Twenty-four-week Clevudine Therapy Showed Potent
and Sustained Antiviral Activity in HBeAg-positive
Chronic Hepatitis B
Byung Chul Yoo,1Ju Hyun Kim,2Young-Hwa Chung,3Kwan Sik Lee,4Seung Woon Paik,1Soo Hyung Ryu,5
Byung Hoon Han,6Joon-Yeol Han,7Kwan Soo Byun,8Mong Cho,9Heon-Ju Lee,10Tae-Hun Kim,11Se-Hyun Cho,7
Joong-Won Park,12Soon-Ho Um,8Seong Gyu Hwang,13Young Soo Kim,14Youn-Jae Lee,15Chae Yoon Chon,4
Byung-Ik Kim,16Young-Suk Lee,7Jin-Mo Yang,7Haak Cheoul Kim,17Jae Seok Hwang,18Sung-Kyu Choi,19
Young-Oh Kweon,20Sook-Hyang Jeong,21Myung-Seok Lee,22Jong-Young Choi,7Dae-Ghon Kim,23Yun Soo Kim,2
Heon Young Lee,24Kwon Yoo,11Hee-Won Yoo,25and Hyo-Suk Lee26
The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24
weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A
total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were ran-
domized (3:1) to receive clevudine 30 mg once daily (n ? 182) or placebo (n ? 61) for 24
weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA
placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was
sustained off therapy, with 3.73 log10reduction at week 34 and 2.02 log10reduction at week
levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who
group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the
of adverse events (AEs) was similar between the clevudine group and the placebo group. No
resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A
24-week clevudine therapy was well tolerated and showed potent and sustained antiviral
effect without evidence of viral resistance during treatment period in HBeAg-positive
chronic hepatitis B. (HEPATOLOGY 2007;45:1172-1178.)
Abbreviations: AE, adverse event; cccDNA, covalently closed circular deoxyribonucleic acid; HBeAg, hepatitis B e antigen; ULN, upper limit of normal; WHV,
woodchuck hepatitis virus.
From the1Samsung Medical Center, Sungkyunkwan University;2Gachon Medical School;3Asan Medical Center;4Yonsei University Hospital;5Inje University Seoul
Paik Hospital;6Kosin Medical School;7The Catholic University of Korea;8Korea University Hospital;9Pusan National University Hospital;10Youngnam University
Medical Center;11Ewha Women’s University;12National Cancer Center;13Pochon CHA University Bundang CHA Hospital;14Inha University Hospital;15Inje
University Busan Paik Hospital;16Kangbuk Samsung Medical Center;17Wonkwang University Hospital;18Keimyung University Dongsan Medical Center;19Chonnam
National University Hospital;20Kyungpook National University Hospital;21Korea Institute of Radiological and Medical Sciences;22Hallym University Medical Center
Kangnam Sacred Heart Hospital;23Chonbuk National University Hospital;24Chungnam National University Hospital25Bukwang Pharmaceutical Co., Ltd.;26Seoul
National University Hospital, Department Internal Medicine, Seoul, Korea.
Received September 21, 2006; accepted December 21, 2006.
Supported by grants from Bukwang Pharmaceutical Co., Ltd. and the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (02-PJ2-PG4-
NIH clinical trial registration number: NCT00313287.
Address for reprint requests: Hyo-Suk Lee, M.D., Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28
Yungun-dong, Chongno-gu, Seoul 110-744, Korea. E-mail: firstname.lastname@example.org; fax: (82) 2-744-8243.
Copyright © 2007 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
rhosis and hepatocellular carcinoma.1The aims of
treatment of chronic hepatitis B are to achieve sustained
suppression of HBV replication and remission of liver
chronic HBV infection do not provide a cure or durable
remission in the majority of patients, there is a growing
demand for new antiviral agents with improved efficacy.
An ideal regimen should be safe with more potent and
sustained viral suppression and with minimal chance of
developing resistant mutants.
syl) thymine, L-FMAU] is a nucleoside analogue of the
unnatural ?-L configuration that has potent activity
against HBV and some activity against Epstein-Barr virus
in vitro.3-5The lack of cytotoxicity reflects the inability of
the 5?-triphosphate of clevudine as a substrate.6,7More-
over, clevudine was found to have no effect on mitochon-
efficiently phosphorylated by 3 intracellular enzymes to
geous characteristic of clevudine is prolonged sustained
suppression of viral replication even after withdrawal of
more than 12 weeks after cessation of dosing.9Serum
WHV DNA remained undetectable for up to 56 weeks
after WHV-infected animals were given oral doses of 10
mg/kg daily clevudine for 12 weeks.10The sustained viral
suppression has been demonstrated to be associated with
significant reduction of covalently closed circular DNA
(cccDNA) in hepatocytes.11,12
In a phase I/II dose-escalating clinical study13and a
randomized phase II clinical trial,144-week and 12-week
clevudine therapy produced potent viral suppression dur-
ing therapy and induced a prolonged antiviral effect after
withdrawal of treatment. The present study was con-
ducted to evaluate the safety and efficacy of 30 mg clevu-
dine once a day for 24 weeks and to assess the durable
antiviral response for 24 weeks after cessation of dosing.
hronic infection with HBV is common, globally
affecting more than 350 million people, and fre-
Patients and Methods
This double-blind, randomized, placebo-controlled
phase III study was conducted at 33 institutions in South
Korea. Patients were randomized, based on a predeter-
mined computer generated list, to receive clevudine 30
mg or placebo (3:1) once daily for 24 weeks with an
additional 24-week follow-up period following the cessa-
tion of dosing.
The study was conducted in accordance with the prin-
ciples of the Declaration of Helsinki and was consistent
consent was obtained from all study participants before
the informed consent form were approved by the ethics
committee at each study site and by the Korean Food and
Patients were monitored at baseline, days 8, 15, and
and 48 without therapy. Patients underwent clinical as-
sessments of tolerability (open-ended interview), physical
exam, electrocardiography, and blood draws to measure
laboratory parameters and serum HBV DNA levels.
hepatitis B e antigen (HBeAg)-positive chronic hepatitis
B, defined as the presence in serum of hepatitis B surface
serum ALT levels between 1.2 and 15 times the upper
limit of normal (ULN). Exclusion criteria included coin-
fection with hepatitis C, hepatitis D, or the human
immunodeficiency virus; evidence of cirrhosis or hepa-
analog that is active against HBV; and use of interferon
alpha within 6 months before enrollment. Breastfeeding
ing to use barrier contraceptive methods were also ex-
The sample size was calculated to detect 50% of statis-
tically significant differences in the proportion of patients
between the clevudine treatment group and the placebo
group, assuming that placebo and clevudine responses
were 10% and 60%, respectively. The sample size was
estimated using the Z-test with an alpha level of 0.05 and
95% power for comparing placebo group with clevudine
treatment group. The ratio of patient numbers in each
group (placebo, clevudine 30 mg) was 1:3. According to
this assumption, a sample size of 39 patients in the clevu-
dine group and 13 patients in the placebo group was
calculated. However, in order to evaluate the safety and
tolerability of clevudine as well as its efficacy, a total of
248 patients, more than 4 times the calculated sample
size, were enrolled.
HEPATOLOGY, Vol. 45, No. 5, 2007YOO ET AL. 1173
The primary efficacy endpoint was reduction in serum
line at the end of treatment and during the follow-up
period after withdrawal of treatment. Serum HBV DNA
levels were measured at a central laboratory using the
Digene Hybrid Capture II assay (Digene Corp., Gaith-
ersburg, MD) with a lower limit of detection of 4700
copies/mL. When HBV DNA was undetectable by Di-
gene Hybrid Capture II assay, the COBAS Amplicor
PCR assay (Roche Molecular Systems, Branchburg, NJ)
to measure lower levels of HBV DNA.
Secondary endpoints included the proportion of pa-
tients with undetectable HBV DNA, as measured by the
COBAS Amplicor PCR assay; HBeAg loss; HBeAg sero-
conversion (HBeAg loss and appearance of hepatitis B e
antibody); and serum ALT normalization.
The safety analysis included data from all 243 eligible
patients who received at least 1 dose of study medication
after randomization. Safety evaluations included analysis
of adverse events (AEs), serious AEs, and deaths. Exacer-
bation of hepatitis B was defined as ALT and/or AST
elevations (1) ?20 ? ULN or (2) ?10 ? ULN and a
tion of hepatitis B was considered as a serious AE.
Genotypic analysis of the HBV DNA polymerase do-
main (amino acids 119 to 247) by dideoxy sequencing
were performed at baseline and at the end of the 24-week
dosing period. For detection of lamivudine-related
tations at rt180 and rt204, RFLP (Restriction Fragment
Length Polymorphism) assay were performed at baseline
and at the end of the 24-week dosing period as described
elsewhere.15HBV DNA breakthrough was defined as an
increase in the level of HBV DNA of at least 1 log10
copies/mL from the lowest point while on treatment.
Results were analyzed on the basis of intention-to-
treat. All 243 eligible patients who received at least 1 dose
the safety analysis. Patients discontinuing the study after
receiving the first study drug dose were included in the
efficacy analysis until the time of their discontinuation.
The overall treatment comparison was assessed using
the Wilcoxon 2-sample test for continuous data, and the
chi-squared test or a 2-sided Fisher’s exact test for cate-
gorical data. Statistical significance was performed with
an alpha level of 0.05.
A total of 243 eligible patients were enrolled at 33 sites
between June 23, 2003 and December 13, 2003 and re-
ceived at least 1 dose of clevudine 30 mg (n ? 182) or
placebo (n ? 61) in a blinded fashion. The 2 treatment
groups were well balanced at the baseline (Table 1).
From 243 patients, 230 patients (173 in the clevudine
group and 57 in the placebo group) completed the 24-
week treatment period and 221 patients (171 in the cle-
the study in the clevudine group due to violation of eligi-
bility criteria in 5 patients, withdrawal of consent in 3
patients, poor compliance in 2 patients, and medication
error in 1 patient. A total of 11 patients discontinued the
study in the placebo group due to withdrawal of consent
in 6 patients, AEs in 2 patients, violation of eligibility
criteria in 2 patients, and concomitant medication in 1
patient (Fig. 1).
Table 1. Patient Characteristics at Baseline
(n ? 182)
(n ? 61)
(n ? 243)
Median age (years)
Sex, n (%)
Median HBV DNA (log10copies/mL)
Median ALT (U/L)
Mean ALT (U/L)
ALT ? 2 ? ULN at baseline n (%)
ALT 2–5 ? ULN at baseline n (%)
ALT ?5 ? ULN at baseline n (%)
37.534 36 0.0947*
*Wilcoxon 2-sample test.†?2-test.‡t test. §Two-sided Fisher’s exact test.
1174YOO ET AL.HEPATOLOGY, May 2007
Virologic and Serologic End Points
Clevudine treatment for 24 weeks produced prompt
and profound viral suppression. Median serum HBV
DNA reductions from baseline at week 24 were 5.10 and
0.27 log10 copies/mL in the clevudine and placebo
groups, respectively (P ? 0.0001). Viral suppression in
the clevudine group was sustained even after withdrawal
of treatment with 3.73 log10reduction at week 34 and
2.02 log10reduction at week 48, compared with 0.51
log10reduction at week 34 and 0.68 log10reduction at
week 48 in the placebo group (P ? 0.0001) (Fig. 2).
At week 24, 102 of 173 of patients (59.0%) in the
clevudine group but none of 57 patients in the placebo
group had undetectable serum HBV DNA levels by Am-
At week 24, HBeAg loss and seroconversion occurred
in 11.1% and 7.6%, respectively, of the patients in the
clevudine group. These rates were similar to those in the
placebo group (12.3% and 8.8%, respectively). At week
48, HBeAg loss and seroconversion occurred in 15.3%
and 10.0%, respectively, of the patients in the clevudine
group. These rates were also similar to those in the pla-
cebo group (12.0% and 12.0%, respectively).
In all the 19 patients in the clevudine group who
achieved HBeAg loss during the 24-week treatment pe-
riod, viral DNA levels were significantly reduced and well
of 7 patients in the placebo group with HBeAg loss
showed no consistent reduction of viral DNA levels
The proportion of patients who achieved normaliza-
tion of ALT levels was 68.2% in the clevudine group and
17.5% in the placebo group at week 24 (P ? 0.0001). In
accordance with sustained viral suppression, ALT nor-
Fig. 1. Flowchart of the present study.
Fig. 2. Median log10hepatitis B virus (HBV) DNA change from base-
Fig. 3. Median log10hepatitis B virus (HBV) DNA change from base-
line in the patients with HBeAg loss at week 24.
HEPATOLOGY, Vol. 45, No. 5, 2007YOO ET AL. 1175
malization in the clevudine group was well maintained
during the post-treatment follow-up period. The ALT
normalization rates in the clevudine group increased fur-
ther after withdrawal of therapy, up to 80.1% at week 34,
and then decreased to 61.2% at week 48; these propor-
tions were significantly higher than in the placebo group
Comparative analysis of genomic sequence of HBV
isolated from the serum of the patients at baseline and at
[rtA181A/T (n ? 3), rtA181T (n ? 2), and rtV191V/I
(n ? 1)] in conserved sites of the DNA polymerase do-
patients had consistently reduced serum HBV DNA lev-
els during treatment and showed no evidence of HBV
DNA breakthrough. In the placebo group, 4 nucleotide
substitutions [rtL132M (n ? 1), rtA181S (n ? 1), and
rtV191V/I (n ? 2)] were observed in 4 patients.
Lamivudine-related YMDD mutations at rt180 and
rt204 were not detected by RFLP assay at baseline and at
the end of 24 weeks dosing period in both groups.
Safety and Tolerability
days. No discontinuation of treatment due to AEs oc-
of hepatitis B in 2 patients.
The AEs reported during the treatment period and the
2. During the treatment period, the incidence of AEs was
similar in the 2 groups. The most frequent AEs, i.e., oc-
curring in ?5% of patients overall, were upper respira-
tory symptoms (14.3%), asthenia, dyspepsia, abdominal
group, the most frequent AEs were upper respiratory
symptoms (16.4%), ALT increased (14.8%), asthenia,
abdominal pain, dyspepsia, and diarrhea. The incidence
of serious AEs during treatment was 5.0% in the clevu-
dine group and 19.7% in the placebo group (P ? 0.001).
ALT elevations to a level ?5 times the ULN were ob-
served significantly less frequently in the clevudine group
(19.2%) than in the placebo group (36.1%). Exacerba-
tion of hepatitis B during treatment were observed in 4
patients in the clevudine group (2.2%) and 9 patients in
the placebo group (14.8%) (P ? 0.0001). In the clevu-
dine group, all the exacerbations of hepatitis B were self-
limiting with continued treatment without signs of
with exacerbation of hepatitis B discontinued participat-
ing in the study due to persistence of exacerbation and
signs of hepatic decompensation.
During the post-treatment follow-up period, the inci-
However, ALT elevations to a level ?5 times the ULN
were observed significantly less frequently in the clevu-
dine group (7.1%) than in the placebo group (19.7%).
In this large, randomized placebo-controlled trial, cle-
vudine 30 mg daily for 24 weeks showed highly potent
antiviral activity in HBeAg-positive chronic hepatitis B
patients. Clevudine suppressed HBV DNA by a median
of 5.10 log10copies/mL, and 59% of clevudine treated
patients had undetectable levels of HBV DNA levels by
PCR assay after 24 weeks of treatment. Although direct
head-to-head comparisons are not available, the degree of
copies/mL) appears higher than those achieved by treat-
ment with 100 mg lamivudine once daily at week 22
(about 3.2 log10copies/mL),1610 mg adefovir dipivoxil
once daily at week 48 (3.57 log10copies/mL),170.5 mg
Table 2. Summary of Cumulative Safety Data
Timing and event
No. of Patients (%)
(n ? 182)
(n ? 61)
Discontinuation due to adverse event
Any adverse event
Serious adverse event
ALT ? 5 ? ULN
Exacerbation of hepatitis B
During treatment-free follow-up
Any adverse event
Serious adverse event
ALT ? 5 ? ULN
0 1 (1.6)
9 (14.8) ?0.0001*
*Two-sided Fisher’s exact test.†?2-test.
Fig. 4. Changes in the serum ALT normalization rate.
1176YOO ET AL.HEPATOLOGY, May 2007
entecavir once daily at week 22 (about 4.8 log10copies/
mL),16and 180 ?g peginterferon alfa-2a once weekly at
week 48 (4.5 log10copies/mL).18However, in interpret-
and 1 PCR-based assay for the assessment of HBV DNA
levels, which makes data interpretation somewhat com-
plicated. Unfortunately, the dynamic range of quantifica-
tion of the 2 HBV DNA assays that were commercially
available at the initiation time of the present clinical trial
varied considerably, and neither covered the full range of
HBV DNA values that can be observed in untreated and
treated patients with chronic HBV.19In the ongoing tri-
PCR assays (HBV Beacom assay and COBAS TaqMan
term phase II clinical trials,13,14clevudine has a peculiar
characteristic of prolonged viral suppression after with-
drawal of treatment. At 24 weeks after discontinuation of
treatment, the median HBV DNA was still 2 logs below
the baseline level. The mechanisms of delayed viral recru-
descence remain to be elucidated. The measured plasma
half-life of clevudine (43 to 61 hours) argues against its
persistence in the blood.13In HepG2 cells, clearance of
intracellular phosphorylated clevudine metabolites and
clearance of intracellular phosphorylated lamivudine me-
tabolites were similar (Cheng YC, unpublished results).
These data negate the possibility that sustained viral sup-
olites in hepatocytes. The most plausible mechanism of
sustained viral suppression may be that the potent sup-
in hepatocytes as observed in woodchucks.11,12With cle-
clined more slowly than replicating viral DNAs,
consistent with a half-life of 33 to 50 days.11The loss of
cccDNA was comparable to that expected from the esti-
mated death rate of hepatocytes in these woodchucks,
suggesting that elimination of infected hepatocytes is one
of the major mechanisms for reduction of cccDNA in
clevudine treated woodchucks. In addition, clevudine
therapy has been proven to break humoral and cell-medi-
ated immune tolerance in chronic WHV infection by
reducing viral and antigen load.22We previously demon-
strated that episodes of acute exacerbations during the
early treatment period in the clevudine-treated groups
were associated with more prolonged viral suppression.14
Collectively, these findings strongly suggest that the lack
tion of intrahepatic cccDNA through the elimination of
HBV-infected hepatocytes. The actual measurement of
clevudine triphosphate levels and cccDNA levels in hepa-
tocytes from the patients undergoing clevudine therapy
still remains to be investigated.
In accordance with potent and sustained viral suppres-
sion, clevudine treatment induced a high normalization
rate of serum ALT levels at the end of the 24-week treat-
ment period, and the ALT normalization was well main-
tained during the post-treatment follow-up period.
In this phase III study, clevudine was well tolerated for
24 weeks at the doses administered, with no specific pat-
tern of AEs emerging during the study. Serious AEs in-
significantly less frequent in the clevudine group than in
the placebo group.
There was no emergence of drug resistance during the
treatment. The rtA181A/T, rtA181T, and rtV191V/I
substitutions observed in patients in the clevudine group
were not associated with HBV DNA breakthrough.
The rtV191V/I, rtA181A/T, rtL132M, and rtA181S
substitutions we found during our studies have not been
described or characterized as resistant variants to lamivu-
dine, adefovir, and entecavir. The rtA181T mutation was
found in some patients treated with lamivudine and ad-
efovir, but its relevance to resistance is not clear.23,24
Despite the potent HBV DNA suppression, the rates
of HBeAg loss and seroconversion in the clevudine group
were no better than in the placebo group. This may be
attributed to the short period of clevudine therapy. Sero-
er-term treatment studies. Interestingly, while HBeAg
loss in the clevudine group was consistently associated
with significant and persistent reduction of HBV DNA
levels, HBeAg loss in the placebo group was not necessar-
ily associated with consistent reduction of viral DNA lev-
well tolerated, and produced a highly potent and sus-
tained antiviral effect associated with sustained normal-
ization of ALT levels without emergence of drug
resistance. We conclude that clevudine shows promising
infection. Further studies are underway to investigate the
safety and efficacy of clevudine at a larger scale and over a
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