A Revisit of Prophylactic Lamivudine for

Chemotherapy-Associated Hepatitis B Reactivation in

Non-Hodgkin’s Lymphoma: A Randomized Trial
Chiun Hsu,1,2 Chao A. Hsiung,3 Ih-Jen Su,4 Wei-Shou Hwang,5 Ming-Chung Wang,6 Sheng-Fung Lin,7 Tseng-Hsi Lin,8
Hui-Hua Hsiao,7 Ji-Hsiung Young,8 Ming-Chih Chang,9 Yu-Min Liao,10 Chi-Cheng Li,11 Hung-Bo Wu,12 Hwei-Fang Tien,2
Tsu-Yi Chao,13 Tsang-Wu Liu,14 Ann-Lii Cheng,1,2,14 and Pei-Jer Chen2,15

Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV-carrying

cancer patients who undergo chemotherapy, but the optimal treatment protocol remains
undetermined. In this study, HBV carriers with newly diagnosed non-Hodgkin’s lymphoma
(NHL) who underwent chemotherapy were randomized to either prophylactic (P) or ther-
apeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of
the first course of chemotherapy and continued treatment until 2 months after completion of
chemotherapy. Group T patients received chemotherapy alone and started lamivudine treat-
ment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5-fold of
the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation
during the 12 months after starting chemotherapy. During chemotherapy, fewer group P
patients had HBV reactivation (11.5% versus 56%, P ⴝ 0.001), HBV-related hepatitis (7.7%
versus 48%, P ⴝ 0.001), or severe hepatitis (ALT more than 10-fold ULN) (0 versus 36%,
P < 0.001). No hepatitis-related deaths occurred during protocol treatment. Prophylactic
lamivudine use was the only independent predictor of HBV reactivation. After completion of
chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two
patients, both in group P, died of HBV reactivation–related hepatitis, 173 and 182 days,
respectively, after completion of protocol treatment. When compared with an equivalent
group of lamivudine-naïve lymphoma patients who underwent chemotherapy, therapeutic
use of lamivudine neither reduced the severity of HBV-related hepatitis nor changed the
patterns of HBV reactivation. Conclusion: Prophylactic lamivudine use, but not therapeutic
use, reduces the incidence and severity of chemotherapy-related HBV reactivation in NHL
patients. (HEPATOLOGY 2008;47:844-853.)

Abbreviations: ALT, alanine aminotransferase; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CI, confidence interval; HBeAg: hepatitis B e antigen;
HBV, hepatitis B virus; IPI, International Prognostic Index; NHL, non-Hodgkin’s lymphoma; ULN, upper limit of normal; YIDD, tyrosine-isoleucine-aspartate-aspartate;
YMDD, tyrosine-methionine-aspartate-aspartate; YVDD, tyrosine-valine-aspartate-aspartate.
From the 1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; the 2Department of Internal Medicine, National Taiwan University
Hospital, Taipei, Taiwan; the 3Division of Biostatistics and Bioinformatics, National Health Research Institutes, Zhunan, Taiwan; the 4Division of Clinical Research,
National Health Research Institutes, Zhunan, Taiwan; the 5Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; the 6Department of Internal
Medicine, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan; the 7Department of Internal Medicine, Kaohsiung Medical University Chung-Ho Memorial Hospital,
Kaohsiung, Taiwan; the 8Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; the 9Department of Internal Medicine, Mackay
Memorial Hospital, Taipei, Taiwan; the 10Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; the 11Department of Internal
Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; the 12Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;
the 13Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan; the 14Division of Cancer Research, National Health Research Institutes, Taipei,
Taiwan; and the 15Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Received August 20, 2007; accepted October 23, 2007.
Supported by the Taiwan Cooperative Oncology Group and the National Health Research Institutes, Taiwan (project T1401).
Address reprint requests to: Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan 7, Chung-Shan South Road,
Taipei, Taiwan, 100. E-mail: alcheng@ntu.edu.tw; fax: (886) 2-23711174; or: Pei-Jer Chen, M.D., Ph.D., Hepatitis Research Center, Nationa Taiwan University
Hospital, Taipei, Taiwan 7, Chung-Shan South Road, Taipei, Taiwan, 100. E-mail: peijerchen@ntu.edu.tw; fax: (886) 2-23317624.
Copyright © 2007 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22106
Potential conflict of interest: Nothing to report.

844
HEPATOLOGY, Vol. 47, No. 3, 2008
H
epatitis B (HBV) reactivation and hepatitis flare
induced by cytotoxic chemotherapy is common
in cancer patients who have chronic HBV in-
fection.1,2 It is best characterized in patients with hema-
tological malignancies but also can occur in patients with
solid tumors. Hepatic decompensation and death attrib-
utable to HBV reactivation occurred to 5% to 40% of
HBV carriers who underwent chemotherapy. Because
most patients who develop HBV reactivation and hepati-
tis have to postpone their scheduled chemotherapy,3 pre-
vention of HBV reactivation may improve the treatment
outcome of cancer patients with chronic HBV infection.
Lamivudine is the first nucleoside analog to show effi-
cacy in the treatment of chronic and acute HBV infec-
tion.4-6 The preventive effect of lamivudine on
chemotherapy-induced HBV reactivation was demon-
strated in a randomized clinical trial as well as in many
prospective case series with or without historical con-
trol.7-10 The incidence of HBV reactivation for patients
who received lamivudine prophylaxis in these studies
ranged from 0 to 20%, compared with 33% to 67% in
controls. The incidence and severity of hepatitis flare was
also significantly reduced by lamivudine prophylaxis.
Although the preventive effect of lamivudine is well
known, several important issues remain undetermined.
First, the duration of lamivudine prophylaxis varied
among different clinical series. Because HBV reactivation
after withdrawal of lamivudine prophylaxis is common,
prolonged lamivudine use is recommended, but the opti-
mal duration is unknown. Second, long-term lamivudine
treatment may induce mutation in the tyrosine-methio-
nine-aspartate-aspartate motif of the HBV DNA poly-
merase gene (the YMDD mutation), which can cause
hepatitis flare.11 Whether the induction of YMDD mu-
tation by lamivudine prophylaxis jeopardizes the clinical
outcome of the cancer patients remains unclear. Third,
the effect of therapeutic use of lamivudine, starting after
clinical evidence of hepatitis, is not fully established. Al-
though early studies indicated that lamivudine treatment
was effective for patients with developed hepatitis,12,13
spontaneous recovery of viral reactivation and hepatitis
was also common.
The study’s objective is to compare the efficacy of pro-
phylactic and therapeutic use of lamivudine for chemo-
therapy-induced HBV reactivation in non-Hodgkin’s
lymphoma (NHL) patients. NHL has been considered a
high-risk population for chemotherapy-induced HBV re-
activation.14 To further explore the potential efficacy of
therapeutic use of lamivudine, the results of this study
were compared with those of our previous study in which
the natural course of HBV reactivation in NHL patients
HSU ET AL. 845
was prospectively followed during and after chemothera-
py.15
Patients and Methods
Study Design and Patient Eligibility. This study,
designed by the Taiwan Cooperative Oncology Group
and approved by the Ethics Committee of the National
Health Research Institutes, Taiwan, in 2001, was con-
ducted in 10 clinical centers in Taiwan. After obtaining
informed consent, the patients were checked for eligibility
for this clinical trial. Patients who fulfilled all the eligibil-
ity criteria were then randomized in a 1:1 ratio to receive
either prophylactic or therapeutic lamivudine treatment.
The Statistical Center of the Division of Biostatistics of
the National Health Research Institutes generated the
randomization list by permuted block randomization.
The randomization code was given only when the patient
passed the eligibility check.
Participants were patients with newly diagnosed, his-
tologically proven intermediate-grade or high-grade
NHL and positive serum HBV surface antigen. Key eli-
gibility criteria included: age 16 to 75 years , alanine ami-
notransferase (ALT) less than 5 times the upper limit of
normal (ULN), bilirubin ⬍ 2.5 mg/dL, neutrophil ⱖ
2000/mm3, platelet ⱖ 100,000/mm3, creatinine ⱕ 1.5
mg/dL, urea nitrogen ⱕ 25 mg/dL, Eastern Cooperative
Oncology Group performance score 0 to 2, and measur-
able tumors on clinical imaging. Key exclusion criteria
included Child-Pugh class B or C cirrhosis, grade 2 or
greater heart failure by the New York Heart Association
classification, previous chemotherapy or radiotherapy,
concurrent glucocorticoid therapy for other reasons, or
other primary liver diseases, such as chronic hepatitis C,
hepatitis D, autoimmune hepatitis, or Wilsons’ disease.
Interventions. All participants received the chemo-
therapy regimen consisting of cyclophosphamide, 750
mg/m2, doxorubicin, 50 mg/m2, and vincristine 1.4
mg/m2 intravenously on day 1 and prednisolone, 60 mg/
m2/day orally on days 1 to 7 (CHOP regimen). The treat-
ment cycles were repeated every 21 days. Participants who
achieved a complete response were given 2 more cycles of
chemotherapy, for a minimum of 6 cycles. Participants
who achieved a maximal response of partial response, sta-
ble disease, or progressive disease were changed to second-
line chemotherapy. The regimens were at the discretion of
individual investigators in different hospitals. Radiation
therapy for residual localized tumors was allowed.
Participants who were randomized to the prophylac-
tic group started lamivudine treatment, 100 mg/day
orally, on day 1 of the first course of chemotherapy.
Lamivudine treatment was continued until 2 months
846 HSU ET AL.
after the completion of chemotherapy, when chemo-
therapy-induced myelosuppression resolved, as con-
firmed by follow-up hemogram examinations. If
second-line chemotherapy was used, lamivudine at the
same dosage was continued until 2 months after com-
pletion of the second-line chemotherapy. Patients who
were randomized to the therapeutic group started lami-
vudine therapy, 100 mg/day orally, when elevation of
ALT was noted during follow-up, and continued lami-
vudine treatment until hepatitis resolved. For patients
whose baseline ALT was normal, the cutoff ALT level
for starting lamivudine treatment was greater than 1.5-
fold ULN. For patients whose baseline ALT was abnor-
mal, the cutoff level was greater than 2.0-fold ULN.
After resolution of hepatitis, prophylactic lamivudine
was not given in subsequent chemotherapy.
Outcomes and Follow-up. The primary endpoint
was the incidence of HBV reactivation during and within
12 months after chemotherapy. Serum samples were col-
lected at baseline, before the start, and at the nadir of every
course of chemotherapy to check hemogram, liver func-
tion, and HBV DNA levels. Hepatitis flare was defined as
a greater than 3-fold increase of serum ALT level that
exceeded 100 IU/L. The hepatitis flare was attributed to
HBV reactivation if it was preceded or accompanied by a
greater than 10-fold increase, compared with previous
nadir levels, of HBV DNA or by the reappearance of
hepatitis B e antigen (HBeAg) in the serum for patients
whose baseline HBeAg was negative. For patients who
developed hepatitis, serum samples were collected every
week until the hepatitis resolved, regardless of the chemo-
therapy schedule.
After completing the protocol treatment (CHOP che-
motherapy plus lamivudine for the prophylactic group,
CHOP chemotherapy alone for the therapeutic group),
serum samples were collected every month during fol-
low-up for 12 months for the examination of liver func-
tion and HBV DNA levels. For patients who underwent
second-line chemotherapy, serum samples were collected
every month until 3 months after the last course of sec-
ond-line chemotherapy.
All the HBV DNA quantification and genotyping tests
were performed by the Hepatitis Research Center of Na-
tional Taiwan University Hospital. Serum DNA was ex-
tracted by using the QIAamp DNA Blood Mini Kit
(Qiagen Inc., Valencia, CA). Methods of HBV DNA
quantification and HBV genotyping were described pre-
viously.16 Detection of the YMDD mutation was con-
firmed by sequencing.
During protocol treatment, patients were followed up
by computed tomography after every 2 cycles of chemo-
therapy to document the response to chemotherapy. The
HEPATOLOGY, March 2008
response was evaluated according to the standardized re-
sponse criteria recommended by the National Cancer In-
stitute.17
To further explore the effect of therapeutic use of lami-
vudine on the outcome of hepatitis, data from our previ-
ous study of chemotherapy-induced HBV reactivation
was used as historical control.15 In the previous study,
patients with newly diagnosed NHL were regularly fol-
lowed up for HBV reactivation and HBV-related hepati-
tis flares during and after chemotherapy. The severity of
hepatitis flare and the types of HBV reactivation were
compared.
Statistical Analysis. The sample size calculation was
based on the assumption that the incidence of HBV reac-
tivation was 50% and 80% for the prophylactic group and
the therapeutic group, respectively. Based on 2-sided tests
with a significance level of 0.05 and a statistical power of
80%, recruiting of 90 patients in the 2 arms was planned.
Secondary endpoints included the incidence of hepatitis,
hepatic failure, the objective response rate to chemother-
apy, and overall survival. The Data and Safety Monitor-
ing Committee of the Taiwan Cooperative Oncology
Group reviewed the safety data of this study every 6
months.
Survival was calculated by the Kaplan-Meier
method and compared by the log-rank test. Cox regres-
sion and unconditional logistic regression were applied
to estimate the hazard ratios and odds ratios, respec-
tively. Categorical variables were compared by the
Fisher’s exact test. Continuous variables were com-
pared by the Wilcoxon rank sum test. The statistical
analyses were done using the SAS software (v.8.2; SAS
Institute, Inc., NC).
Results
Patient Characteristics. The study started patient
enrollment on October 1, 2001. After the publication7 of
a randomized study demonstrating the efficacy of lamivu-
dine prophylaxis, the Data and Safety Monitoring Com-
mittee performed an interim analysis. The conditional
power, calculated by the method of stochastic curtail-
ment, of rejecting the null hypothesis was 0.95651, given
the data already observed. Therefore, the Committee de-
cided that early termination of patient recruitment was
indicated. At the time of the early termination, a total of
52 patients were randomized (Fig. 1).
The baseline characteristics of the participants are sum-
marized in Table 1. Patients in the therapeutic group
appeared more likely to have positive HBeAg (8 versus 2,
P ⫽ 0.04) and HBV DNA of more than 1,000,000 cop-
ies/mL (9 versus 3, P ⫽ 0.05). Other clinical characteris-
HEPATOLOGY, Vol. 47, No. 3, 2008 HSU ET AL. 847

tics were similar between the 2 groups. The patients Table 1. Baseline Characteristics of the Patients
received a median of 6 cycles of chemotherapy (range, 1-8 Prophylactic Therapeutic
cycles). Group Group
(n ⴝ 26) (n ⴝ 25) P
HBV Reactivation and Hepatitis Flare. All of the
Age in years (median/range) 50.5 (32–67) 41(20–74) 0.16
26 patients in the prophylactic group and 17 patients in
Male/female 12/14 13/12 0.78
the therapeutic group received lamivudine treatment. 0.25
The median duration of lamivudine treatment was 190 Pathology
days (range, 85-385 days) for the prophylactic group and Diffuse large cell/ immunoblastic 24 20
Others 2 5
139 days (range, 17-276 days) for the therapeutic group. Performance status (ECOG score) 0.35
The primary endpoint of this study is HBV reactiva- 0–1 25 22
tion during chemotherapy and within 12 months of end- 2 1 3
IPI index 0.42
ing chemotherapy. The HBV reactivation rate was 30.8% Low-risk 9 5
[95% confidence interval (CI), 14.3%-51.8%] in the pro- Low-intermediate 7 8
phylactic group and 60.0% (95%CI, 38.7%-78.9%) in High-intermediate 9 8
the therapeutic group (P ⫽ 0.05). Patients in the prophy- High-risk 1 4
HBeAg 0.04
lactic group had a significantly longer time-to-HBV reac- Negative 24 17
tivation (hazard ratio, 0.35; 95%CI, 0.15-0.84; P ⫽ Positive 2 8
0.018). HBV DNA quantity (copies/mL) 0.05
⬍1,000,000 23 16
The relationship between protocol treatment, HBV ⬎1,000,000 3 9
reactivation, and hepatitis flare is summarized in Table HBV genotypes* 0.22
2. During protocol treatment, patients in the prophy- B 18 15
B⫹C 1 0
lactic group had a significantly lower risk of HBV re- C 0 2
activation [11.5% (95%CI, 2.5%-30.2%) versus 56%
(95%CI, 34.9%-75.6%); P ⫽ 0.001]. In the prophy- Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, predniso-
lone; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic
lactic group, hepatitis flare occurred in 4 patients; 2 Index.
episodes were attributed to HBV reactivation. None of *HBV DNA was detectable in only 19 patients in the prophylactic group and 17
these patients developed severe hepatitis, defined as an patients in the therapeutic group.

increase of ALT to more than 10-fold ULN or bilirubin

to more than 1.5-fold ULN. By contrast, in the thera- (60.0%; 95% CI, 38.7%-78.9%) and 12 of these epi-
peutic group, hepatitis flare occurred in 15 patients sodes were attributed to HBV reactivation. The inci-
dence of severe hepatitis was significantly higher in the
therapeutic group. Logistic regression analysis was
Randomized
(n=52)
done to determine the predictive value of the following
risk factors on HBV reactivation during chemother-
Prophylactic group Therapeutic group
(n=26) (n=26)

Table 2. Incidence of HBV Reactivation and Hepatitis

Allocated to intervention (n= 26) Allocated to intervention (n=26)
Prophylactic Therapeutic
Received allocated intervention (n=26) Allocation Received allocated intervention (n= 25)
Did not receive allocated intervention Did not receive allocated intervention
Group Group P-Value
(n=0) (n=1)
Give reasons: withdrawn due to
During protocol treatment n ⫽ 26 n ⫽ 25
ineligibility (renal dysfunction) HBV reactivation 3 14 0.001
Hepatitis flare 4 15 0.001
Lost to follow-up (n= 0)
HBV reactivation and hepatitis flare 2 12 0.001
Completion of assigned therapy and
Lost to follow-up (n= 0) HBV reactivation and ALT10 ⫻
Completion of assigned therapy and
observation (21) Follow-Up
observation (13)
ULN 0 9 ⬍0.001
Discontinued intervention (n= 5)
Discontinued intervention (n=12) HBV reactivation and bilirubin ⬎
Give reasons:
Tumor progression (2)
Give reasons: 1.5 ⫻ ULN 0 5 0.023
Excessive toxicity (2)
Tumor progression (6)
After protocol treatment n ⫽ 26 n ⫽ 21
Excessive toxicity (4)
Patient withdrawal (1) HBV reactivation 5 3 0.716
Patient withdrawal (2)
Hepatitis flare 7 3 0.475
HBV reactivation and hepatitis flare 4 1 0.362
Analyzed (n=26 ) Analyzed (n= 25) HBV reactivation and
Excluded from analysis (n= 0) Analysis Excluded from analysis (n= 1)
ALT⬎10 x ULN 3 0 0.242
Give reasons: withdrawn due to
ineligibility (renal dysfunction) HBV reactivation and bilirubin
⬎ 1.5 x ULN 3 0 0.242
Hepatitis-related death 2 0 0.242
Fig. 1. Study flow diagram.
848 HSU ET AL.
apy: patient age, sex, baseline ALT level (normal versus
elevated), HBeAg status (negative versus positive),
baseline HBV DNA level (⬍1,000,000 copies/mL ver-
sus 1,000,000 copies/mL), lymphoma staging (by Ann
Arbor staging and the International Prognostic Index
[IPI]),18 and lamivudine treatment (prophylactic ver-
sus therapeutic). The only 2 significant predictors
identified were prophylactic lamivudine use (P ⫽
0.002) and high baseline HBV DNA level (P ⫽ 0.008).
Multivariate analysis indicated that prophylactic lami-
vudine use was the only independent predictor of HBV
reactivation (odds ratio, 0.04; 95% CI, 0.005-0.344;
P ⫽ 0.003)
The incidence of HBV reactivation and hepatitis
after completion of protocol treatment did not differ
significantly between the 2 groups. HBV reactivation
was found in 8 patients (5 in the prophylactic group
and 3 in the therapeutic group) (Figs. 2, 3). The me-
dian duration from the completion of protocol treat-
ment to the occurrence of HBV reactivation for these 8
patients was 93.5 days (range, 25-182 days). The cu-
mulative risk of HBV reactivation-associated hepatitis
after the completion of protocol treatment was 15.4%
(95%CI, 4.4%-34.9%) for the prophylactic group and
4.8% (95%CI 0.1%-23.8%) for the therapeutic group
(P ⫽ 0.36). No risk factors, including patient age, sex,
HBeAg status, baseline ALT or HBV DNA levels, and
lymphoma staging, were found to be independently
predictive of HBV reactivation after the completion of
chemotherapy.
For the 5 patients in the prophylactic group who de-
veloped HBV reactivation after protocol treatment, 2
died of hepatitis flare at 173 and 182 days after comple-
tion of protocol treatment, respectively (Fig. 2A, B). A
third patient (Fig. 2C) died of tumor progression. All of
these 3 patients received lamivudine treatment at the time
of diagnosis of hepatitis flare. The remaining 2 patients
did not have hepatitis flares, and lamivudine treatment
was not given. For the 3 patients in the therapeutic group
who developed HBV reactivation after protocol treat-
ment, none received lamivudine treatment. No hepatitis-
related death occurred.
Two patients, both in the prophylactic group, devel-
oped YMDD mutation (1 YVDD [tyrosine-valine-as-
partate-aspartate] and 1 YIDD [tyrosine-isoleucine-
aspartate-aspartate]) after 173 days and 196 days of
prophylactic lamivudine treatment, respectively (Fig. 4).
The mutations were detected during episodes of hepatitis
flares, which occurred after withdrawal from lamivudine
prophylaxis. HBV DNA elevation was also detected, but the
magnitude was less than 10-fold that of previous nadir levels.
The hepatitis flares subsided spontaneously in both patients.
HEPATOLOGY, March 2008
Comparison With the Historical Control Group.
The baseline clinical characteristics of patients in the cur-
rent study and in the historical control group are com-
pared in Table 3. More patients in the current study had
advanced tumor status (IPI high or high-intermediate
groups), whereas more patients in the historical control
group had elevated HBV DNA levels at baseline. Other
demographic features were similar between the 2 groups.
The incidence of HBV reactivation and hepatitis and
the patterns of HBV reactivation are compared between
the therapeutic group of the current study and the histor-
ical control group in Table 4. No significant difference
was found between the 2 groups of patients, and the pat-
terns of HBV reactivation did not appear to be changed
by lamivudine treatment. Three patients in the historical
group died of HBV reactivation–related hepatitis,
whereas no patients in the therapeutic group of the cur-
rent study had hepatitis-related death. However, the dif-
ference is not statistically significant.
To further clarify the role of lamivudine use in the
clinical course o HBV carriers who undergo chemother-
apy for NHL, the incidence, severity, and patterns of
HBV reactivation are compared between the whole group
of the current study and the historical control group (Ap-
pendix Table 1). Again, no significant difference was de-
tected.
Because ALT elevation that occurs in chemothera-
py-induced HBV reactivation is usually preceded by
HBV DNA elevation,3,9 it is important to determine
whether the timing of lamivudine treatment may be
delayed significantly by using our criteria of ALT ele-
vation as the starting point. We compared the timing
of HBV DNA reactivation with that of ALT elevation
for the 12 patients in the therapeutic group who devel-
oped HBV reactivation and hepatitis during protocol
treatment. HBV DNA surge was preceded by ALT
elevation for a median of 31.5 days (range, 4-84 days)
in 4 of these patients and coincided with ALT elevation
in another 2 patients. In the remaining 6 patients,
HBV DNA reactivation preceded ALT elevation by a
median of 23 days (range, 7-97 days). In 4 of these 6
patients, HBV DNA levels were still elevated when
lamivudine treatment was started, whereas in the re-
maining 2 patients HBV DNA levels had decreased at
the start of lamivudine treatment.
Response to Chemotherapy and Clinical Outcome.
The response rate to CHOP chemotherapy was 88.5%
(95%CI, 69.9%-97.6%) (12 complete and 11 partial re-
sponses) in the prophylactic group and 84.0% (95%CI,
63.9%-95.5%) (12 complete and 9 partial responses) in
the therapeutic group (P ⫽ 0.70). Reduction of chemo-
therapy doses was required, mostly because of myelosup-
HEPATOLOGY, Vol. 47, No. 3, 2008 HSU ET AL. 849

Fig. 2. The clinical course and patterns of HBV viral reactivation and hepatitis flares for the 5 patients in the prophylactic group of this study. ALT,
alanine transaminase. Bil, bilirubin. CR, complete response. HbeAg, hepatitis B e antigen. PR, partial response. The dashed lines at the bottom of
each panel indicate the duration of lamivudine treatment.
850 HSU ET AL.
Fig. 3. The clinical course and patterns of HBV viral reactivation and hepatitis flares for the 3 patients in the therapeutic group of this study.
pression, in 5 patients of the prophylactic group and 3
patients in the therapeutic group (P ⫽ 0.70). Nine pa-
tients in the prophylactic group and 14 in the therapeutic
group had to delay chemotherapy because of serious ad-
verse events (P ⫽ 0.16).
The median overall survival had not been reached in
either group as of October 31, 2006, after a median fol-
low-up duration of 33.2 months for the prophylactic
group and 38.6 months for the therapeutic group. The
3-year overall survival rate was 69% (95%CI, 51%-87%)
in the prophylactic group and 72% (95%CI, 54%-90%)
in the therapeutic group (P ⫽ 0.98). Ten patients in the
prophylactic group and 7 in the therapeutic group died
HEPATOLOGY, March 2008
during follow-up. The most common causes of death
were tumor progression (15 patients) and hepatitis-in-
duced liver failure (2 patients).
Discussion
In this study we confirmed the efficacy of lamivudine
in preventing chemotherapy-associated HBV reactivation
in NHL patients during chemotherapy. By contrast, lami-
vudine therapy started at the time of ALT elevation did
not appear to change the natural course of chemotherapy-
associated HBV reactivation.
HEPATOLOGY, Vol. 47, No. 3, 2008 HSU ET AL. 851

The current study is so far the largest prospective, Appendix Table 1. Comparison of Incidence, Severity, and
randomized trial of lamivudine prophylaxis for chemo- Patterns of HBV Viral Reactivation Between the Current
therapy-associated HBV reactivation in NHL patients. Study and the Historical Control Group
The patient population and the chemotherapy regimen The Current Study The Historical Control
(n ⴝ 51) Group (n ⴝ 48) P Value
used in this study are more homogenous than in previ-
ously reported studies.7-10 Lamivudine prophylaxis was Incidence of HBV
reactivation and
found to be the only factor that independently pre- hepatitis
dicted the risk of HBV reactivation during chemother- HBV reactivation 23 26 0.804
apy. The previous randomized trial by Lau et al.7 Hepatitis flare 27 27 0.619
HBV reactivation and
indicated that lamivudine prophylaxis completely pre-
hepatitis flare 19 20 0.462
vented HBV reactivation during chemotherapy.7 HBV reactivation and
However, our data indicated that HBV reactivation- ALT ⬎10 ⫻ ULN 12 13 0.436
associated hepatitis can still occur during chemother- HBV reactivation and
bilirubin ⬎ 1.5 ⫻
apy for patients with lamivudine prophylaxis, but the ULN 8 5 0.295
incidence of HBV reactivation and the severity of hep- Hepatitis-related death 2 3 0.546
atitis flare were both significantly reduced. Patterns of HBV
reactivation 0.324
Clinical data necessary to establish the optimal du- Protracted 5 10
ration of lamivudine prophylaxis are lacking. Most pre- Repeated 7 4
vious studies continued lamivudine prophylaxis for 1 Transient 11 12
to 3 months after completion of chemotherapy, but
HBV reactivation after withdrawal from lamivudine
prophylaxis was frequently found, especially with be required for patients with high baseline HBV
longer follow-up.3,19 In 2004 the American Association DNA.21 However, when the current study was de-
for the Study of Liver Diseases recommended contin- signed, the optimal duration of lamivudine prophylaxis
uation of lamivudine prophylaxis for 6 months after was unknown.22 In addition, our data indicate that
the completion of chemotherapy, based on level III HBV reactivation and life-threatening hepatitis may
evidence (evidence based on clinical experience, de- occur more than 6 months after completion of chemo-
scriptive studies, or reports of expert committees).20 In therapy, irrespective of baseline HBV DNA levels.
2007, American Association for the Study of Liver Dis- Therefore, a longer duration of antiviral prophylaxis
eases updated its recommendation, suggesting that should be considered for all patients. The incidence of
lamivudine prophylaxis for more than 6 months may YMDD mutation after lamivudine prophylaxis was
7.7% in the current study and may increase with more
prolonged lamivudine therapy. The emergence of
Table 4. The Effects of Therapeutic Use of Lamivudine: YMDD mutant usually resulted in clinical hepatitis;
Comparison with the Historical Group thus, agents with more favorable resistance profiles,
Therapeutic Group of The Historical such as adefovir or entecavir, may be better prophylac-
the Current Study Control Group
(n ⴝ 25) (n ⴝ 48)P P Value tic agents.21
The fact that no hepatitis-related death occurred in
Incidence of HBV
reactivation and the therapeutic group of this study while 3 of the 48
hepatitis patients in the historical control group died of hepatitis
HBV reactivation 15 26 0.804 suggests some effects of therapeutic use of lamivudine.
Hepatitis flare 16 27 0.619
HBV reactivation and The difference is not significant, probably because of
hepatitis flare 13 20 0.462 the limited sample size of the 2 studies. Previous stud-
HBV reactivation and ies indicated that the efficacy of therapeutic use of
ALT ⬎ 10 ⫻ ULN 9 13 0.436
HBV reactivation and
lamivudine may depend on an early start of treat-
bilirubin ⬎ 1.5 ⫻ ment.2,23,24 For chemotherapy-associated hepatitis,
ULN 5 5 0.295 monitoring of HBV DNA levels is now the gold stan-
Hepatitis-related death 0 3 0.546
dard for diagnosis of HBV reactivation, but quantita-
Patterns of HBV
reactivation 0.324 tive HBV DNA assays are not routinely available in
Protracted 2 10 clinical laboratories. Therefore, in this study we chose
Repeated 6 4 to use follow-up ALT levels as the guide for starting
Transient 7 12
lamivudine treatment and set a more stringent cutoff
852 HSU ET AL. HEPATOLOGY, March 2008

Fig. 4. The clinical course and patterns of HBV viral reactivation and hepatitis flares for the 2 patients with documented YMDD mutation.

point. Although most of the patients in the therapeutic Acknowledgment: The authors thank Mei-Hsing
group who had HBV reactivation can start lamivudine Chuang and Yueh-Ling Ho of the National Health Re-
treatment, timely HBV DNA quantification may still search Institutes of Taiwan, ROC, for their help in data
be the best assay for monitoring in the near future. management and statistical analysis and Microbial
Two patients in the prophylactic group died of HBV Genomics Core at National Taiwan University for HBV
reactivation–related hepatitis after stopping of lamivu- study. The authors also thank the investigators and re-
search nurses from all centers who participated in this
dine prophylaxis. Both of them received lamivudine
study for their assistance with patient recruitment, clinical
treatment at the diagnosis of hepatitis. However, be- care, and follow-up.
cause of less stringent follow-up of liver function tests
(once every month, according to the study protocol),
Table 3. Comparison of Baseline Clinical Characteristics
these patients may not be able to receive lamivudine Between the Present Study and the Historical Control Group
treatment early enough to prevent liver damage. Be-
Current Study The Historical Control
sides, these patients might already have unrecognized (n ⴝ 51) Group (n ⴝ 48) P Value
liver diseases, rendering them more vulnerable to liver
Age in years (median/
damage induced by HBV reactivation. Therefore, pa- range) 45.0(20–74) 44.0(16–70) 0.51
tients should be monitored weekly or biweekly by HBV Male/female 25/26 28/20 0.42
DNA quantification so that antiviral therapies could be Pathology 0.30
Diffuse large cell/
given in time.9 immunoblastic 44 37
Others 7 11
Performance status
(ECOG score) 0.35
0–1 47 41
2 4 7
IPI index 0.02
Low risk 14 24
Low-intermediate 15 16
High-intermediate 17 7
High risk 5 1
HBeAg 1.00
Negative 41 39
Positive 10 9
HBV DNA quantity 0.01
ⱕ 2.5 pg/mL 37 23
⬎ 2.5 pg/mL 14 25

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, predniso-

lone; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic
Fig. 5. Overall survival of the patients. Index.
HEPATOLOGY, Vol. 47, No. 3, 2008
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