Nrclinonc.2012.1

REVIEWS
Reactivation of hepatitis B virus and
hepatitis C virus in patients with cancer
Harrys A. Torres and Marta Davila
Abstract | Infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) are associated with significant
morbidity and mortality among patients with cancer, especially in patients with hematologic malignancies and
those who undergo hematopoietic stem-cell transplantation. Reported rates of HBV reactivation in HBV carriers
who undergo chemotherapy range from 14–72%. In these patients, mortality rates range from 5–52%. HCV
reactivation seems to be less common than HBV reactivation and is usually associated with a good outcome
and low mortality. However, once severe hepatitis develops, as a result of viral reactivation, mortality rates seem
to be similar among patients infected with HBV or HCV. Liver damage owing to viral reactivation frequently leads
to modifications or interruptions of chemotherapy, which can negatively affect patients’ clinical outcome. Risk
factors for the development of severe HBV or HCV reactivation need to be better defined to permit identification
of patients who may benefit from preventive measures, early diagnosis, and therapy. In this article, we review
the epidemiology, pathogenesis, risk factors, and clinical and laboratory manifestations associated with
reactivation of HBV and HCV during immunosuppressive therapy. We also discuss strategies for the prevention
and treatment of viral reactivation, including the management of reactivation with new antiviral agents.
H. A. Torres, & M. Davila Nat. Rev. Clin. Oncol. 9, 156–166 (2012); published online 24 January 2012; doi:10.1038/nrclinonc.2012.1

Introduction

Department of
Infectious Diseases,
Infection Control and
Employee Health, Unit
1460 (H. A. Torres),
Department of
Gastroenterology,
Hepatology and
Nutrition, Unit 1466
(M. Davila), The
University of Texas MD
Anderson Cancer
Center, 1515 Holcombe
Boulevard, Houston,
Texas 77030, USA.
Correspondence to:
H. A. Torres
htorres@
mdanderson.org

Viral infections are common and associated with signifi
cant morbidity and mortality in patients with cancer,
especially in patients with hematologic malignancies and
in those who undergo hematopoietic stem-cell trans
plantation (SCT). The impaired immunity associated
with the underlying malignancy or the chemotherapyinduced immunosuppression predispose these patients
to the development of new infections or reactivations
of common viruses, including herpes simplex virus,
varicella-zoster virus, cytomegalovirus, respiratory syn
cytial virus, influenza virus, parainfluenza virus among
others.1 Among the major viral infections observed in
cancer patients and SCT recipients are hepatitis B virus
(HBV) infection and hepatitis C virus (HCV) infection.
Similarities and differences between these two viral infec
tions are shown in Table 1 and Box 1. In this article, we
review the epidemiology, pathogenesis, risk factors, and
clinical and laboratory manifestations associated with the
reactivation of HBV and HCV during immunosuppressive
therapy, and discuss strategies for the prevention and
treatment of viral reactivation.

Reactivation of HBV infection
Reactivation of HBV is a well-known complication in
patients with cancer who undergo cytotoxic chemo
therapy or other forms of immunosuppressive therapy.
Competing interests
H. A. Torres declares associations with the following companies:
Astellas, Merck, Vertex. See the article online for full details of
the relationships. M. Davila declares no competing interests.

156 | MARCH 2012 | VOLUME 9

Although HBV reactivation has been reported mostly in
patients who tested positive for the hepatitis B surface
antigen (HBsAg), viral reactivation can also occur in
previously infected patients in whom the virus has appar
ently been cleared. Such patients can be identified by the
presence of antibodies against hepatitis B core antigen
(anti-HBc) or against HBsAg (anti-HBs).2,3 Rates of HBV
reactivation in HBV carriers who undergo chemotherapy
vary, with reported values ranging from 14–72%. 2,4
Possible explanations for this wide variation include dif
ferences in patient populations, types of tumors, chemo
therapy regimens, definitions of reactivation, and study
designs. Whereas some patients with HBV reactiva
tion are asymptomatic, others have classic symptoms of
hepatitis, including fatigue, anorexia, jaundice, ascites,
and coagulopathy. Reactivation can also lead to hepatic
encephalopathy, liver failure, and death. The disruption
of anticancer treatment as a result of HBV reactivation
can decrease overall survival.2,5 Mortality associated with
HBV reactivation ranges from 5–52%.6–8

Diagnosis
Definitions of HBV reactivation vary among investi
gators. However, most scientists define HBV reactivation
using one of the following three definitions: the develop
ment of hepatitis in association with an increase in serum
HBV DNA level to more than 1 log10 copies/ml higher
than the level before therapy was initiated; an absolute
increase in HBV DNA level exceeding 6 log10 copies/ml;
or conversion of serum HBV-DNA-test results from
negative to positive.9 Investigators also differ in their
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© 2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
definitions of acute hepatitis. For study purposes, some
researchers have defined acute exacerbation of chronic
hepatitis as a more than threefold increase in serum
levels of the enzyme alanine aminotransferase (ALT)
between two consecutive determinations made at least
5 days apart.9 In the evaluation of patients with possi
ble HBV reactivation, it is important to rule out other
causes of hepatitis, including superinfection with other
viruses (for example, hepatitis A virus, hepatitis D virus,
cytomegalovirus, herpes simplex virus, varicella-zoster
virus, Epstein–Barr virus, or adenovirus), chemotherapy-
induced or drug-induced liver injury, sinusoidal obstruc
tion syndrome, graft-versus-host disease, and the presence
of tumor cells in the liver.

Pathogenesis and clinical manifestations
Stages of reactivation
HBV reactivation as a result of cytotoxic chemo herapy
t
can generally be divided into three distinct stages
(Figure 1). 10–12 Reactivation typically starts with an
increase in viral replication caused by chemotherapyinduced immune suppression. The degree of increase
in viral replication can be estimated by the magnitude
of the rise in HBV DNA levels in serum. This rise can
precede an elevation of ALT levels by up to 3 weeks.
The first stage of increased viral replication can also
feature re ppearance of hepatitis B e antigen (HBeAg)
a
and HBsAg, as well as a decrease in anti-HBs antibody
titers. In the second stage of reactivation, functionality
of the immune system is restored after chemotherapy is
discontinued, and hepatocytes infected with HBV are
destroyed. This stage can also involve an increase in ALT

Key points
■■ Patients with cancer who are at risk of infection with hepatitis B virus (HBV) or
hepatitis C virus (HCV) should undergo standard viral screening before initiation
of cancer therapy
■■ HBV-DNA levels and HCV-RNA levels should be measured in patients who are at
high risk of viral reactivation
■■ A substantial proportion of cancer patients with HBV or HCV infection develop
liver dysfunction during chemotherapy, which often leads to discontinuation of
potentially life-saving chemotherapy
■■ Treatment with antiviral agents can effectively prevent HBV reactivation,
should be initiated before cancer therapy, and maintained during as well as for
6–12 months after discontinuation of immunosuppressive therapy
■■ HCV reactivation seems to be less frequent and less severe than HBV
reactivation, but if severe hepatitis develops, mortality rates seem to be similar
to those of HBV-infected patients
■■ Treatment of HCV reactivation is mainly supportive and new agents for the
treatment of patients with HCV reactivation are urgently needed

levels and the appearance of jaundice owing to hepato
cellular injury. Furthermore, HBV DNA levels may
decrease. The third stage of reactivation is the recovery
phase, during which clinical hepatitis resolves and HBV
markers return to baseline levels.10,12
The general pattern of HBV reactivation delineated
by these three stages is not experienced by all patients,
as specific patterns of reactivation can vary. In some
patients, HBV DNA levels remain elevated but acute
hepatitis does not develop owing to the lack of immune
reconstitution. Occasionally, the second stage is more
severe and can even be lethal. Other patients do not have
a recovery stage, and may experience chronic hepatitis
and deterioration of liver function.13

Table 1 | Basic differences between HBV and HCV24,99,100,101
Feature

HBV

HCV

Size of virus

42 nm

40–70 nm

Type of virus

DNA virus of the Hepadnaviridae family

RNA virus of the Hepacivirus genus within the
Flaviviridae family

Integration into the host
genome

Yes

No

Prevalence of infection

Approximately 350 million people with chronic
infections worldwide; an estimated 620,000
people die from HBV-related liver disease each
year

An estimated 180 million people are infected
worldwide; HCV infection is the principal cause of
death from liver disease and the leading indication
for liver transplantation in the USA

Geographic distribution

Endemicity of HBV infection is high in some
geographic areas, such as, south-east Asia and
Sub-Saharan Africa

Highest prevalence in north Africa (for example,
Egypt) and south Asia. Most common genotypes
(1–3) have a worldwide distribution

Serologic pattern of
infection

Varied and complex

The diagnosis generally requires testing of sera
for antibodies to anti-HCV and HCV RNA

Antigens or antibodies
associated with infection

HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBc,
anti-HBe

Anti-HCV

Duration of therapy

Several serologic end points of antiviral therapy
are used but optimal duration of therapy has not
been established

Standardized duration of therapy for the
most-common viral genotypes

Vaccination

Available and highly effective in preventing
infection

HCV heterogeneity hinders the development
of vaccines

Post-exposure prophylaxis
(immunoglobulin, vaccine)

Available and effective

Not available

Abbreviations: HBcAg, hepatitis B core antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.

NATURE REVIEWS | CLINICAL ONCOLOGY

VOLUME 9 | MARCH 2012 | 157

REVIEWS
Box 1 | Similarities between HBV, HCV, and associated disease24,99,100
■■
■■
■■
■■
■■
■■
■■

■■
■■

■■
■■

■■

Worldwide distribution
Liver is the primary site of viral replication
Both viruses can cause either acute or chronic hepatitis
Patients with chronic infection can remain asymptomatic for years and, being
unaware of their infections, are at risk of infecting others
The differentiation between acute and chronic hepatitis depends mainly on the
clinical presentation
PCR-based diagnostic assays are available for the detection of nucleic acid levels
Chronic infection is responsible for the majority of cases of viral-related
morbidity and mortality, with liver failure, cirrhosis, and liver cancer as common
causes of death
Antiviral agents are available to treat chronic infection
All patients with chronic infection should receive monitoring to assess
progression of liver disease, development of hepatocellular carcinoma, and
need for treatment
Immunosuppressed patients (for example, those with HIV-coinfection or who are
on hemodialysis) are at increased risk of infection
Patients with chronic infection who initiate cytotoxic or immunosuppressive
therapy (for example, patients with cancer, or recipients of organ or stem-cell
transplants) are at risk for viral reactivation
No standard definition of viral reactivation exists

Risk factors
The risk of HBV reactivation is influenced by both
the type of malignancy and the particular immuno
suppressive therapy that is administered. Most patients
in whom HBV is reactivated have hematologic malig
nancies. Patients with lymphoma may be at particular
risk.14,15 Nonetheless, an increasing number of cases
have been described among patients with solid tumors,
among whom the highest rates of HBV reactivation have
been reported for patients with breast cancer (as high as
41–56%).16,17 HBV reactivation has also been observed in
up to 36% of patients with hepatocellular carcinoma who
received systemic chemotherapy.18 High rates of reactiva
tion and substantial exacerbation of HBV in patients with
HBV-related hepatocellular carcinoma who were under
going transarterial chemoembolization (TACE) has been
reported in one study,19 but not in another study.20
Other host and viral factors have also been identified
as significant risk factors for HBV reactivation. One of
the most important risk factors is a high serum HBV
viral load.21 In a study of 137 patients who underwent
autologous hematopoietic SCT, HBV reactivation was
more common among HBsAg-positive patients with
detectable serum HBV DNA before transplantation than
among patients in whom no HBV DNA was detected.21
Furthermore, a high HBV DNA level (105 copies/ml)
was the most-important risk factor for HBV reacti
vation.21 Other risk factors include male sex, young
age (mean age 44 years, range 20–64 years), HBeAg
seropositivity, use of corticosteroids or use of certain
chemothera eutic agents, including anthracyclines,
p
cyclophosphamide, and vinca alkaloids. 2,14,15 Use of
monoclonal antibodies (such as rituximab8 and alem
tuzumab22) alone or in combination with other agents
has also been linked to HBV reactivation. Accounting
for 39% of the reported cases, HBV reactivation was the
most frequent viral infection in patients treated with
rituximab and associated with a 52% mortality rate

owing to liver failure.8 Furthermore, HBV reactivation
was observed among rituximab-treated patients who
were HBsAg-negative but anti-HBc positive.23

Prevention and treatment
Screening
Preventing HBV reactivation might be superior to inter
vention after reactivation has already occurred. The first
step in prevention should be screening for HBV markers
before initiation of chemotherapy in patients who are at
increased risk of viral reactivation. These include patients
who were born in regions of intermediate and high HBV
endemicity (HBsAg prevalence ≥2%), children of indivi
duals who were born in regions with high HBV endemi
city (HBsAg prevalence ≥8%), patients with a history
of intravenous drug use, patients undergoing hemo
dialysis, HIV-positive patients, and men who have sex
with men.24 Since physicians may not accurately identify
individuals who are at high risk of HBV infection, one
could make a case that all patients who are scheduled to
receive immuno uppressive therapy should be screened
s
for HBV given the substantial consequences of reacti
vation. Indeed, such routine testing was recommended
by the US Centers for Disease Control and Prevention
(CDC) in 2008.24 This recommendation prompted ASCO
to develop a provisional clinical opinion on the subject
of HBV screening, which was published in 2010.25 ASCO
stated that insufficient evidence exists to determine the
net benefits and harms of routine screening for chronic
HBV infection in patients with cancer who are about to
receive immunosuppressive therapy or who are already
receiving such therapy. Physicians are advised to con
sider screening of high-risk patients or those in whom
highly immuno uppressive therapy is planned, includ
s
ing (but not limited to) patients undergoing hemato
poietic SCT or who are treated with drug regimens that
include rituximab.25
If screening is undertaken, it should include testing for
the presence of HBsAg and anti-HBc (Figure 2). Patients
who are HBsAg-positive should be tested for HBeAg,
antibodies against HBeAg (anti-HBe), and levels of HBV
DNA should be determined. Patients who are HBsAgnegative but anti-HBc-positive should be tested for antiHBs antibodies. Patients who are negative for anti-HBs
antibodies have not developed immunity against HBV,
and HBV-DNA testing should be the next step to rule
out an occult HBV infection.
Use of antiviral drugs
Prophylaxis against HBV reactivation should be initiated
as early as possible before the onset of immunosuppres
sive therapy in HBsAg-positive patients.5,7,11 In patients
with high HBV DNA levels (2,000 inter ational units
n
[IU]/ml) and elevated ALT levels, therapy should be ini
tiated immediately with the aim of lowering viral rep
lication and disease activity as much as possible before
chemotherapy is administered. Although five orally
administered drugs are currently approved for the
treatment of chronic HBV infection in the USA (lami
vudine, telbivudine, adefovir, entecavir, and teno ovir),
f


REVIEWS
1st stage

2nd stage

3rd stage

Initiation of cytotoxic
chemotherapy

Discontinuation of
cytotoxic chemotherapy

Recovery of
liver function

Immunosuppresion

Immune recovery

Return to chronic viral
replication level (baseline)

Rapid viral replication
in hepatocytes

Rebound of the
T-cell response

T cells
Hepatocytes

Natural
killer cells

Increased
inflammatory
activity

T cells
Inhibition of cytokine
production and
cytotoxicity by HCV
and possibly HBV

Hepatocytes

T cells

Virus

ALT levels

Normal

Increased, occasionally normal

Normal

Viral load

Increased

Decreased

Decreased or return to baseline

Figure 1 | The three stages in the pathogenesis of HBV and HCV reactivation. Reactivation of HBV or HCV as a result of
chemotherapy can generally be divided into three stages. Reactivation typically starts with an increase in viral replication
caused by chemotherapy-induced immune suppression (stage 1). After chemotherapy is discontinued, the function of the
immune system is restored, and hepatocytes infected with HBV or HCV are destroyed (stage 2). In the recovery stage
(stage 3), clinical hepatitis (indicated by an increase in ALT levels) resolves and markers of HBV or HCV infections return to
baseline levels. Abbreviations: ALT, alanine aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus.

the published experience in 2011 on the prevention
and treatment of HBV reactivation is mostly limited
to lamivudine.
Lamivudine has proven efficacy in the prevention of
HBV reactivation in patients with hematologic malig
nancies and in patients with solid tumors, and has an
excellent safety profile. In one study, 30 patients with
lymphoma who were positive for HBsAg were randomly
assigned to receive lamivudine 100 mg daily 1 week
before initiation of chemotherapy or only when serologic
evidence of HBV reactivation was observed. None of the
patients in the prophylactic-therapy group experienced
HBV reactivation, as opposed to eight patients (53%) in
the deferred-treatment group (P = 0.002).26 In another
randomized study in which 43 HBsAg-positive patients
with non-Hodgkin lymphoma were randomly assigned
to receive prophylactic lamivudine either on day 1 of
chemo herapy or not until they had shown an increase
t
in ALT levels, patients in the prophylactic-therapy group
had a significantly lower risk of HBV reactivation than

patients who were withheld lamivudine initially (11.5%
versus 56%; P = 0.001).27
The efficacy of preventive lamivudine was addressed in
a meta-analysis of 14 studies, which included 275 patients
who received lamivudine and 475 control partici ants.28
p
The investigators found that preventive treatment with
lamivudine was associated with a relative risk of 0.00–0.21
for HBV reactivation and HBV-related hepatitis.28 Despite
differences in their design, all studies showed beneficial
effects of preventive lamivudine, with the exception of
one study in which one HBV-related death was noted.28
In another meta-analysis, which included nine studies
and a total of 396 participants, the cumulative prevalence
of HBV reactivation was 8.6% (11 of 127 patients) in the
prophylaxis group versus 50.6% (136 of 269 patients) in
the control group. Again, lamivudine prophylaxis signifi
cantly reduced HBV reactivation, and a trend towards a
reduction in HBV-associated mortality was observed.29
When to start or discontinue anti-HBV treatment for
prevention of HBV reactivation is an area of uncertainty.



REVIEWS
HBsAg-positive

HBsAg-negative
Anti-HBc-positive

Check HBV DNA

Anti-HBs-positive

Conventional
chemotherapy

Monoclonal antibody
therapy or stem-cell
transplantation

Use lamivudine
Prophylaxis recommended
for at least 6 months after
discontinuation of all
immunosuppressive therapy

Use entecavir or tenofovir
Prophylaxis recommended
for 12 months or more
after discontinuation of

Use entecavir or tenofovir
Patients should be on
treatment until they reach
end points as in
immunocompetent patients

No treatment
needed

Check HBV DNA

HBV DNA-positive

HBV DNA
2,000 IU/ml (2)

HBV DNA
2,000 IU/ml (1)

Anti-HBs-negative

HBV DNA-negative

Start antiviral
therapy according
to HBV DNA
level (1) or (2)

Consider HBV
vaccination

Figure 2 | Algorithm for the management of patients with possible HBV infection who undergo immunosuppressive therapy.
Patients with cancer should be screened for HBV infection by testing them for the presence of HBsAg, and antibodies against
HBc or the HBsAg. Patients who are HBsAg-positive or who are anti-HBc positive but HBsAg-negative or anti-HBs-negative,
should have HBV DNA levels measured to guide future management. An individualized approach with careful monitoring of ALT
levels and HBV DNA levels is recommended if chemotherapy or other immunosuppressive therapy is initiated. Abbreviations:
HBc, hepatitis B core antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; IU, international units.

For HBsAg-positive patients receiving conventional
chemo herapy, lamivudine was recommended to be
t
administered for at least 6 months after discontinua
tion of all immunosuppressive therapy.7,10,11,30 Patients
who receive therapies with monoclonal antibodies or
undergo hematopoietic SCT may need to take lamivudine
for 12 months or more.31–33 Should HBV be reactivated
in a patient who has not received prophylactic anti-HBV
therapy, antiviral treatment must be instituted immedi
ately and all chemotherapy must be suspended. However,
rates of mortality from hepatic failure may still be high
even when lamivudine is administered.7,32
Patients with high baseline HBV DNA levels
(2,000 IU/ml) should continue lamivudine treatment
until they reach clinical treatment end points, as is the
practice in immunocompetent patients who receive anti
viral treatment.30 These end points include normaliza
tion of serum ALT levels, decrease in serum HBV DNA
to undetectable levels, loss of HBeAg (with or without
detection of anti-HBe), and improvement in liver histo
logy.30 Over the course of lamivudine therapy, mutations
in the YMDD motif of the HBV DNA-polymerase gene
can develop, which confer resistance to lamivudine.7 In
immunocompetent patients with chronic HBV infec
tion, the cumulative rate of resistance to lamivudine
is reported to be 24% after 1 year of treatment, and
65–70% after 5 years of treatment.34 For patients who
need prolonged anti-HBV therapy (over 12 months), it is
appropriate to avoid lamivudine and to use instead drugs
associated with a low incidence of resistance, such as
entecavir or tenofovir, as first-line anti-HBV therapy.30,35

HBsAg-negative but anti-HBc-positive patients
The precise incidence of reactivation in patients who
are HBsAg-negative but anti-HBc-positive is unknown.

Various studies have suggested a low risk of reactiva
tion in this group (2%).2,32 However, the risk might
be much higher if such patients receive rituximab (2.7–
45%). 36 Reactivation of HBV infection in anti-HBspositive patients can also occur, a phenomenon known as
‘reverse seroconversion’. In patients who have undergone
allo eneic hematopoietic SCT, the rate of reverse sero
g
conversion has been reported to be as high as 40% after
2 years and 70% after 5 years.37
Patients who are HBsAg-negative but anti-HBc-
positive should undergo further testing for HBV DNA
to rule out an occult infection. Patients who are HBVDNA-positive should be considered for antiviral pro
phylaxis, especially if they might undergo prolonged
immunosuppression or SCT. 10 Alternatively, such
patients can be followed closely by performing serial
HBV DNA tests, although this approach has not been
thoroughly evaluated in clinical studies (Figure 2). In our
own practice, we favor prophylactic therapy in patients
who are HBV-DNA-positive. If the patient refuses pro
phylactic treatment, we offer monthly serum HBV DNA
testing during therapy and for 6 months after comple
tion of therapy. Well-designed clinical trials are needed
to investigate the efficacy and safety of early diagnosis
of reactivation by HBV DNA monitoring in patients
who are HBsAg-negative and anti-HBc-positive and/or
anti-HBs-positive.

Reactivation of HCV infection
In patients with cancer, HCV infection is more common
than HBV infection, even in geographic areas where
HBV infection is endemic.38,39 However, HCV reactiva
tion following immunosuppressive therapy is rare.15,38–41
For instance, in an Italian study of 98 patients with
B‑cell non-Hodgkin lymphoma, three of eight (38%)


REVIEWS
HBsAg-positive patients experienced HBV reactivation
after chemo herapy, but none of the 11 patients with
t
anti-HCV antibodies experienced HCV reactiva ion.42
t
In another study of patients with B‑cell non-Hodgkin
lymphoma, the incidence of acute exacerbation of hepa
titis (indicated by an ALT increase) was higher among
patients with chronic HCV infection than in HCVuninfected patients (26.3% versus 2.1%),43 suggesting
that HCV reactivation occurred and can cause clinically
relevant complications.
Although HCV reactivation seems to be more
common in patients with hematologic malignancies,38,44
it has also been reported in patients with solid tumors45,46
and in patients who have undergone SCT.47,48 At present,
no reliable methods to predict an individual’s risk
of HCV reactivation exist. The health consequences of
HCV reactivation seem to be less severe than those
of HBV reactivation.49,50 Only a few deaths related to
HCV reactivation have been reported.51 However, if
severe hepatitis secondary to viral reactivation develops,
mortality rates of HBV-infected and of HCV-infected
patients seem to be similar.52–54 In the absence of severe
hepatitis, the likelihood of a fatal outcome of HCV
reactivation is somewhat unpredictable.55

Diagnosis
Studies of HCV reactivation are hard to compare
directly as definitions for HCV reactivation vary. We
and others39,50 have defined HCV reactivation as an at
least threefold increase in serum ALT level in a patient in
whom the tumor has not infiltrated the liver, who did not
receive hepatotoxic drugs and who had no recent blood
transfusions or other systemic infections besides HCV.
Changes in liver enzyme levels can be accompanied by
reappearance of HCV RNA or a sudden increase in the
serum HCV RNA level.39
Whether immunosuppressive therapy leads to HCV
reactivation in patients with cancer in whom the infec
tion has cleared either spontaneously or secondary to
therapy is uncertain. When HCV RNA clearance is
achieved either spontaneously or in response to anti
viral therapy in recipients of solid organ transplants, no
relapse is observed in plasma, liver, or peripheral blood
mononuclear cells during chronic immuno uppressive
s
treatment with agents such as calcineurin inhibi
tors, cortico teroids, antimetabolites, anti-thymocyte
s
globulins, or anti-IL‑2-receptor blockers. This find
ing suggests the complete and permanent cure of
HCV infection resulting from the elimination of HCV
before transplantation.56
Chronically infected patients have stable HCV RNA
levels that may vary by approximately 0.5 log10 IU/ml.57
Therefore, an increase in HCV viral load of more
than 1 log10 IU/ml may be a sign of HCV reactivation.
However, more studies are needed to better define the
relationship between changes in HCV viral load and liver
function during chemotherapy.58
HCV infection is diagnosed using serologic assays
for antibodies and molecular tests for viral parti les.
c
However, patients with cancer, especially those with

hematologic malignancies, can have false-negative
antibody results. 59–62 Thus, in patients infected with
HCV in whom HCV reactivation is suspected during
chemo herapy, HCV RNA levels should be measured to
t
confirm reactivation.

Pathogenesis and clinical manifestations
HBV and HCV reactivation seem to be mediated by
similar pathogenetic mechanisms. 41,63–65 As for HBV
reactivation,39,66 reactivation of HCV infection occurs
when chemotherapy-induced immunosuppression facili
tates HCV replication by reducing the immune response
that controls viral infections (Figure 1).65 In addition,
when the administration of cytotoxic chemotherapy
or immuno uppressive drugs is suspended in patients
s
with chronic HCV infection the period of depressed cel
lular immunity can be followed by an ‘immunological
rebound’. This phenomenon is characterized by resto
ration of immune function and increased inflamma
tory activity in the liver, resulting in rapid destruction
of the HCV-infected hepato ytes and liver injury.44,65
c
Some subgroups of cancer patients that seem to have an
elevated risk for HCV reactivation include males and
patients with lymphoma (mainly non-Hodgkin lym
phoma), lymphopenia, or use of corticosteroids as part of
anticancer treatment.44,50,51
Reactivation after specific treatments
Corticosteroids have traditionally been associated
with cases of HCV reactivation.51,67 Several pathogenic
mechanisms have been postulated, including enhanced
HCV infectivity owing to upregulated expression of
viral receptors on the surface of the hepatic cells (which
facilitates virus entry into hepatocytes), 68 increased
replication of HCV in vitro (noted in peripheral blood
mononuclear cells that were cultivated in the presence of
corticosteroids),69 and enhanced viral replication in vivo
(observed in liver-allograft recipients after the injection
of a high dose of corticosteroids).69
HCV reactivation has been associated with several
immunosuppressive and chemotherapeutic agents,
including alemtuzumab, bleomycin, busulfan, cisplatin,
cyclophosphamide, cyclosporine, cytarabine, dacarba
zine, doxorubicin, etoposide, gemcitabine, methotrexate,
vinblastine, and vincristine. 45,47,48,51,58,70–73 However,
many patients with HCV reactivation during treatment
with one of these drugs were simultaneously treated with
corticosteroids.48,70,72,74 We found that administration of
systemic corticosteroids was linked to HCV reactiva
tion75 but was not associated with acute exacerbation of
chronic HCV infection.73 Whether corticosteroid therapy
alone or in combination with other agents leads to reac
tivation of HCV infection and acute exacerbation of
chronic HCV infection remains to be determined.
A possible relationship between rituximab and
HCV reactivation in patients with cancer has been
reported,70,74,76 but whether rituximab has an adverse
effect on the natural history of HCV infection and its
complications is unclear. 77 Some studies suggest that
rituximab is not associated with HCV reactivation. In



REVIEWS
a case series of HCV-infected patients with lymphoma
who received a rituximab-based regimen, chemotherapy
was changed as a result of HCV reactivation in only one
of nine patients, and none of the patients developed
hepatic failure.78 Moreover, rituximab is increasingly
being used for the treatment of HCV-associated cryo
globulinemic vasculitis, and data from short-term use
of rituximab in this setting indicate a favorable clinical
response with only mild elevation of HCV RNA levels (to
approximately twice the baseline levels), no substantial
changes in serum transaminase levels, and no deteriora
tion of liver disease.79 Whether the likelihood of HCV
reactivation differs between patients receiving rituximab
because of HCV-related vasculitis and those receiving the
drug for the treatment of conditions unrelated to HCV
remains unknown.
Other studies, however, indicate that rituximab is
associated with HCV reactivation. We recently analyzed
308 HCV-infected patients with a variety of cancer
types who were treated with various regimens tailored
to their underlying malignancy.75,80 Interestingly, only the
administration of rituximab-containing chemo herapy
t
was associated with both acute exacerbation80 and reacti
vation75 of chronic HCV infection. In a recently pub
lished series from Italy that included eight HCV-infected
patients (five with B‑cell non-Hodgkin lymphoma and
three with chronic lymphocytic leukemia), all seven
patients who underwent rituximab-based chemo
therapy had an increase in the plasma HCV load of at
least 1.5 log10 IU/ml (median 2.2; range 1.5–2.6 IU/ml).81
Whether HCV reactivation is related to high cumula
tive doses of rituximab, as observed for HBV reactiva
tion, remains uncertain.73 Evidence of a lack of HCV
reactivation in patients receiving chemotherapy not
including rituximab has been reported in three studies
of patients with non-Hodgkin lymphoma.42,43,81 Given
the association between rituximab and HBV reactiva
tion, a hypo hetical association between rituximab
t
and HCV reactivation ought to be examined with
well-designed studies.8
In HCV-infected patients without active hepatitis,
findings of the majority of studies suggest that inhibi
tors of tumor necrosis factor (such as infliximab) are
either bene icial or, at least, not detrimental.82,83 No case
f
of HCV reactivation associated with the use of these
agents has been reported.
Studying 84 patients with HCV-associated hepato
cellular carcinoma treated with TACE, we compared
HCV RNA levels before and after TACE in three patients
from whom such samples were available and who under
went a total of six TACE procedures. Six episodes of
acute exacerba ion of hepatitis were noted—one after
t
each TACE procedure. No signs of HCV reactivation
(1 log10 IU/ml increase in HCV RNA levels from base
line) were identified in the three patients.84 Larger pro
spective series are warranted to better define the risk of
HCV reactivation after TACE.
Patients with HCV infection who undergo SCT
can experience severe hepatic dysfunction and ful
minant hepatic failure. HCV RNA levels can increase

substantially during immunosuppressive therapy
—which usually includes cyclosporine, prednisone,
or both—and fulminant hepatitis can develop when
immuno uppressive drugs are withdrawn. 47,48,85,86 In
s
a large Italian study of 57 HCV-infected patients who
underwent SCT, the risk of reactivation after transplan
tation was significantly lower if patients underwent
autologous SCT rather than allogeneic SCT (16% versus
100%, P = 0.004). In the allogeneic SCT group, reactiva
tion occurred mainly within 6 months after SCT, whereas
in the autologous SCT group, reactivation predominantly
occurred within the first 3 months.53 In a Japanese multi
center study of 135 patients with HBV or HCV infection
who received allo eneic transplants, transient hepati
g
tis was more common in HBV-infected patients than
in HCV-infected patients, but the rates of fulminant
hepatitis and death due to hepatic failure were similar in
both groups.54 However, these data should be analyzed
with caution as they were obtained retrospectively and
without consideration of other factors associated with
liver dysfunction (such as co-infections with pathogens
other than HBV or HCV, or use of hepatotoxic drugs)
or viral loads.
Timing of reactivation
The timing of HCV reactivation in relation to the
administration of chemotherapeutic drugs varies. Acute
exacerbation of HCV infection (indicated by an ALT
increase) can occur during chemotherapy, but is usually
observed weeks or months after chemotherapy, corti
costeroids, or after both have been withdrawn.44,49,50,60
Among 18 patients with hematologic malignancies
and acute exacerbation of chronic HCV infection,
the increase in ALT levels was first noted at a mean of
19 days (range 14–32 days) after withdrawal of chemo
therapy (mostly after the fourth or fifth cycle).49 In our
recent study that included 19 patients with acute exac
erbation of HCV infection after initiation of rituximab,
the time to onset of hepatitis flare was 30 days (median;
range 1–200 days) after discontinuation of rituximab.75
Among HCV-infected patients who experienced severe
liver dysfunction during chemotherapy, liver function
tests returned to normal within 2–3 weeks after the caus
ative agent was discontinued.49 However, in patients with
fulminant hepatitis, peak ALT levels above 6,000 IU/l and
recovery times of about 7 weeks have been reported.51
In most patients with HCV reactivation, acute eleva
tion of ALT levels or HCV RNA levels causes no symp
toms, and ALT elevations are mild and transient. In
some studies, the increase in ALT can be preceded by an
increase in HCV RNA levels.81 For instance, in a recent
study of eight patients with hematologic malignancies,
HCV reactivation was followed by an increase in ALT
serum values 3–5 months after rituximab-based chemo
therapy was discontinued.81 The possibility that patients
were evaluated at the different stages of HCV reactiva
tion (Figure 1) could explain the lack of simultaneous
elevation of HCV viral load and ALT levels in some cases.
The diagnosis of HCV reactivation can be further
compli ated because low HCV RNA levels are
c


REVIEWS
Anti-HCV-positive before initiation of immunosuppressive therapy*

Measure baseline HCV RNA and ALT levels

If indicated, start chemotherapy or immunosuppressant monitoring ALT every 1–2 weeks
and HCV RNA every 4 weeks (until 3 months after treatment withdrawal of each cycle)

Normal ALT level

Raised ALT level†

At least 1 log IU/ml increase in
HCV RNA level compared to
baseline HCV RNA viral load

Continue monitoring

Check HCV RNA levels every
2–4 weeks while monitoring ALT.
If at least 1 log IU/ml increase
in HCV RNA level compared with
baseline HCV RNA viral load

Consider discontinuation of
chemotherapy or other
only if increasing ALT level
precludes their use

Figure 3 | Approach to management of HCV-positive patients with cancer who undergo chemotherapy or
immunosuppressive therapy. Patients with cancer should be screened for HCV infection with serologic assays that detect
specific antibodies against HCV (anti-HCV). In patients with anti-HCV antibodies, an HCV RNA assay is recommended for
diagnosis. An individualized approach with careful monitoring of ALT and HCV RNA levels is recommended if chemotherapy
or other immunosuppressive therapy is initiated. *Or HCV RNA level in high-risk patients (for example, patients with nonHodgkin lymphoma and unexplained liver disease). ‡Defined as an at least threefold increase from baseline. Abbreviations:
ALT, alanine aminotransferase; HCV, hepatitis C virus.

occasi nally observed in cases of severe acute exacerba
o
tion, possibly because of the absence of suitable cells for
viral replication secondary to massive liver-cell necrosis.51
Occurrence of severe hepatic dysfunction
Few studies have compared the development of severe
hepatic dysfunction between HCV-infected patients
and those not infected with HCV. In a study of patients
with acute myelogenous leukemia, ALT serum levels
were higher in HCV-infected patients than in patients
who were not infected with HCV.87 Data from one study
demonstrated that the incidence of severe hepatic dys
function during or after chemotherapy was higher in
HCV-infected patients than in HCV-negative patients.88
However, in a study of 33 HCV-positive patients with
hematologic malignancies who received intermittent
chemotherapy, severe flare of hepatitis occurred in only
two patients.49
Findings from noncomparative studies indicate that
some HCV-positive patients may have severe exacer
bation of HCV infection resulting in necrosis, hepatic
failure, and death.51,58,72 Besson and colleagues, demon
strated that up to 65% of patients with chronic HCV
infection developed significant liver dysfunction during
chemotherapy against diffuse large B‑cell lymphoma,
and that almost half of the patients with liver dysfunc
tion had grade 3–4 hepatic dysfunction.89 The proportion
of HCV-positive patients with hepatic dysfunction and
the severity of dysfunction tended to increase with the
number of chemotherapy courses.89 In some cases of fatal
fulminant hepatitis, HCV RNA levels increased dramati
cally during treatment, and a sharp decrease in HCV
RNA levels together with a marked increase in ALT levels
were observed when chemotherapy was withdrawn.51

Prevention
No drugs are currently approved for the prevention of
HCV reactivation in patients with HCV infection who
undergo chemotherapy. The risk of HCV reactivation
in such patients might be reduced by using lower doses
of immunosuppressive drugs, close monitoring of ALT
levels (especially after chemotherapy is reduced or with
drawn), and by measuring HCV RNA levels early during
episodes of potential viral reactivation. Given the pos
sibility of immune-mediated hepatocyte injury upon
HCV reactivation, some researchers have speculated
that gradual tapering of immunosuppressants could
be another strategy to prevent HCV reactivation.51,85,90
However, as it is unknown which patients with chronic
HCV infection are at risk of reactivation after cessation
of immunosuppressive treatment, caution is advised with
respect to this intervention, which has not been formally
tested and could negatively affect patients’ response to
cancer therapy without preventing HCV reactivation.
Implications for chemotherapy
An approach to the management of HCV-positive
patients with cancer who are undergoing chemo herapy
t
or other immunosuppressive therapy is shown in Figure 3.
Chemotherapy can generally be administered in selected
patients with HCV infection if they are monitored for
viral reactivation during therapy.55
Several studies have shown that hepatic dysfunction
can lead to frequent modifications or interruptions of
chemotherapy in patients with HCV reactivation, wors
ening their overall outcomes.45,49,60,78,89,91,92 In a series
of 160 HCV-positive patients with non-Hodgkin lym
phoma, eight patients (5%) did not complete the planned
treatment and 15 patients (9%) had their treatment



REVIEWS
postponed because of liver dysfunction.58 In that study,
median progression-free survival was significantly
shorter for patients who experienced liver dysfunction
than for those who did not (2 years versus 3.7 years;
P = 0.03).58 At our institution, chemotherapy was discon
tinued in up to 45% of patients with acute exacerbation
of HCV infection,80 but chemotherapy can usually be
restarted once liver function returns to normal.

Treatment
What constitutes the best treatment for HCV reactiva
tion is unclear, and, at present, treatment is mainly sup
portive. Patients with chronic HCV infection are treated
with the combination of pegylated interferon‑α and riba
virin.93,94 The use of direct-acting antiviral drugs (such
as the recently approved inhibitors of nonstructural
protein 3/4A (NS3/4A) protease [boceprevir or telapre
vir], or NS5B polymerase inhibitors) has not been evalu
ated in patients with cancer. Boceprevir and telaprevir
can inhibit hepatic drug-metabolizing enzymes such
as cytochrome P450 (CYP) 2C, CYP3A4, or CYP1A.95
Therefore, these agents potentially interact with various
drugs that are co-administered in patients with cancer.
These new antiviral drugs should be used with caution in
patients with cancer and preferably should be prescribed
only by clinicians with extensive experience in working
with this patient population.96
Anti-HCV therapy has traditionally been avoided
during chemotherapy in HCV-infected patients with
cancer because the hematologic adverse effects of antiHCV drugs can exacerbate the toxicity of chemotherapy,
which can involve complications such as severe cyto
penias and potentially life-threatening infections. 91
Results of a small case series published in 2010 suggest
that antiviral treatment can be considered when liver
dysfunction prohibits the administration of life-saving
chemotherapy.97 However, there is currently not enough
information to recommend administering anti-HCV
therapy concomitantly with standard chemotherapy
even in patients with HCV reactivation. Large-scale
studies are needed to better define which patients with
cancer are most likely to benefit from simultaneous
antiviral therapy and cytotoxic chemotherapy. Notably,
antiviral treatment with pegylated interferon α and rib
avirin should not be used early in the post- ransplant
t
period (2 years after transplantation) in patients
who have undergone allogeneic SCT as interferon‑α
1.

2.

3.

Torres, H. A., Boeckh, M. Chemaly, R. F.
in Medical Care of Cancer Patients
(eds Yeung, S. J., Escalante, C. Gagel, R. F.)
151–161 (B. C. Decker Inc Publisher, Shelton, CT,
2009).
Lok, A. S. et al. Reactivation of hepatitis B virus
replication in patients receiving cytotoxic therapy.
Report of a prospective study. Gastroenterology
100, 182–188 (1991).
Law, J. K. et al. Fatal reactivation of hepatitis B
post-chemotherapy for lymphoma in a hepatitis B
surface antigen-negative, hepatitis B core
antibody-positive patient: potential implications
for future prophylaxis recommendations. Leuk.
Lymphoma 46, 1085–1089 (2005).


4.

5.

6.

therapy might precipitate or induce the development of
graft-versus-host disease.98

Conclusions
Reactivation of HBV or HCV is associated with sub
stantial morbidity and mortality in patients with cancer.
Therefore, patients who require chemotherapy, SCT, or
treatment with high-dose corticosteroids should rou
tinely be screened for HBV and HCV before institution
of immunosuppressive therapy with standard tests such
as measurements of HBsAg, anti-HBc antibodies, and
anti-HCV antibodies. Screening for serum HBV DNA
and HCV RNA should also be performed in patients who
are at high risk of viral hepatitis.
In any patient with a history of chronic infection who
develops liver dysfunction during or after chemotherapy,
the possibility of HBV or HCV reactivation should be
considered. Periodic monitoring (at least monthly)
of ALT levels is recommended during chemotherapy
and after chemotherapy is reduced or withdrawn. In
patients with elevated ALT levels, levels of HBV DNA
and HCV RNA should be measured to confirm viral
reactivation. A substantial proportion of cancer patients
with HBV or HCV infection—mainly those with nonHodgkin lymphoma—develop liver dysfunction during
chemo herapy, which often leads to discontinuation of
t
potentially life-saving chemotherapy.
Unlike HCV reactivation, HBV reactivation is a
serious but preventable complication of immuno
suppressive therapy. Prophylactic anti-HBV therapy with
lamivudine is effective, and lamivudine has an excellent
safety profile. For patients with high HBV DNA levels
and for those who require prolonged therapy, the use of
newer nucleoside or nucleotide analogs such as enteca
vir or tenofovir is recommended. As treatment of HCV
reactivation is currently mainly supportive, new agents
to treat HCV reactivation are urgently needed.
Review criteria
Information for this Review was identified by searches
of the PubMed database and of the extensive reference
resources of the authors. The search terms included
“hepatitis B virus”, “hepatitis C virus”, and “reactivation”.
Abstracts and reports from meetings were included only
when they related directly to subsequently published
work. We reviewed all articles published in English
between January 1970 and October 2011.

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Acknowledgments
We thank Stephanie P Deming, scientific editor at the
.
Department of Scientific Publications at the MD
Anderson Cancer Center, for editorial assistance. No
funding sources were involved in the writing of this
Review or the decision to submit the Review for
publication.
Author contributions
Both authors researched data for the article, made
substantial contributions to the discussion of
content, wrote the article, and reviewed and edited
the manuscript before submission.


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