Dig Dis Sci (2015) 60:1457–1464
DOI 10.1007/s10620-014-3486-7
ORIGINAL ARTICLE
Seven-Year Efficacy and Safety of Treatment with Tenofovir
Disoproxil Fumarate for Chronic Hepatitis B Virus Infection
Maria Buti • Naoky Tsai • Joerg Petersen • Robert Flisiak • Selim Gurel •
Zahary Krastev • Raul Aguilar Schall • John F. Flaherty • Eduardo B. Martins •
Prista Charuworn • Kathryn M. Kitrinos • G. Mani Subramanian •
Edward Gane • Patrick Marcellin
Received: 19 August 2014 / Accepted: 7 December 2014 / Published online: 23 December 2014
 The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract eligible to receive open-label TDF for a total duration of
Background Long-term tenofovir disoproxil fumarate 8 years (384 weeks).
(TDF) treatment for chronic hepatitis B (CHB) is associ- Results Of 641 patients initially randomized, 585
ated with sustained viral suppression and regression of (91.3 %) entered the open-label phase; 437/585 (74.7 %)
fibrosis and cirrhosis at year 5 (240 weeks) and no TDF remained on study at year 7. For patients on treatment at
resistance through 6 years (288 weeks). year 7, 99.3 % maintained viral suppression (HBV
Aim We assessed the efficacy, safety, and resistance of DNA\ 69 IU/mL), 80.0 % achieved serum alanine ami-
TDF for up to 7 years (336 weeks) in HBeAg-positive and notransferase normalization, and in HBeAg-positive
HBeAg-negative CHB patients. patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved
Methods Patients who completed 1 year (48 weeks) of HBeAg and HBsAg loss, respectively. One/375 (0.3 %)
randomized treatment with TDF or adefovir dipivoxil were HBeAg-negative patients achieved HBsAg loss. No resis-
tance to TDF was detected through 7 years. During the
open-label phase, grade 3/4 drug-related adverse events
Electronic supplementary material The online version of this were uncommon (1.0 %); ten (1.7 %) patients had eleva-
article (doi:10.1007/s10620-014-3486-7) contains supplementary tion of serum creatinine C0.5 mg/dL above baseline. No
material, which is available to authorized users.
M. Buti (&) S. Gurel
Department of Hepatology, Hepatic and Digestive Diseases Department of Gastroenterology, University of Uludag, Özlüce
(CIBERehd), Hospital General Universitari Vall d’Hebron and Mh., 16120, Bursa 16059, Turkey
Networked Biomedical Research Center, Pg. Vall d’Hebron, e-mail: gurels@uludag.edu.tr
119-129, 08035 Barcelona, Spain
e-mail: mbuti@vhebron.net Z. Krastev
Department of Gastroenterology, University Hospital, St. Ivan
N. Tsai Rilsky, 15 Akademik Ivan Geshov, 1431 Sofia, Bulgaria
Department of Medicine, Queens Medical Center, University of e-mail: zahkrastev@gmail.com
Hawaii at Manoa, 550 S. Beretania Street,
POB III #405, Honolulu, HI 96734, USA R. Aguilar Schall  J. F. Flaherty  E. B. Martins 
e-mail: naoky@hawaii.edu P. Charuworn  K. M. Kitrinos  G. Mani Subramanian
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City,
J. Petersen CA 94404, USA
Head, Liver Unit, IFI Institute at the Asklepios Klinik St. Georg e-mail: Raul.Aguilar@gilead.com
Hamburg, University of Hamburg, Haus L, Lohmühlenstr. 5,
J. F. Flaherty
20099 Hamburg, Germany
e-mail: John.Flaherty@gilead.com
e-mail: petersen@ifi-medizin.de
E. B. Martins
R. Flisiak e-mail: Eduardo.Martins@gilead.com
Department of Infectious Diseases and Hepatology Medical,
P. Charuworn
University of Białystok, 15-540 Białystok, Poland
e-mail: Prista.Charuworn@gilead.com
e-mail: robert.flisiak@umb.edu.pl
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1458 Dig Dis Sci (2015) 60:1457–1464
significant change in bone mineral density was observed baseline cirrhosis [7]. No evidence of resistance to TDF has
from year 4 to year 7 (week 192 to week 336). been observed through year 6 (288 weeks) of treatment [8].
Conclusions Long-term TDF treatment was associated Here, we report the efficacy, safety, and resistance results
with sustained virologic, biochemical, and serologic of patients remaining on study at year 7 (week 336) of
responses, without resistance. TDF treatment was well follow-up.
tolerated, with a low incidence of renal and bone events.
These data confirm the safety and efficacy of long-term
TDF for CHB. Methods
Keywords Antiviral agent  Cirrhosis  Hepatitis B Study Design
e antigen  Liver disease
The designs of the two randomized, controlled studies, GS-
US-174-0102 (NCT00117676; Study 102) and GS-US-
Introduction 174-0103 (NCT00116805; Study 103), have been descri-
bed previously [6]. Briefly, hepatitis B e antigen (HBeAg)-
Disease progression to cirrhosis, liver failure, or hepato- positive or (HBeAg)-negative CHB patients (18–69 years
cellular carcinoma (HCC) occurs in up to 40 % of patients of age) with compensated liver disease and Knodell necr-
with chronic hepatitis B (CHB) [1]. Elevated hepatitis B oinflammatory score C3 were randomized 2:1 to TDF
virus (HBV) DNA viral load correlates with increased risk 300 mg once daily or ADV 10 mg once daily for 1 year,
of HCC and cirrhosis [2], and conversely, treatments that after which all patients switched to or continued on TDF
suppress viral replication without breakthrough can delay during the open-label phase for up to 7 years, for a total
disease progression [3]. Several antiviral agents are study duration of up to 8 years (384 weeks). Emtricitabine
approved for treatment of CHB [4], although prospective (FTC) could be added to the treatment regimen, at the
long-term clinical data beyond 5 years of treatment with discretion of the investigator, for confirmed viremia on or
oral antiviral agents for CHB are limited. after 1.5 years (week 72).
TDF is an orally available prodrug of the nucleotide Efficacy assessments included virologic response,
analogue tenofovir, a potent and selective inhibitor of HBV defined as plasma HBV DNA levels\69 IU/mL (\400
DNA polymerase/reverse transcriptase (pol/RT) in vitro copies/mL). The proportion of patients with plasma HBV
[5]. TDF is currently approved for treatment of CHB in DNA\29 IU/mL (\169 copies/mL, the lower limit of
patients 12 years of age and older. In two international, quantification of the COBAS Taqman assay) was also
multicenter, randomized, double-blind phase 3 studies of analyzed. Biochemical response based on normalized ala-
once-daily TDF versus once-daily adefovir dipivoxil nine aminotransferase (ALT) levels was assessed as
(ADV) for 1 year (48 weeks) in 641 patients, TDF was described previously [6, 7]. Serologic endpoints included
more effective than ADV in viral suppression and serum HBeAg loss and seroconversion to anti-HBe
improving histologic inflammation [6]. In addition, at year (HBeAg-positive patients), and serum hepatitis B surface
5 (week 240), TDF therapy led to histological improvement antigen (HBsAg) loss and seroconversion to anti-HBs.
(defined as a C2-point reduction in Knodell necroinflam- Patients with confirmed HBsAg loss or seroconversion
matory score with no worsening of fibrosis) in 87.4 % could stop treatment at the investigator’s discretion, pro-
(304/348) of patients, and 74.0 % (71/96) had reversal of vided they remained on follow-up. Viral resistance testing
for genotypic changes within the HBV reverse transcriptase
(HBV pol/RT) was performed annually for patients with
K. M. Kitrinos HBV DNA C69 IU/mL (C400 copies/mL) who experi-
e-mail: Katie.Kitrinos@gilead.com enced virologic breakthrough or persistent viremia, and
G. Mani Subramanian those who discontinued from the study with HBV DNA
e-mail: Mani.Subramanian@gilead.com C69 IU/mL (C400 copies/mL) [8]. Conserved-site changes
or polymorphic-site changes detected in[ 1 patient by
E. Gane
genotypic analysis were confirmed by phenotyping, as
Department of Gastroenterology and Hepatology, Auckland City
Hospital, 2 Park Road, Auckland 1142, New Zealand described previously [8, 9].
e-mail: EdGane@adhb.govt.nz Safety and tolerability assessments, including adverse
events (AEs), treatment discontinuations, and patient
P. Marcellin
deaths, were conducted on an ongoing basis. Predefined
Service d’Hepatologie, Hôpital Beaujon, 100 Boulevard du
General Leclerc, 92110 Clichy, France renal endpoints included creatinine clearance\50 mL/
e-mail: patrick.marcellin@bjn.aphp.fr min, serum creatinine C0.5 mg/dL above baseline, and
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Dig Dis Sci (2015) 60:1457–1464 1459
serum phosphate\2 mg/dL. Bone mineral density (BMD) measures) who remained on study at year 7, including 99.3 %
was assessed annually by dual-energy X-ray absorptiome- (both measures) of HBeAg-negative patients and 99.4 %
try scan from year 4 (week 192) through year 7 (week 336). (both measures) of HBeAg-positive patients (Table 1).
Virologic and biochemical response were assessed using
a modified, long-term evaluation-TDF (LTE-TDF) only Biochemical and Serologic Response
analysis, in which (a) patients with missing data or with
FTC added were counted as failures at all time points Biochemical responses at year 7 are summarized in Table 1.
following addition, and (b) patients with HBsAg loss who Of patients on study at year 7 who had abnormal ALT at
discontinued study drug and met endpoint criteria at the baseline, 80.0 % experienced ALT normalization, including
last on-study visit were counted as successes and had the 83.5 % of HBeAg-negative patients and 74.2 % of HBeAg-
last value carried forward. An on-treatment analysis was positive patients. Of the 42 HBeAg-negative and 40 HBeAg-
also conducted, in which patients with non-missing data, positive patients on study who did not achieve ALT nor-
regardless of the treatment received, were included in the malization, the median [mean] ALT (U/L) levels were 49
analysis, and patients with missing data were excluded. [55] and 51 [57], respectively. Among 154 observed HBeAg-
positive patients on study at year 7, 84 (54.5 %) experienced
HBeAg loss and 61 (39.6 %) experienced seroconversion to
Results anti-HBe. In a Kaplan–Meier analysis of the intent-to-treat
population of HBeAg-positive patients, 27 (11.8 %) expe-
Patient Disposition rienced HBsAg loss and 21 (9.7 %) experienced serocon-
version to anti-HBs. Among 375 HBeAg-negative initially
At year 7, a total of 437/641 (68.2 %) of HBeAg-positive randomized patients, one experienced HBsAg loss at year 5.
and HBeAg-negative patients initially randomized and Of the 28 HBeAg-positive and HBeAg-negative patients
437/585 (74.7 %) of patients entering the open-label phase who experienced HBsAg loss during the study, three
remained on study (Fig. 1). In total, 148 of 585 (25.3 %) remained on study drug through year 7, and 25 subsequently
patients discontinued during the open-label phase for discontinued study drug and entered treatment-free follow-
withdrawal of consent (n = 51); loss to follow-up up (TFFU). Fourteen of these discontinued study participa-
(n = 37); investigator discretion (n = 27); safety, tolera- tion before year 7, while 10 remained on study under TFFU,
bility, or efficacy reason (n = 17); HBsAg or HBeAg and one restarted treatment (Fig. 2).
seroconversion (n = 8); protocol violation (n = 7); and
sponsor decision (n = 1) (Fig. 1). Resistance Surveillance
Virologic Response Overall, the majority of patients (533/585, 91.1 %) who
entered open-label treatment had HBV DNA\ 69 IU/mL at
Suppression of HBV DNA levels at both\ 69 and\ 29 IU/ their last time point on TDF through year 7. Fifty-two patients
mL was observed in nearly all patients (99.3 % for both (8.8 %) qualified for genotypic analysis at their last time point
Fig. 1 Patient disposition at
year 7
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Table 1 Biochemical and virologic response to tenofovir disoproxil fumarate at year 7 (week 336)
By HBeAg status All
HBeAg-negativea HBeAg-positiveb
HBV DNA\ 69 IU/mL [% (n/N)]
LTE-TDFc 77.3 (269/348) 60.3 (149/247) 70.3 (418/595)
On treatmentd 99.3 (271/273) 99.4 (159/160) 99.3 (430/433)
HBV DNA\ 29 IU/mL [% (n/N)]
LTE-TDFc 77.1 (269/349) 60.3 (149/247) 70.1(418/596)
On treatmentd 99.3 (271/273) 99.4 (159/160) 99.3 (430/433)
ALT normalization [% (n/N)]
LTE-TDFc 64.6 (210/325) 46.9 (113/241) 57.1 (323/566)
On treatmentd 83.5 (213/255) 74.2 (115/155) 80.0 (328/410)
HBeAg loss [% (n/N)] – 54.5 (84/154) –
HBeAg seroconversion [% (n/N)] – 39.6 (61/154) –
HBsAg loss [K-M % (95 % CI)] – 11.8 (8.1, 16.9) –
HBsAg seroconversion [K-M % (95 % CI)] – 9.7 (6.4, 14.6) –
ALT alanine aminotransferase, CI confidence interval, HBeAg hepatitis B e-antigen, HBV hepatitis B virus, K–M Kaplan–Meier
a HBeAg-negative patients were enrolled in Study 102
b HBeAg-positive patients were enrolled in Study 103
c In the long-term evaluation–TDF only (LTE-TDF) analysis, patients with missing data or emtricitabine added to their treatment regimen were
counted as failures
d In the on-treatment analysis, patients with missing data were excluded and patients with emtricitabine added to their treatment regimen were
included in the analysis
Fig. 2 Disposition at year 7
(week 336) of patients who
experienced confirmed HBsAg
loss. aCompleted through year
7. bOne patient experienced
seroreversion, restarted on
treatment, and seroconverted
again
on TDF, with three patients qualifying during year 7. Thirty- analysis prior to year 7 were previously evaluated [9]. For the
nine of the 585 patients (6.7 %) who entered open-label four patients who qualified for genotypic analysis during year
treatment switched to FTC/TDF through year 6 of open-label 7, two had no changes in HBV pol/RT from baseline and two
treatment. Seven patients qualified for genotypic analysis at were unable to be genotyped. Three of the patients who
their last time point on FTC/TDF, with one patient qualifying qualified for genotypic analysis were non-adherent to study
during year 7. The 48 patients that qualified for genotypic treatment, as confirmed by undetectable levels of study drug in
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Dig Dis Sci (2015) 60:1457–1464 1461
Table 2 Safety summary of the open-label period
Parameter By initial treatment assignment All (N = 585)
TDF–TDF (n = 389) ADV–TDF (n = 196)
Deaths [n (%)] 9a (2.3) 3b (1.5) 12 (2.1)
Study drug-related AE leading to drug discontinuation [n (%)] 2 (0.5) 1 (0.5) 3 (0.5)
Study drug-related serious AE [n (%)] 5 (1.3) 2 (1.0) 7 (1.2)
Study drug–related grade 3 or 4 AE [n (%)] 3 (0.8) 3 (1.5) 6 (1.0)
Renal impairmentc,d [n (%)]
Serum creatinine C 0.5 mg/dL above baseline 6 (1.5) 4 (2.0) 10 (1.7)
Serum phosphate\ 2 mg/dL 5 (1.3) 4 (2.0) 9 (1.5)
Creatinine clearance\ 50 mL/min 3 (0.8) 3 (1.5) 6 (1.0)
ADV adefovir dipivoxil, AE adverse event, SD standard deviation, TDF tenofovir disoproxil fumarate
a Causes of death included motor vehicle accident (n = 2), hepatocellular carcinoma (n = 2), liver cancer, lung cancer (n = 2), nasopharyngeal
carcinoma, and unknown cause
b Causes of death included cervical cancer with pulmonary metastases, hepatocellular carcinoma, and multifocal carcinoma
c Each parameter was confirmed on retest
d A given patient may have had more than one event of renal impairment; 21 patients had 25 confirmed renal events
plasma. All four patients achieved HBV DNA\ 69 IU/ml seven patients who experienced serum creatinine increa-
prior to year 7, and at their qualifying time point during year 7, se C0.5 mg/dL above baseline, seven patients with serum
the mean HBV DNA level was 100.1 IU/ml (range phosphate\2 mg/dL, and two patients with CrCl\ 50 mL/
89-113 IU/ml). One of the four subjects discontinued from the min. Between year 5 and year 7, an additional three patients
study prior to week 336 and is not included in the on-treatment experienced an increase in serum creatinine C 0.5 mg/dL
HBV DNA suppression analysis. above baseline, two patients with serum phosphate\2 mg/
dL, and four patients with CrCl\ 50 mL/min. Comparing
Safety baseline characteristics of patients who did and did not have
renal AEs, mean age (47 vs. 40 years;P = 0.003), mean CrCl
Safety findings during the open-label period are summarized (98.5 vs. 117.4 mL/min; P = 0.003), and mean serum phos-
in Table 2. Of 585 patients who entered the open-label phase, phate (2.8 vs. 3.3 mg/dL; P = 0.002) were statistically dif-
13 (2.2 %) patients discontinued study drug because of AEs, ferent between groups. Of the 21 patients who developed renal
including three (0.5 %) that were considered study drug insufficiency, seven patients had hypertension, two patients
related. Reasons for discontinuation (in some cases multiple) had diabetes mellitus, two patients had underlying renal dis-
for these 13 patients included hepatic neoplasm (n = 3), ease (HBV-associated glomerulonephritis, IgA nephropathy),
endometrial cancer (n = 1), lung neoplasm (n = 1), fatigue two patients had nephrolithiasis, three patients were older than
(n = 1), abdominal pain (n = 1), septic shock (n = 1), non- 60 years of age, and 12 patients had no known risk factors
specified injury (n = 1), road traffic accident (n = 1), dis- listed in their medical history. Additionally, no patients
turbance in attention (n = 1), dizziness (n = 1), increased experienced concurrent decrease in CrCl\ 50 mL/min and
blood creatinine (i = 1), osteoporosis (n = 1), breast cancer serum phosphate\2 mg/dL.
(n = 1), and drug dependence (n = 1). Seven (1.2 %) Annual BMD assessments were undertaken at year 4
patients had study drug-related serious AEs during the open- through year 7 in patients enrolled in the open-label phase.
label period, in some cases multiple events, although none had Overall, no significant changes in BMD were observed
new onset during year 7. These serious AEs included acute from year 4 (325 hip and spine scans) to year 7 (288 hip
pancreatitis (n = 1), osteopenia (n = 1), osteoporosis scans and 294 spine scans), and no trends in T or Z scores
(n = 2), renal failure (n = 1), increased ALT (n = 2), and were apparent over the 3 years (Supplemental Table 1).
facial spasm (n = 1). To date, 12 deaths have occurred during
the open-label phase, none of which were study drug related.
Overall, 21/585 (3.6 %) patients had 25 confirmed AEs Discussion
under renal impairment (defined as serum creatinine increa-
se C0.5 mg/dL above baseline, serum phosphate\2 mg/dL, The results described in this report demonstrate that long-
and creatinine clearance [CrCl]\50 mL/min [Cockcroft– term treatment with TDF for chronic HBV infection provides
Gault]) during the open-label phase. Up to year 5, there were potent and durable viral suppression and normalization of
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1462 Dig Dis Sci (2015) 60:1457–1464
serum ALT levels. In addition, the proportion of patients The proportion of patients with HBsAg loss in HBeAg-
with HBsAg loss was 11.8 % (Kaplan–Meier estimation) at positive patients through year 7 was 11.8 % by Kaplan–
up to 7 years of TDF treatment. Of particular importance, no Meier analysis. This is consistent with rates of HBsAg loss
resistance to TDF has been detected with up to 7 years of determined by different methodologies reported in the lit-
treatment. These results also demonstrate that TDF treatment erature for other oral antiviral agents: a retrospective study
is safe and well tolerated, with few discontinuations related in HBeAg-positive patients reported HBsAg loss in 18/354
to AEs and no new safety signals identified through 7 years. (5.1 %) patients after 96 weeks of entecavir treatment and
Renal AEs occurred infrequently, were generally mild, and 10/355 (2.8 %) patients after 96 weeks of lamivudine
improved with dose modification. Although introduced only treatment [18], and an open-label extension of a random-
at year 4, serial assessments of BMD suggest no evidence of ized study of entecavir in HBeAg-positive patients reported
bone loss over 3 years of evaluation. HBsAg loss in 2/145 (1.4 %) patients after up to 5 years of
The lack of resistance to TDF after prolonged exposure is treatment [19]. Although this is higher than the rate of
striking, considering the high rates of resistance observed spontaneous HBsAg loss (0.5–0.8 % per year) [20],
with other nucleotide/nucleoside analogues, ranging from HBsAg loss rates remain low with current CHB nucle-
20 % at 5 years of ADV treatment [10] to 65 % at 5 years os(t)ide therapy, indicating that achievement of HBsAg
of lamivudine treatment [11]. Entecavir treatment is asso- loss is a relatively rare but dependable clinical end point.
ciated with a low rate of resistance in treatment-naive Achieving higher rates of HBsAg loss might require the
patients (1.2 % of patients treated for up to 5 years) [12], addition of immune-based therapies, with an approach
although rates of entecavir resistance are considerably currently under investigation in an ongoing TDF and
higher in those who are ADV nonresponders (4 % of pegylated interferon combination study (NCT01277601).
patients treated for a median of 20 months) [13], lamivudine In summary, our 7-year follow-up is the first CHB study
resistant (51 % of patients treated for up to 5 years) [12], to show that long-term use of an oral nucleos(t)ide agent—
and lamivudine and ADV dual resistant (91 % of patients TDF monotherapy for chronic HBV infection—is able to
with virologic breakthrough after treatment for a median of suppress viral replication without development of resis-
24 months) [14]. In this study, we report the lack of resis- tance and is well tolerated.
tance to TDF through 7 years in mostly treatment-naive
patients. Additionally, lack of resistance to TDF has been Acknowledgments This study and the analyses presented were
sponsored by Gilead Sciences, Inc. Anna Lau, PhD, and Evelyn Albu,
reported through 3.5 years (168 weeks) in prior ADV-trea-
PhD, of Percolation Communications LLC provided editorial assis-
ted patients [15] and through 2 years (96 weeks) in lami- tance during manuscript development. Gilead Sciences, Inc., provided
vudine-resistant patients [16]. The absence of viral financial support for manuscript development.
resistance to TDF carries important implications for clinical
Conflict of interest The authors disclose the following financial
outcomes, because patients without resistance development
relationships that may be viewed as potential conflict of interest.
may have a lower risk of liver disease progression [17].
Author Employment Stock Consultancy Honoraria Research grant Paid Other
ownership expert
testimony
MB Bristol-Myers Bristol-Myers
Squibb; Gilead Squibb; Gilead
NT AbbVie; Gilead; AbbVie; Bayer; AbbVIe;
Janssen Bristol-Myers Beckman;
Squibb; Bristol-Myers
Gilead; Squibb; Gilead;
Janssen; Janssen; Roche;
Merck; Vertex
Roche; Salix
JP Abbott; AbbVie; Bristol-Myers Abbott; Bristol-
Bristol-Myers Squibb; Myers Squibb;
Squibb; Novartis; Boehringer;
Boehringer; Gilead; Roche Gilead; Kedrion;
GlaxoSmithKline; Janssen; Merck;
Kedrion; Janssen; Merck Sharp &
Merck; Merck Dohme; Novartis;
Sharp & Dohme; Roche
Novartis, Roche
123
Dig Dis Sci (2015) 60:1457–1464 1463
Author Employment Stock Consultancy Honoraria Research grant Paid Other
ownership expert
testimony
RF AbbVie; Bristol- AbbVie; Bristol- Roche
Myers Squibb; Myers Squibb;
Gilead; Janssen; Gilead; Janssen;
Merck; Novartis; Merck; Novartis;
Roche Roche
SG AbbVie; Bristol- AbbVie; Bristol-
Myers Squibb; Gilead; Myers Squibb;
Janssen; Merck Sharp & Gilead; Janssen;
Dohme; Roche Merck Sharp &
Dohme; Roche
ZK Gilead; Idenix;
Jansen; Novartis;
Receptos; Roche
RAS Gilead Gilead
JFF Gilead Gilead
EBM Gilead Gilead
PC Gilead Gilead
KMK Gilead Gilead
GMS Gilead Gilead
EG Achillion; Gilead;
Idenix; Janssen;
Merck; Novartis;
Novira; Roche
PM Abbott; Boehringer Bristol-Myers
Ingelheim; Bristol- Squibb; Gilead;
Myers Squibb; Janssen/Tibotec;
Gilead; Janssen/ Merck; Novartis;
Tibotec; Merck; Roche
Novartis; Pfizer;
Roche; Vertex
Open Access This article is distributed under the terms of the phosphonates on human hepatitis B virus and duck hepatitis B
Creative Commons Attribution Noncommercial License which per- virus infections in tissue culture. Antimicrob Agents Chemother.
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