European Journal of Haematology ISSN 0902-4441

REVIEW ARTICLE

Liver dysfunction after chemotherapy in lymphoma patients

infected with hepatitis C
Omer Dizdar1, Umit Tapan2, Sercan Aksoy1, Hakan Harputluoglu1, Saadettin Kilickap1, Ibrahim Barista1
1

Division of Medical Oncology, 2Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara, Turkey

Abstract
Reactivation of hepatitis B virus (HBV) infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented complication. However, data on
the consequence of chemotherapy on the course of hepatitis C virus (HCV) infection in HCV(+) patients
have been controversial. Here, we review the current knowledge about the complications related to HCV
in lymphoma patients receiving chemotherapy immunosuppressive therapy. Although less frequent than
HBV, these complications occur in a subset of patients with mortality rates up to 45%. Therefore, baseline
screening for HBV and HCV before initiation of chemotherapy is crucial. High-risk patients having chronic
active hepatitis, high baseline HCV viral load, HBV co-infection and receiving cytotoxic drugs, corticosteroids and rituximab (particularly if combined) should be closely monitored for serum transaminase, bilirubin
and HCV RNA levels.
Key words hepatitis C virus; lymphoma; hepatotoxicity; chemotherapy; rituximab
Correspondence Omer Dizdar, Department of Medical Oncology, Hacettepe University Institute of Oncology, Sihhiye, Ankara
06100, Turkey. Tel: +90 312 305 29 41; Fax: +90 312 324 20 09; e-mail: omerdiz@yahoo.com
Accepted for publication 4 January 2008

The prevalence of hepatitis C virus (HCV) infection is

reported to be higher in patients with B-cell non-Hodgkins lymphoma (NHL) (15%) than general population
(1.5%), particularly in geographical areas with high incidence of HCV infection, suggesting a role of HCV in the
etiology of B-cell NHL (13). HCV(+) lymphoma
patients have a distinctive presentation and natural history. There are studies which report comparable or less
favorable overall survival and decreased quality of life
for HCV(+) lymphoma patients than their HCV())
counterparts (46). Treatment of HCV(+) lymphoma
patients is a challenge as many chemotherapeutic agents
are hepatotoxic or metabolized in liver. Impaired hepatic
functions may preclude the use of chemotherapy in standard doses and intervals. A major issue that has to be
considered in treatment of these patients is the effect of
commonly used agents in lymphoma treatment, i.e. cytotoxic drugs, corticosteroids and rituximab, on the course
of HCV infection. Reactivation of hepatitis B virus
(HBV) infection in asymptomatic hepatitis B surface
antigen carriers undergoing chemotherapy or immuno-

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doi:10.1111/j.1600-0609.2008.01039.x

suppressive therapy is a well-documented and potentially

fatal complication. The available data clearly support the
use of prophylactic lamivudine in these subjects (7).
However, data on the consequence of chemotherapy on
the course of HCV infection in HCV(+) patients have
been controversial.
Pathogenesis of HCV-related liver dysfunction

HCV-related liver dysfunction generally occurs 24 wk

after the cessation of chemotherapy (811). Widely
accepted hypothesis considering the pathogenesis denotes
enhanced viral replication with a consequent increase in
the number of infected hepatocytes following immunosuppressive treatment. Withdrawal of immunosuppressive
therapy leads to restoration of the host immune function,
resulting in the rapid destruction of infected cells and
hepatic injury (8, 12). Severe liver dysfunction was found
to occur at a lower incidence in HCV(+) patients than
HBV(+) patients (13). The reason for this phenomenon
is unknown. HCV is not directly cytopathic for infected

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host cells and the immune response plays a central role

in the pathogenesis of liver damage. Functional defects
of T cells in HCV infection are the major factors for progression of HCV infection to chronicity (14). These
defects may also justify the blunted response to the
administration and withdrawal of immunosuppressive
therapy in HCV(+) patients.
Incidence of HCV-related liver dysfunction following chemotherapy

Incidence of HCV-related liver dysfunction following

chemotherapy remains unclear. There are studies which
have demonstrated increased hepatotoxicity after chemotherapy in HCV(+) patients; however, most of them
were retrospective and how many of these toxicities were
linked to HCV is not clear as pre- and postchemotherapy
HCV RNA levels or liver biopsies were not evaluated in
all the patients (4, 5, 13, 15). Clinical settings, treatment
protocols and end-points (hepatotoxicity vs. HCV reactivation) are heterogeneous in these reports and number of
patients is low to draw a denite incidence.
Although there are studies which found no difference
considering severe hepatotoxicity after chemotherapy
between HCV(+) and HCV()) patients, these data
should be interpreted cautiously because most of these
studies were in prerituximab era and included limited
number of patients. Rituximab induces various viral
infections including HBV, HCV, cytomegalovirus, etc.
(16). Rituximab was reported to increase HCV viral load
and alanine aminotransferase (ALT) levels in patients
with HCV-related cryoglobulinemia (17, 18) and lymphoma (19). Therefore, combined use of rituximab with
chemotherapy poses an additional risk for exacerbation
of HCV infection.
One of the most important articles in the pertinent literature which suggest the safety of chemotherapy in
HCV(+) patients belongs to Zuckerman et al. They
reported a similar incidence and severity of hepatic dys-

Dizdar et al.

function secondary to chemotherapy in HCV(+) and

HCV()) patients with various hematological malignancies (mostly B-cell lymphoma). However, moderate and
severe liver dysfunction [transaminases 2.5 times upper
level of normal (ULN) and or total bilirubin
3.1 mg dL] were seen in 8 33 of HCV(+) patients and
36 241 of HCV()) patients and indeed the difference
approached signicance (24% vs. 15%, P = 0.13). No
patients received rituximab in this study (20). Among
patients with Hodgkins disease (HD) and NHL, Markovic et al. reported nine instances of HBV reactivations
among eight HBs-antigen positive patients and none in
HCV(+) patients after chemotherapy but there were
only three HCV(+) patients in this study and HCV
RNA was negative in one of the patients (21). Luppi
et al. detected no severe liver dysfunction and chemotherapy interruption among 35 HCV(+) patients with Bcell NHL, mostly treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen.
Eight patients with HCV received interferon in this study
and older patients with lymphoplasmacytoid lymphoma
and follicular lymphoma received either no treatment or
less-intensive regimens like chlorambucil monotherapy.
Additionally, HCV genotypes lb-2 which are generally
associated with a more severe liver disease had an unexpectedly lower prevalence in these patients (22).
On the other hand, there are reports of increased
HCV-related hepatotoxicity hepatitis following chemotherapy in the literature (Table 1). The most remarkable
data of hepatotoxicity come from Groupe dEtude des
Lymphomes de lAdulte study (5). A total of 15 of 23
HCV(+) lymphoma patients (65%) had hepatic toxicity
during chemotherapy; among them, seven had a grade 3
to 4 hepatic toxicity, which was signicantly higher than
matched HCV()) patients. Three patients died. Viral
load measured in four cases with hepatic toxicity was
highly positive. Liver biopsy was performed in one
patient and showed signs of toxic and viral hepatic
injury. Substantial hepatotoxicity was linked to the use

Table 1 Reports on the increased hepatotoxicity of chemotherapy immunosuppressive treatment in HCV(+) patients with various diseases
Author

Ref.

Disease

Treatment

No. of cases with

hepatic toxicity

Death

Besson et al.
Kawatani et al.

(5)
(13)

Various regimens
Various regimens

15 23 patients
4 22 patients

3
1

Visco et al.
Cavanna
Takai et al.
Nakamura et al.

(4)
(15)
(12)
(25)

CHOP or similar regimens

Various regimens
Various regimens
Various regimens

5 132 patients
7 104 patients
4 22 patients
11 patients

1
1

Vento et al.

(8)

NHL
Various hematological malignancies
including NHL
B-cell NHL
NHL
NHL
Various hematological malignancies
including NHL
B-cell NHL and Hodgkins disease

ABVD and CHOP like regimen

2 patients

HCV, hepatitis C virus; NHL, non-Hodgkins lymphoma; ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine; CHOP, cyclophosphamide,
doxorubicin, vincristine and prednisone.

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Dizdar et al.

of aggressive chemotherapy regimens in this study. Two

patients had HBV co-infection and both had grade 34
hepatotoxicity. HCV infection was associated with
decreased overall survival. In the study of Visco et al.
among 132 patients with HCV(+) diffuse large B-cell
lymphoma, ve patients (4%) had to discontinue treatment due to severe liver function impairment while 15
patients (11%) required prolongation of treatment intervals or dose reductions. One patient with HBV co-infection died secondary to grade 4 hepatotoxicity. In
multivariate analysis, HBV co-infection had an independent negative impact on overall survival of the patients.
Thirty-ve patients received rituximab containing combination regimens in this study without any hepatotoxicity;
however, the authors still recommended close follow-up
for liver function and viremia in HCV(+) patients considering the promoter effect of rituximab on HBV replication and the short follow-up period of their study (4).
Among 104 HCV(+) B-cell NHL patients who underwent chemotherapy, Cavanna et al., reported seven cases
who had developed hepatic toxicity that had modied
the planned treatment. One patient had died secondary
to hepatic toxicity together with progressive disease in
this study (15). In another study in patients with hematological malignancies, severe liver dysfunction (ALT 10
times ULN and or bilirubin 5 mg dL) after chemotherapy was observed in four of 22 HCV(+) patients, but in
none of 237 non-infected patients. One HCV(+) patient
died secondary to fulminant hepatitis. Steroid treatment
was observed as a risk factor for hepatotoxicity in
HCV(+) group in that study. All HCV(+) patients who
had severe liver dysfunction had received steroid containing chemotherapy regimens (13). Previously, stimulatory
effect of steroids on HCV replication both in vivo and in
vitro had been shown (23, 24). In the study of Takai
et al., four of 22 patients with NHL experienced acute
exacerbation of HCV, with one jaundice, but no deaths.
All patients were treated with CHOP-like regimens, had
baseline chronic active hepatitis and increased serum
HCV RNA levels during or after chemotherapy (12).
Nakamura et al. reported 11 cases with severe hepatitis
following chemotherapy in HCV(+) patients with
hematologic malignancies, ve of whom died. The incidence of severe hepatitis was higher in patients given corticosteroids, particularly if abruptly terminated (25). Two
HCV(+) cases with B-cell NHL and HD who developed
fulminant hepatic failure after the end of chemotherapy
were formerly reported. Both patients had baseline
chronic active hepatitis (8).
In the light of these data, 730% of the lymphoma
patients with HCV seem to have experienced HCVrelated hepatotoxicity secondary to chemotherapy, particularly if combined with corticosteroids. Once hepatotoxicity develops, mortality may be as high as 2045%
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Liver dysfunction after chemotherapy

among HCV(+) patients (5, 25). Differences in distribution of HCV genotypes, baseline HCV viral loads of the
patients, patient characteristics and chemotherapy regimens may account for the divergent rates of liver injury,
but it may be concluded that HCV-related hepatotoxicity
is not a marginal phenomenon in lymphoma patients
and may result in severe clinical consequences. Welldened risk factors can not be derived from these
reports; however, presence of active hepatitis (5, 8, 10
12), HBV co-infection (4, 5) and corticosteroid treatment
(13, 25) were the noteworthy factors increasing liver
injury risk. Baseline abnormality in liver function tests
did not predict development of hepatotoxicity (4, 5, 20).
The prognostic importance of these ndings was revealed
in the study of Musto et al. They evaluated the clinical
outcome of 44 HCV(+) patients with diffuse large B-cell
lymphoma treated with CHOP CHOP-like + rituximab or ProMACECytaBOM regimens. High viral load
and evidence of active hepatitis or cirrhosis at liver
biopsy were found to be associated with more frequent
hepatic failure under treatment and reduced survival
(26). High baseline viral load was also found to be the
most important risk factor for HBV reactivation in
patients positive for HBV surface antigen undergoing
cytotoxic chemotherapy (27, 28).
In addition to increased acute complications following
chemotherapy, HCV infection also generates long-term
risk of progressive damage to liver. In one study, 24% of
HCV-infected survivors with allogeneic transplants progressed to cirrhosis after 20 yr, which is much more
rapid than in patients without transplants. The median
time to cirrhosis in transplant recipients was 18 yr as
compared with 40 yr in the control population (29).
Although allogeneic bone marrow transplantation is a
different clinical setting, chemoimmunotherapy may also
accelerate progression to cirrhosis in HCV(+) patients
with chronic hepatitis in addition to acute toxicity.
Long-term follow-up data is lacking for these patients.
Treatment of HCV in patients with lymphoma

Utility of antiviral treatment in patients receiving chemotherapy is an area of research. The only data on the
combined use of chemotherapy and antiviral treatment
come from the study of Musto et al., the concomitant
administration of R-CHOP plus antiviral treatment with
pegylated interferon (0.51 mcg kg s.c., once-a-week)
and ribavirin (10001200 mg d p.o.) to four patients
with HCV(+) diffuse large B-cell lymphoma resulted in
excessive hematological toxicity. Thus, pegylated interferon plus ribavirin was given after chemotherapy for
3 months to the rest of patients. Such a sequential treatment was found effective, better tolerated and resulted in
a high rate of complete virus clearance (26). Although

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Liver dysfunction after chemotherapy

long-term data is not available yet, the preliminary

results were encouraging.
Furthermore, there are several reports which revealed
therapeutic effect of antiviral therapy on certain subtypes
of lymphoma. In patients with splenic lymphoma with
villous lymphocytes who were infected with HCV, treatment with interferon (ribavirin) resulted in regression
of the lymphoma (30). In another study, 13 patients with
histologically proven low-grade B-NHL and carrying
HCV infection underwent antiviral treatment alone with
pegylated interferon and ribavirin. Complete hematologic
response was obtained in 58% and partial response in
16% of the patients. Hematologic responses were signicantly associated with clearance or decrease in serum
HCV viral load (31). Therefore, antiviral treatment may
have benecial effects on the course of primary disease
as well as hepatitis in patients with lymphoma.
Conclusions

As the prevalence of HCV infection is higher in B-cell

lymphoma patients and as these patients are commonly
treated with R-CHOP or similar regimens which contain
rituximab, cytotoxics and corticosteroids, they represent
a distinctive subset in view of HCV-related hepatotoxicity secondary to chemotherapy. Rituximab, corticosteroids and cytotoxics may well cause hepatotoxicity
individually; therefore, combined use of these agents can
increase the risk of subsequent liver damage. It is obvious that giving less aggressive chemotherapy to prevent
hepatotoxicity is not feasible since fatal hepatitis has
been described even in patients treated with only one
immunosuppressive agent (32). Hence baseline screening
for HBV and HCV is crucial in lymphoma patients.
High-risk patients having baseline chronic active hepatitis, HBV co-infection, high HCV viral load and receiving
the offending drugs should be closely monitored for
serum transaminase, bilirubin and HCV RNA levels.
Further studies should be performed to evaluate effects
of anti-HCV treatment on prevention of HCV-related
hepatotoxicity and on overall survival in B-cell NHL
patients receiving chemotherapy.
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