Suda Goki (Orcid ID: 0000-0003-0098-9106)

Kawagishi Naoki (Orcid ID: 0000-0002-2953-6242)

Morikawa Kenichi (Orcid ID: 0000-0002-3891-5113)

Entecavir treatment of hepatitis B virus-infected patients with severe renal

impairment and those on hemodialysis

Short title: ETV in patients with severe renal dysfunction

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

University, Hokkaido, Japan

2
Department of Gastroenterology, Hakodate Municipal Hospital, Hokkaido, Japan
3
JCHO Hokkaido Hospital, Hokkaido, Japan

*KS and GS contributed equally to this work.

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

This article is protected by copyright. All rights reserved.

*Correspondence to: Naoya Sakamoto, M.D., Ph.D.

Department of Gastroenterology and Hepatology/Graduate School of Medicine, Hokkaido University.

North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan

Phone: +81 11-716-1161; Fax: +81 11-706-7867; Email: sakamoto@med.hokudai.ac.jp

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

Meguro (Hokkaido Gastroenterology Hospital), Akiyoshi Saga (Kaisei Hospital), Munenori

Okamoto (Aiiku Hospital), Masaki Katagiri (Sapporo Hokuyu Hospital), Takuto

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), Atsuhiko Kawakami (Sapporo Century Hospital), Izumi Tsunematsu (Touei

hospital), Keisuke Shinada (Keiwakai Ebetsu Hospital), and Yoshiya Yamamoto (Hakodate

Municipal Hospital)

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Disclosure statement

This study was supported in part by grants from the Japan Agency for Medical

Research and Development (AMED; grant number 19fk0210022h0103, 19fk0210018h0003,

19fk0310101s0503, 19fk0210048s0501, 19fk0210058h0001, 19fk0210047s0401) and SPS

KAKENHI; (Grant Number 19K08458).

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.

This article is protected by copyright. All rights reserved.

Abstract

Background: Entecavir (ETV), tenofovir-disoproxil-fumarate (TDF), and

tenofovir-alafenamide (TAF) are first-line nucleos(t)ide analogues for hepatitis B virus

(HBV)-infected patients. However, consecutive TDF administration causes renal dysfunction,

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

disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with

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

HBV-DNA, alanine transaminase normalization, and virological breakthrough was similar

between patients with or without renal dysfunction. ETV showed high efficacy for all 10

hemodialysis patients without virological breakthrough.

Conclusions: ETV for HBV-infected patients with severe renal dysfunction, including

hemodialysis patients, is highly effective and does not affect renal function.

Keywords: Hepatitis B virus, renal impairment, entecavir, dialysis

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 Hepatitis B virus (HBV) has currently infected 350 million patients worldwide. HBV
1-3
infection causes approximately 1 million deaths per year ; thus, appropriate treatments for

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

replication, and suppression of the incidence of hepatocellular carcinoma.4 However, the

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

attention; ETV may be more suitable for such patients.7

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

dysfunction, especially hemodialysis patients, in a real-world setting is limited.11 Additionally,

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

be evaluated, as data are still lacking.

Recently, tenofovir alafenamide (TAF), a novel prodrug of tenofovir, was approved

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for patients with chronic HBV infection. Clinical trial data for TAF in HBV patients revealed

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,

because the number of elderly HBV-infected patients is increasing, HBV-infected patients

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

with severe renal dysfunction, including hemodialysis patients, is clinically crucial.

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 article is protected by copyright. All rights reserved.

Materials and Methods

Patients and study design

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

primary sclerosing cholangitis, uncontrolled malignancy, poorly controlled cardiac disease, a

history of hypersensitivity to NAs, or declined to participate in this study.

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

after treatment initiation.

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

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provided written informed consent to participate or declined participation in this study. This

study was approved by the ethics committee of Hokkaido University Hospital (Clinical

research number: IRB 016-0387).

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

mg every 7 days in patients with Ccr <10 ml/min or on hemodialysis.

Test of hepatitis virus and biochemical markers

Serum titers of HBsAg were measured by a chemiluminescence immunoassay

(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

point. Additionally, we evaluated ALT normalization according to the American Association

for the Study of Liver Diseases (AASLD) criteria (30 U/L for men and 19 U/L for women).9

Treatment outcomes and observation factors

The treatment outcome was evaluated based on the normalization of ALT and

seronegative HBV-DNA test according to renal function. In addition, we assessed changes in

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HBsAg in patients who had paired HBsAg data both at baseline and assessment point, the

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

treatment.25 A suboptimal virological response was defined as HBV-DNA >4 log10

copies/mL after 12 months of antiviral treatment.25

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

Japan, Tokyo, Japan).

Results

Patient characteristics

A total of 567 patients with HBV infection treated with ETV monotherapy

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between July 2006 and June 2018 were screened. Of those patients, 148 with uncontrolled

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).

The baseline characteristics of the patients according to renal function are

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.

Treatment outcome according to renal function

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

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treatment duration (94%, 96.2%, and 96.8% at 2, 3, and 5 years after ETV initiation,

respectively). As shown in the Supplementary Table 1, the rate of insufficient virological

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

dysfunction (Table 3).

Rate of virological breakthrough and suboptimal response according to renal function

As shown in Table 2, a total of seven (2.5%) patients experienced insufficient

virological response during the treatment (5 (1.8%) and 2 (0.7%) with a virological

breakthrough and suboptimal response, respectively). Detailed information of these seven

patients is shown in Supplemental Table 2. Of the four patients with virological

breakthrough, 75% (3/4) had resistance associated substitutions to ETV.

Changes in HBsAg during ETV treatment according to renal function

We analyzed changes in HBsAg between baseline and 1 year after ETV initiation

(n=161). As shown in Supplementary Table 3, HBsAg was significantly decreased at 1 year

after ETV initiation compared with baseline.

Comparison of ETV treatment outcome between patients with and without renal

dysfunction

We compared the baseline characteristics and ETV treatment outcome between

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

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disappearance, ALT normalization, and virological breakthrough was similar between

patients with and without renal dysfunction.

Changes in eGFR during ETV therapy according to renal function

We analyzed changes in eGFR during ETV treatment according to renal function. As

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

baseline and 5 years after treatment initiation, P=0.184, Table 4).

Safety and efficacy of ETV for hemodialysis patients with HBV infection

We conducted an extensive analysis on 10 hemodialysis patients treated with ETV. As

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),

waiting for kidney transplantation (n=3), and prophylactic administration of prednisolone

(n=1). All hemodialysis patients achieved undetectable serum HBV-DNA at 1 year after ETV

initiation, and no included hemodialysis patients experienced severe adverse events or

discontinuation due to adverse events. As shown in Supplementary Table 4, the rate of ALT

normalization, HBV-DNA disappearance, and virological failure were similar between HD

patients with HBV infection and non-HD.

Discussion

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 After the development of NAs, anti-HBV therapy became highly effective and safe.

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

with severe renal dysfunction is also insufficient.

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

evaluated, and hemodialysis patients were not included in the study.21

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

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study, they revealed that the effect of ETV on renal function was not significantly different

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

ETV and hemodialysis patients were not included in the study.

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),

including hemodialysis patients (n=10). Although ETV is required at a modified dose in

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

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treatment for HBV may have a positive effect on renal function in patients with some degree

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

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no patients experienced virological breakthrough or a suboptimal response during the

observation period. Thus, our results indicate that ETV for HBV infected hemodialysis

patients is highly effective.

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

function were analyzed simultaneously according to renal function. In addition, because we

actively conduct many clinical studies regarding anti-hepatitis therapy for hemodialysis

patients,16-18, 31 we could include a moderate number of hemodialysis patients in this study.

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,

prospective study with a larger number of patients is required.

In conclusion, ETV for HBV-infected patients with moderate to severe renal

dysfunction, including hemodialysis patients, is highly effective. ETV is indicated to be safe

for patients with renal dysfunction.

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This article is protected by copyright. All rights reserved.
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 Table 1. Baseline characteristics of the participating patients according to renal function

CKD stage HD G4/5 G3 G1/2

eGFR (ml/min/1.73 m2) All range <30 31-60 61<

Total number (%) 273 10 (3.7%) 5 (1.8%) 25 (9.2%) 233 (85.3%)

Age (years) a 57 (20-88) 61 (25-86) 58 (49-88) 65 (35-87) 56 (20-88)

Age (years) >70 n (%) 33 (12.1%) 2 (20.0%) 1 (20.0%) 8 (32.0%) 22 (9.4%)

Sex (male/female) 145/128 6/4 2/3 15/10 122/111

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 AST level (IU/L) a 46 (10-2540) 20 (12-254) 53 (30-80) 39 (13-604) 49 (10-2540)

Baseline ALT level (IU/L) a 55 (5-2522) 20 (5-266) 74 (26-159) 42 (9-544) 57 (12-2522)

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)

FIB-4 index >3.25 n (%) 90 (33.0%) 5 (50.0%) 1 (20.0%) 5 (20.0%) 79 (33.9%)

Previous Tx (IFN/LAM) (15/19) (0/0) (0/0) (1/1) (14/18)

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Genotype (B/C/unknown)

HBs antigen (IU/ml) 46/137/90 3/4/3 0/3/2 7/9/9 36/121/76

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)

HBV-DNA (Log copies/ml) 25.5 37.5 0.0 20.8 26.1

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)

-History of HCC 68 (24.9%) 2 (20.0%) 0 (0.0%) 7 (28.0%) 59 (25.3%)

DM 57 (20.9%) 2 (20.0%) 0 (0.0%) 7 (28.0%) 48 (20.6%)

Hypertension 30 (11.0%) 2 (20.0%) 2 (40.0%) 0 (0%) 26 (11.2%)

Dyslipidemia 49 (17.9%) 2 (20.0%) 1 (20.0%) 5 (20.0%) 41 (17.6%)

Follow up duration (year) 20 (7.3%) 0 (0.0%) 0 (0.0%) 4 (16.0%) 16 (6.9%)

Carrier/CH/LC 5 (1-10) 1 (1-10) 5 (2-10) 4 (1-10) 6 (1-10)

LC (%) 14/196/63 1/5/4 0/5/0 1/20/4 12/166/55

23.1 40.0 0.0 16.0 23.6

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.

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Table 2. Treatment response according to renal function

CKD stage HD G4/5 G3 G1/2

Total number (%) 273 10 (3.7%) 5 (1.8%) 25 (9.2%) 233 (85.3%)

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%)

(less than 1×ULN)

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

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 12 months n (%) 230/273 (84.2%) 10/10 (100.0%) 3/5 (60.0%) 21/25 (84.0%) 196/233 (84.1%)

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%)

Insufficient Virological response

Total 7 (2.5%) 0 (0.0%) 1 (20.0%) 1(4.0%) 5 (2.1%)

Viorogical breakthrough 5 (1.8%) 0 (0.0%) 1 (20.0%) 1 (4.0%) 3 (1.3%)

Suboptimal response 2 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (0.8%)

AASLD, American Association for the Study of Liver Diseases; ALT, alanine transaminase; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HD,

hemodialysis; LAM, lamivudine; ULN, upper limit of the normal.

a
Data are shown as median (range) values.

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Table 3. Comparison of baseline characteristics and treatment response according to renal function

CKD stage G3/4/5/HD G1/2

eGFR (ml/min/1.73 m2) <60 61<

Total number (%) 40 (14.7%) 233 (85.3%)

Baseline characteristics

Age (years) a 64 (25-88) 56 (20-88) P<0.001

Sex (male/female) 23/17 122/111 P=0.608

Baseline platelet count ( 104/µL) a 17.0 (1.5-37.2) 16.4 (0.9-45.2) P=0.456

Baseline AST level (IU/L) a 33 (12-604) 49 (10-2540) P=0.004

Baseline ALT level (IU/L) a 37 (5-544) 57 (12-2522) P=0.001

Baseline AFP (ng/ml) a 3.2 (0.6-34.1) 5.0 (1.3-454.8) P=0.017

Baseline Creatinine (mg/dl) a 1.26 (0.73-12.80) 0.69 (0.39-1.00) P<0.001

eGFR (ml/min/1.73 m2) a 46.2 (3.5-59.8) 82.4 (60.6-166.0) P<0.001

FIB-4 index a 2.60 (0.66-36.15) 2.35 (0.43-72.20) P=0.989

HBs antigen (IU/ml) a 679.4 (0.6-130950.0) 1361.0 (0.0-257000.0) P=0.166

HBe Antigen positive (%) 21.6 26.1 P=0.686

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HBV-DNA (Log copies/ml) a 5.1 (2.1-8.8) 5.9 (2.1-9.1) P=0.015

DM 4 (10.0%) 26 (11.2%) P>0.999

Hypertension 8 (20.0%) 41 (17.6%) P=0.661

Dyslipidemia 4 (10.0%) 16 (6.9%) P=0.509

ALT normalization

12 months n (%) 30/40 (75.0%) 146/233 (62.7%) P=0.154

24 months n (%) 25/32 (78.1%) 131/202 (64.9%) P=0.161

36 months n (%) 24/27 (88.9%) 127/184 (69.0%) P=0.038

60 months n (%) 16/18 (88.9%) 105/147 (71.4%) P=0.159

(AASLD criteria)

HBV-DNA disappearance

12 months n (%) 34/40 (85.0%) 196/233 (84.1%) P>0.999

24 months n (%) 31/32 (96.9%) 187/200 (93.5%) P=0.698

36 months n (%) 26/27 (96.3%) 174/181 (96.1%) P>0.999

60 months n (%) 16/17 (94.1%) 137/141 (97.2%) P=0.438

HBeAg disappearance

12months n (%) 3/7 (42.8%) 6/53 (11.3%) P=0.061

Insufficient Virological Response

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 Virological breakthrough n (%) 2 (5.0%) 3 (1.3%) P=0.157

Suboptimal response n (%) 0 (0.0%) 2 (0.8%) P>0.999

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.

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Table 4. Changes in renal function (eGFR) according to renal function

Baseline 5 year

Non-HD
80.5(24.0-166.0) 73.5(16.8-130.0) <0.001
(n=163)

G3/4 (n=15) 48.8(24.0-59.2) 56.0(23.1-66.7) 0.184

G1/2 (n=148) 82.9(60.6-166.0) 74.8(16.8-130.0) <0.001

G1 (n=48) 97.6(90.0-166.00) 89.6(16.8-130.0) <0.001

G2 (n=100) 76.1(60.6-89.80) 70.1(33.4-110.4) <0.001

HD, hemodialysis
a
Data are shown as median (range) values.

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 Table 5. Safety and efficacy of ETV for hemodialysis patients with HBV infection

Renal Baseline 1 year after ETV initiation

disease Indications Treatment ETV HBV DNA HBV DNA

Age Sex HBeAg HBsAg Levels HBsAg Levels ALT
due to for ETV duration (mg/week) LC Levels Levels
Status (IU/ml) (IU/ml) (IU/ml)
HD (year) (Log copies/ml) (Log copies/ml)

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

3 25 M unknown LC 9 0.5 ○ Positive 3.8 - Undetectable - 20

4 86 M unknown Acute on chronic 6 0.5 Positive 8.8 36924 Undetectable 0.05 8

5 51 F unknown Developing HCC 7 0.5 ○ Negative 3.5 703 Undetectable 513 21

Waiting for kidney

6 69 F IgA nephropathy 1 0.5 Negative 4.3 1329 Undetectable 1454 7
transplantation

Waiting for kidney

7 62 M Renal abscess 1 0.5 Negative 4.9 64 Undetectable 53 19
transplantation

Focal Waiting for kidney

8 61 M 1 0.5 Negative 2.6 108 Undetectable 113.3 14
glomerulosclerosis transplantation

Polycystic
9 77 M LC 1 0.5 ○ Negative 3.2 3.24 Undetectable 7.3 5
kidney disease

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 Preventing HBV
10 50 F unknown 1 0.5 Negative 2.1 4.01 Undetectable 0.82 8
re-activation

ALT, alanine transaminase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LC, liver cirrhosis

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Figure 1. Changes in median eGFR during ETV treatment

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

mL/min/1.73 m2. HD, hemodialysis

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