Journal of

Oncology
Pharmacy
Practice

Original Article

Adherence to hepatitis B screening and

prophylactic lamivudine for prevention
of rituximab-associated hepatitis B
reactivation

J Oncol Pharm Practice

19(1) 1823
! The Author(s) 2012
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DOI: 10.1177/1078155212447975
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Chin Y Liu
Department of Pharmacy, Karmanos Cancer Center, Detroit, MI, USA

Pranatharthi H Chandrasekar
Division of Infectious Diseases, Wayne State University, Detroit Medical Center, Detroit, MI, USA

Ashiq Masood
Department of Internal Medicine, Wayne State University, USA; Detroit Medical Center, Detroit, MI, USA

Charles A Schiffer
Division of Hematology/Oncology, Wayne State University, Karmanos Cancer Center, Detroit, MI, USA

Abstract
Purpose: Treatment with rituximab can be associated with hepatitis B reactivation leading to fulminant hepatitis and
sometimes fatal hepatitis. The manufacturer has recommended screening the high-risk patients and monitoring hepatitis
B virus carriers during and several months after the therapy. Prophylaxis with lamivudine has been recommended to
prevent reactivation in hepatitis B virus carriers receiving rituximab. An institutional guideline was developed and
implemented. This study evaluated the adherence to these clinical guidelines of hepatitis B screening in patients receiving
rituximab-based treatment, the use of lamivudine prophylaxis, and the prevalence of positive hepatitis B virus surface
antigen in this patient population in southeast Michigan.
Methods: A retrospective chart review of patients begun on rituximab therapy from January 2009 through June 2010
was conducted.
Results: Two hundred and eighty patients who received rituximab were identified. Approximately 70% of patients had hepatitis
B virus surface antigen screening test prior to rituximab therapy. Antibody to hepatitis B virus core antigen was detected in
11.1% of patients, although the hepatitis B virus surface antigen positive rate was only 0.6%. One patient had hepatitis B virus
reactivation despite lamivudine prophylaxis, but fully recovered after antiviral therapy was changed to tenofovir.
Conclusion: The prevalence of hepatitis B virus surface antigen positivity is low in this study; however, antibody to
hepatitis B virus core antigen positivity is high. Education to clinicians is warranted to increase awareness and further
improve adherence to the clinical guidelines.

Keywords
Hepatitis B virus, HBV reactivation, rituximab

Introduction
Reactivation of hepatitis B virus (HBV) replication
with an increase in serum HBV DNA has been reported
in 2050% of hepatitis B carriers undergoing immunosuppressive or cancer chemotherapy.1,2 Among the
hematologic malignancies, lymphoma patients who
are HBV surface antigen (HBsAg) positive are noted

to have a higher risk of HBV reactivation after chemotherapy than other cancer patients.3 This may be
Corresponding author:
Chin Y Liu, Department of Pharmacy, Karmanos Cancer Center, 4100
John R, Detroit, MI 48098, USA.
Email: liuc@karmanos.org

Liu et al.
related to the relatively more immunosuppressive chemotherapeutic drugs used for lymphoma and also possibly the intrinsic immunosuppressive eect of
lymphoma per se.4 Rituximab is a chimeric murine
human monoclonal antibody targeting the CD20+
antigen on the surface of normal and malignant B
lymphocytes. Circulating CD20+ B cells are depleted
within the rst three doses and the depletion can be
sustained for up to 69 months post treatment in
83% of patients.5 B-cell recovery begins at approximately 6 months and median B-cell levels return to
normal by 12 months following completion of treatment. In October 2004, the Food and Drug
Administration (FDA) warned healthcare professionals
via letter, of postmarketing clinical safety reports of
HBV reactivation, along with fulminant hepatitis, hepatic failure, and death, in some patients with hematologic malignancies receiving rituximab therapy. Several
retrospective and prospective studies reported a
reduced incidence of HBV reactivation using prophylactic lamivudine in cancer patients receiving rituximab- or udarabine-based chemotherapy.610
At our institution, we observed a severe case of HBV
reactivation in an Asian male patient with
Waldenstroms macroglobulinemia, 12 months after
completing rituximab in combination with udarabine
chemotherapy. This case, in conjunction with the literature reports had prompted an ad hoc group consisting
of hematology, infectious diseases, and pharmacy to
develop an institutional guideline in 2008 on urgent
basis as there were no standard guidelines available at
that time. Our institutional guideline intended to provide a standard to screen HBV serology (HBsAg, antibody to HBV core antigen (HBcAb), and antibody to
HBsAg (HBsAb)) in patients receiving rituximab and
to utilize lamivudine prophylaxis in patients with positive HBsAg. The aims of this retrospective study were

19
to evaluate adherence to this clinical guideline of hepatitis B screening in patients receiving rituximab-based
treatment, the use of lamivudine prophylaxis, and to
estimate the prevalence of positive HBsAg in this
patient population from the southeast Michigan area.

Methods
The guidelines were reviewed and approved by the
Pharmacy and Therapeutics Committee in November
2008 (Table 1) and implemented throughout the infusion center at our institution in January 2009. In order
to remind prescribers this new guideline, a statement
which recommended HBV screening tests with antiviral
prophylaxis for positive HBsAg was added to the rituximab chemotherapy order form which is utilized for
more than 95% of rituximab orders received in the
infusion center. Our infusion center not only serves
cancer patients, but also provides rituximab and cyclophosphamide to some non-cancer patients. A list of
patients who received rituximab from January 2009
through June 2010 was generated from the pharmacy
database. Patients with pregnancy or age <18 years
were excluded from the study. A retrospective medical
record review was conducted. Data collection included
age, gender, race, indication for rituximab therapy,
screening test of hepatitis B serology, chemotherapy
regimen, and antiviral prophylaxis use in HBsAgpositive patients. The study was approved by the
Human Investigation Committee. SPSS v19.0 (SPSS
Incorporated, Chicago, IL) statistical software was
used to analyze the data and descriptive statistics.

Results
A total of 280 patients who received rituximab therapy
from January 2009 through June 2010 were identied.

Table 1. Screening and management of rituximab-associated hepatitis B reactivation.

Screening test of HBV serology (HBsAg, HBcAb, and HBsAb) before rituximab therapy
HBV vaccination is recommended for HBsAg-negative patients
Recommend lamivudine prophylaxis in HBsAg-positive patients
Lamivudine 100 mg po daily starting 7 days before rituximab and continuing for at least 12 weeks after completing
rituximab. Treatment may need to be extended for longer periods for those patients at higher risk of reactivation
Renal function (CrCl, mL/min)
Lamivudine dose
50
100 mg
3049
100 mg 1, then 50 mg daily
1529
100 mg 1, then 25 mg daily
514
35 mg 1, then 15 mg daily
<5
35 mg 1, then 10 mg daily
Monitoring liver function test every month
HBV: hepatitis B virus; HBsAg: hepatitis B virus surface antigen; HBcAb: antibody to HBV core antigen; and HBsAb: antibody to HBV
surface antigen.

20
The mean age was 54.5 years; 54.6% were male. A
total of 235 patients receiving rituximab had cancer,
with non-Hodgkins lymphoma (NHL) as the main
indication. Non-malignancy indications include idiopathic/thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, and systemic lupus
erythematous (Table 2). HBV serologic screening testing was not performed in a uniform fashion, with
HBsAg tested in 195 patients and HBsAg + HBcAb
tested in 162 patients (Table 3). The HBV screening
test was not performed in 20% of patients prior to the
initiation of rituximab therapy and none of them
developed hepatitis B reactivation during the study
period. HBsAb was tested in 217 patients, and
67 patients were positive (30.9%) which indicates
immunity due to vaccination or previous infection.
Seventeen patients were HBsAg/HBcAb+ and one
cancer patient was HBsAg+/HBcAb+; nine of these
18 patients had a documented past history of HBV
infection. Nine patients were on antiviral prophylaxis
(either lamivudine or tenofovir) and followed closely
by either gastroenterologists or infectious diseases specialists. None of the 17 HBsAg/HBcAbpatients
developed hepatitis reactivation during the study
time frame. The only patient with positive HBsAg/
HBcAb developed HBV reactivation while on antiviral
prophylaxis. This was a Middle Eastern male patient
with past medical history of chronic hepatitis B,
herpes zoster reactivation, and postherpetic neuralgia prior to the diagnosis of chronic lymphocytic
leukemia (CLL) in 2009. The HBV screen test prior
to chemotherapy (udarabine + cyclophosphamide +
rituximab) showed HBcAb+, HBsAg+, HBV polymerase chain reaction (PCR). Hepatitis C virus
PCR was also negative. Lamivudine prophylaxis was
initiated before and continued after the ve cycles of
chemotherapy which was completed in April 2010.
The patient achieved a suboptimal response to chemotherapy and was lost to follow-up until October 2010
when he developed rapid progression of his CLL
which manifested as cytopenia and tumor lysis
syndrome. His condition was further complicated by
congestive heart failure with non-ST elevation myocardial infarction and hepatitis B reactivation which
manifested as hyperbilirubinemia (total bilirubin:
28.2 mg/dL, direct bilirubin: 21.8 mg/dL), elevated
hepatic transaminase (alanine aminotransferase
777 units/L, AST 1121 units/L), and HBV DNA PCR
(2180 IU/mL). The patients clinical status and liver
function tests returned to normal 1 month after antiviral therapy was changed to tenofovir 300 mg daily.
HBV screening was done more frequently in patients
with cancer than in those with non-malignant disorders
(71.9% for HBsAg and 63% for HBcAb vs 57.7% for
HBsAg, and 31.1% for HBcAb, respectively).

Journal of Oncology Pharmacy Practice 19(1)

Table 2. Patient demographics.
Characteristics
Age (years)
Mean (SD)
Range
Gender
Female
Male
Race
Caucasian
African American
Asian
Other/unknown
Indication for rituximab
Cancer
NHL
Leukemia
Others
Non-cancer
Idiopathic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Autoimmune hemolytic anemia
Systemic lupus erythematous
Neuromyelitis optica
Others

N 280

54.5 (14.65)
2084
127
153
162
89
3
26
235
151
57
27
45
9
3
8
7
5
13

NHL: non-Hodgkins lymphoma.

Discussion
Rituximab is prescribed in a wide variety of both hematological and non-hematological disorders. FDA
approved indications include NHL, CLL, rheumatoid
arthritis in combination with methotrexate, Wegeners
granulomatosis, and microscopic polyangiitis in adult
patients in combination with glucocorticoids. Common
o-label uses include treatment of antibody mediated
diseases such as acquired factor VIII deciency disease,
autoimmune hemolytic anemia, systemic lupus erythematous, and idiopathic/thrombotic thrombocytopenic purpura. Rituximab-associated hepatitis B
reactivation with fulminant hepatitis, sometimes fatal,
is listed under the warnings and precautions in the
manufacturers package insert and thus it is recommended to screen high-risk patients and monitor
HBV carriers during and several months after therapy.
Discontinuation of rituximab is recommended if HBV
reactivation occurs.5
Recently, the American Society of Clinical Oncology
(ASCO) issued a provisional clinical opinion in agreement with the Center for Disease Control and
Prevention stating that physicians may consider

Liu et al.

21
Table 3. HBV screening results.

Not screened
HBsAg screen
Positive HBsAga
HBsAg + HBcAb screen
Positive HBcAba

Cancer patients (%)

N 235

Non-cancer patients (%)

N 45

Total (%)
N 280

37/235 15.9
169/235 71.9
1/169 0.6
148/235 63
17/148 11.5

19/45 42.2
26/45 57.7
0
14/45 31.1
1/14 7.1

56/280 20
195/280 69.6
1/169 0.6
162/280 57.9
18/162 11.1

HBV: hepatitis B virus; HBsAg: hepatitis B virus surface antigen; and HBcAb: antibody to HBV core antigen.
a
One patient with both positive HBsAg and HBcAb.

screening those patients at heightened risk for chronic

HBV infection, or if highly immunosuppressive therapy
is planned.11 Highly immunosuppressive treatment
includes, but is not limited to, hematopoietic cell transplantation and regimens including rituximab. Screening
based on a high risk of prior HBV exposure or risk of
reactivation due to planned therapeutic regimens
should include testing for HBsAg as a serologic
marker for HBV infection. In some populations, testing
for HBcAb should also be considered. However, the
2009 American Association for the Study of Liver
Disease (AASLD) practice guidelines recommended
routine HBsAg and HBcAb testing should be performed in patients who are at high risk of HBV
infection, prior to initiation of chemotherapy or
immunosuppressive therapy.2 The dierence in recommend screening tests by these two organizations may
explain the discrepancy of our study resultschecking
HBsAg or HBcAb solely, or checking both.
The adherence to our institutional guidelines was
about 70%, based on HBsAg screening test prior to
rituximab therapy. The rates of HBsAg and HBcAb
positivity were 0.6% and 11.1%, respectively. These
results are similar to data from several presentations
at the recent ASCO meeting in 2010. A prospective
quality assurance study was conducted at the
Memorial SloanKettering Cancer Center.12 The
screening consisted of serologies for HBsAg and
HBcAb. If either test was positive, HBV PCR was measured. A total of 3343 patients were screened for HBV
prior to the initiation of immunosuppressive therapy
(chemotherapy, antibody therapy, and high-dose dexamethasone). They reported a prevalence of 1.3% for
HBsAg and 9% for HBcAb. A retrospective analysis
from the MD Anderson Cancer Center noted that 13%
of 12,340 patients receiving chemotherapy had HBV
screening with 1% patients positive for HBsAg and
8% positive for HBcAb.13 Another study conducted
in Australia reported 1% positivity for HBsAg and
14.9% positivity for HBcAb in 206 solid tumor
patients.14

Several reports have shown that lamivudine

prophylaxis reduces the incidence and severity of
hepatitis B in HBV carriers undergoing chemotherapy.8,10,1518 Loomba et al.17 conducted a systematic
review of 14 studies (275 patients in the preventive
lamivudine group and 475 control participants) for
the primary end point of HBV reactivation. They
reported that lamivudine signicantly reduced the
risk for both HBV reactivation and HBV-related
hepatitis by 79% or more. In addition, preventive
lamivudine may reduce the risk for HBV-related hepatic failure and death in patients who test positive for
HBsAg and receive chemotherapy. Lamivudine was
well tolerated, and no adverse eects were noted.
The AASLD practice guidelines recommend that
lamivudine (grade I recommendation) or telbivudine
(grade III recommendation) be used if the anticipated
duration of immunosuppressive or cytotoxic therapy is
12 months and baseline serum HBV DNA is not
detectable.2 Tenofovir or entecavir is preferred if
longer duration of treatment (>12 months) is anticipated due to a higher risk of resistance to lamivudine.
The antiviral prophylaxis should be started before
chemotherapy and continued for at least 6 months
following completion of all treatment for patients
who are at high risk because of HBsAg seropositivity
and low HBV DNA <2000 IU/mL. Our patient on
lamivudine prophylaxis developed HBV reactivation
5 months after completion of chemotherapy which is
close to the median time from last rituximab dose to
HBV reactivation (3 months) from the FDA analysis
report.19 Possible explanations for why our patient
developed HBV reactivation while on antiviral
therapy include medication non-compliance and/or
potential development of resistance to lamivudine.
Unfortunately, the testing to detect the lamivudineselective mutant strain (the tyrosinemethionine
aspartateaspartate, YMDD mutation) was not
performed in this patient. Upon changing antiviral
therapy to tenofovir, resolution of hepatitis B reactivation and normal liver function tests resulted.

22
Although the risk for HBV reactivation in patients
with HBsAg/HBcAb+ is low, several reports suggest
that rituximab associated HBV reactivation can occur
in up to 8.9% of such patients.2022 However, at present, there are no clear recommendations for this population from major organizations. In this retrospective
study, we are unable to draw a conclusion about management of HBcAb+ patients since no HBV reactivation was observed and 50% of these 17 patients with
HBsAg/HBcAb+ received antiviral prophylaxis. A
prospective study to investigate the role of antiviral
prophylaxis is needed to address this issue. In the
interim, close monitoring of liver function tests and
HBV-related markers should be considered in this
population receiving rituximab therapy.
The result of HBV screening prior to rituximab therapy in our hospital was suboptimal. The adherence to
the institutional guidelines was higher in the cancer
patient group which may indicate greater awareness
among the hematologists. Physicians prescribing rituximab for non-cancer treatment (such as neurologist and
rheumatologist) may not be fully aware of this serious
complication and may use fewer doses of rituximab
which may not prompt them to check HBV screening.
In view of this result, better education (such as
in-services, newsletters, etc.) for all health care professionals is urgently needed. With the recent implementation of computerized physician order entry at our
hospital, the HBV screening test can be built as a part
of standard of care for cancer patients prior to rituximab-based chemotherapy which may enhance the
adherence to this guideline. In the interim, before accepting rituximab order, pharmacists are advised to check
the status of HBV tests and inform physicians if such
tests are not done. However, this will require adequate
stang and training to perform the task. Furthermore,
in patients with negative HBsAb test (69.1% in this
study), hepatitis B vaccination should be considered
prior to immunosuppressive therapy if possible.
There are several limitations of this study. HBV
reactivation cases may be under-reported due to the
retrospective nature of this study design, and some
such patients may have been admitted or followed at
other hospitals. Patients who transferred their medical
care from other hospitals/clinics may have had a
HBV screening test performed but the results were
not available in our electronic medical records. The
information about total number of doses or duration
of rituximab administered to each patient during
this study time frame could not be collected completely
due to several reasons: switching chemotherapy regimen, discontinuing chemotherapy upon remission and
then restarting chemotherapy for recurrent malignancy, and initiating or nishing chemotherapy at
other facilities.

Journal of Oncology Pharmacy Practice 19(1)

Conclusion
The use of rituximab is increasing with expanding new
indications, such as maintenance therapy for follicular
lymphoma. HBV reactivation and clinical hepatitis associated with rituximab therapy can increase the morbidity
and mortality. Screening for HBV prior to rituximab therapy and the use of antiviral prophylaxis are important to
reduce the risk of HBV reactivation and its complications
in patients who test positive for HBsAg. Although the
prevalence of HBsAg was low in our study, this would
likely vary in dierent geographic regions. However,
patients with isolated positive HBcAb also are at high
risk for HBV reactivation and should be monitored closely for serum hepatic transaminase levels and HBV DNA
levels during and after rituximab therapy, especially in
patients with hematological malignancies and in those
undergoing stem cell transplantations. Patients with
non-cancer disorders receiving rituximab therapy should
also be under surveillance for hepatitis B. Furthermore,
the screening test should consist of HBsAg, HBsAb, and
HBcAb. HBV immunization is recommended for patients
with negative results of HBsAg, HBsAb, and HBcAb
prior to rituximab therapy.
Funding
This research received no specic grant from any funding
agency in the public, commercial, or not-for-prot sectors.

Conflict of interest statement

The authors declare that there are no conicts of interest.

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