3.3-28.9) 24.6 (1.5-27.9) 17.1 (8.1-37.2) 16.4 (0.9-45.2)
Baseline AFP (ng/ml) 4.6 (0.6-454.8) 2.9 (1.9-34.1) 3.9 (2.9-4.6) 3.1 (0.6-8.5) 5.0 (1.3-454.8)
Baseline Creatinin (mg/dl) 0.70 (0.39-12.80) 8.30 (3.65-12.80) 1.71 (1.40-2.00) 0.99 (0.73-1.99) 0.69 (0.39-1.00)
eGFR (ml/min/1.73 m2) a 78.6 (3.5-166.0) 5.2 (3.5-11.8) 28.8 (24.0-29.8) 53.3 (30.6-59.8) 82.4 (60.6-166.0)
FIB-4 index a 2.38 (0.43-72.20) 2.79 (0.66-8.76) 1.65 (1.07-36.15) 2.89 (0.81-7.75) 2.35 (0.43-72.20)
HBe Antigen positive (%) 1220.0 (0.0-257000.0) 703.0 (3.2-36924.0) 295.0 (0.6-25900.0) 679.4 (1.1-130950.0) 1361.0 (0.0-257000.0)
Alb (g/dl) 5.8 (2.1-9.1) 4.1 (2.1-8.8) 5.1 (2.2-8.8) 5.4 (2.1-8.1) 5.9 (2.1-9.1)
History of malignancy 4.1 (2.2-5.1) 3.7 (3.1-4.2) 4.0 (3.5-4.5) 4.2 (2.5-4.8) 4.1 (2.2-5.1)
AFP, alpha fetoprotein; Alb, albumin; ALT, alanine transaminase; AST, aspartate aminotransferase; CH, chronic hepatitis; CKD, chronic kidney disease; DM, diabetes
mellitus; eGFR, estimated glomerular filtration rate; HD, hemodialysis; IFN, interferon; LAM, lamivudine; LC, liver cirrhosis
a
Data are shown as median (range) values.
ALT normalization
12 months n (%) 245/273 (89.7%) 10/10 (100.0%) 4/5 (80.0%) 24/25 (96.0%) 207/233 (88.8%)
24 months n (%) 215/234 (91.9%) 4/4 (100.0%) 5/5 (100.0%) 23/23 (100.0%) 183/202 (90.6%)
36 months n (%) 196/211 (92.9%) 4/4 (100.0%) 4/4 (100.0%) 19/19 (100.0%) 169/184 (91.8%)
60 months n (%) 153/165 (92.7%) 4/4 (100%) 3/3 (100%) 10/11 (90.9%) 136/147 (92.5%)
12 months n (%) 176/273 (64.5%) 9/10 (90.0%) 4/5 (80.0%) 17/25 (68.0%) 146/233 (62.7%)
24 months n (%) 156/234 (66.7%) 3/4 (75.0%) 5/5 (100.0%) 17/23 (73.9%) 131/202 (64.9%)
36 months n (%) 151/211 (71.6%) 4/4 (100.0%) 4/4 (100.0%) 16/19 (84.2%) 127/184 (69.0%)
60 months n (%) 121/165 (73.3%) 4/4 (100%) 3/3 (100%) 9/11 (81.8%) 105/147 (71.4%)
(AASLD criteria)
HBV-DNA disappearance
24 months n (%) 218/234 (94.0%) 4/4 (100.0%) 4/5 (80.0%) 23/23 (100.0%) 187/200 (93.5%)
36 months n (%) 200/208 (96.2%) 4/4 (100.0%) 3/4 (75.0%) 19/19 (100.0%) 174/181 (96.1%)
60 months n (% ) 153/158 (96.8%) 3/3 (100.0%) 3/3 (100.0%) 10/11 (90.9%) 137/141 (97.2%)
HBeAg disappearance
12months n (%) 9/60 (15.0%) 1/2 (50.0%) 2/5 (40.0%) 6/53 (11.3%)
AASLD, American Association for the Study of Liver Diseases; ALT, alanine transaminase; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HD,
Baseline characteristics
ALT normalization
(AASLD criteria)
HBV-DNA disappearance
HBeAg disappearance
AFP, alpha fetoprotein; ALT, alanine transaminase; AST, aspartate aminotransferase; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular
filtration rate.
a
Data are shown as median (range) values.
Baseline 5 year
Non-HD
80.5(24.0-166.0) 73.5(16.8-130.0) <0.001
(n=163)
HD, hemodialysis
a
Data are shown as median (range) values.
Diabetic
1 54 M LC 1 0.5 ○ Positive 4.8 2077 Undetectable 1955 14
nephropathy
2 60 F IgA nephropathy Developing HCC 10 0.5 Negative 5.4 3760 Undetectable 4562 17
Polycystic
9 77 M LC 1 0.5 ○ Negative 3.2 3.24 Undetectable 7.3 5
kidney disease
ALT, alanine transaminase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LC, liver cirrhosis
The mean estimated glomerular filtration rate (eGFR) during entecavir (ETV) treatment
according to renal function. A stratified analysis was conducted based on renal function as
follows: CKD stage G1, eGFR > 90 mL/min/1.73 m2; CKD stage G2, eGFR = 60–89
mL/min/1.73 m2; CKD stage G3, 30–59 mL/min/1.73 m2; and CKD stage G4, eGFR = 15–29