We read Shibolet et al's recent article1 with great interest. In an endemic area for chronic hepatitis B infection, exacerbation of this virus is indeed a serious cause of morbidity and mortality in patients undergoing cytotoxic or immunosuppressive therapy.2 Careful prospective serologic testing has shown that liver damage due to hepatitis B virus (HBV) exacerbation is a 2-stage process. The initial stage occurs during intense cytotoxic or immunosuppressive therapy and is characterized by enhanced viral replication, as reflected by increases in serum levels of HBV DNA, hepatitis B e antigen (HBeAg), and HBV DNA polymerase, which presumably results in widespread infection of hepatocytes. The second stage is related to restoration of immune function following withdrawal of cytotoxic or immunosuppressive therapy, which causes rapid immune-mediated destruction of infected hepatocytes. Clinically, this may lead to hepatitis, hepatic failure, and even death.2 

The data presented by Shibolet et al provided a possible new solution to the problem: to administer lamivudine in a prophylactic manner for hepatitis B patients treated with chemotherapy. This approach is indeed more logical than deferring treatment with lamivudine until hepatitis due to HBV reactivation has occurred. In keeping with this, both lamivudine3 and famciclovir4 have been used to treat hepatitis due to HBV exacerbation. Despite the use of these antiviral agents, some patients positive for hepatitis B surface antigen (HBsAg) still developed hepatic failure and died.3 This is probably related to the late institution of the nucleoside analogues when the immune-mediated liver damage has already been established.

Although the data provided by Shibolet is promising, we feel that it is still inconclusive on the use of prophylactic lamivudine in HBsAg-positive patients undergoing immunosuppressive therapy. First, the study is retrospective and the diagnosis of HBV reactivation is based on serology such as the presence of new anti-HBc (hepatitis B core) IgM and/or sign of viral replication with a seroconversion from anti-HBe–positive to HBeAg-positive. But HBsAg-positive patients could suffer from reactivation even if they remain HBeAg-negative and previous sequence analysis of the HBV isolated from these patients had demonstrated the presence of point mutation in the precore region that inhibited the synthesis of HBeAg.5 On the other hand, serum IgM antibody to hepatitis B core antigen (anti-HBc) is not specific enough to diagnose HBV reactivation in patients with chronic HBV infection.6Therefore, it would be better to demonstrate the presence of HBV reactivation by showing an increase of serum HBV DNA by quantitation. Another shortcoming of the study is the differences in the chemotherapy regimen that was involved in the control and treatment arm. This could be of relevance; in particular, the use of steroids could greatly enhance HBV viral replication by stimulating the HBV glucocorticoid-responsive element.7 Lastly, HBV virologic factors, such as prechemotherapy serum HBV DNA, has been shown to affect postchemotherapy HBV reactivation.8 Hence, we feel that further prospective controlled studies, with all these factors taken into consideration, are urgently needed before we can establish the role of prophylactic use of lamivudine in HBsAg-positive patients undergoing chemotherapy or immunosuppressive therapy.

1
Shibolet
O
Ilan
Y
Gillis
S
Hubert
A
Shouval
D
Safadi
R
Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers.
Blood.
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2002
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Liang
R
Lau
GKK
Kwong
YL
Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem.
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1999
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Yeo
W
Steinberg
JL
Tam
JS
et al
Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy.
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Lau
GKK
Liang
RHS
Wu
PC
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CK
Lim
WL
Au
WY
Use of famciclovir to prevent HBV reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation.
J Hepatol.
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1998
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Steinberg
JL
Yeo
W
Zhong
S
et al
Hepatitis B virus reactivation in patients undergoing cytotoxic chemotherapy for solid tumours: precore/core mutations may play an important role.
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2000
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Colloredo
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Bellati
G
Leandro
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et al
Role of IgM antibody to hepatitis B core antigen in the diagnosis of hepatitis B exacerbations.
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8
1993
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7
Tur Kaspa
R
Burk
RD
Shaul
Y
Shafritz
DA
Hepatitis B virus DNA contains a glucocorticoid-responsive element.
Proc Natl Acad Sci U S A.
83
1986
1627
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8
Lau
GK
Leung
YH
Fong
DY
et al
High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.
Blood.
99
2002
2324
2330
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