screening, prevention and treatment of viral hepatitis b

Screening, prevention and treatment of viral hepatitis Breactivation in patients with haematological malignancies

Gadi Lalazar,1 Deborah Rund2 and Daniel Shouval1

1Liver Unit, Departments of Medicine and 2Department of Haematology, Hadassah-Hebrew University Hospital, Jerusalem, Israel

Summary

The prevalence of hepatitis B virus (HBV) infection in patients

with haematological malignancies is increased compared with

the general population worldwide. HBV reactivation is com-

mon following chemotherapy and is associated with a high

mortality despite prompt anti-viral treatment. HBV reactiva-

tion may necessitate interruption of chemotherapy with

adverse prognostic consequences for the haematological dis-

ease. Chemotherapy-induced immune suppression may lead to

increased HBV replication. Immune reconstitution within the

weeks and months following recovery from chemotherapy may

be associated with a flare of hepatitis B manifested by

hepatocellular injury. Risk factors associated with HBV

reactivation include detectable hepatitis B surface antigen

(HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen,

antibodies to hepatitis B core antigen (anti-HBc), treatment

with corticosteroids, young age and male gender. Lamivudine

is effective during HBV reactivation due to immune suppres-

sion. Clinical trials have demonstrated that pre-emptive

antiviral treatment with lamivudine is superior to deferred

treatment. Current recommendations emphasise screening for

HBV infection in all haematology patients, particularly prior to

chemotherapy. Patients who are HBsAg positive or HBV DNA

positive should receive pre-emptive treatment with lamivudine

before chemotherapy. The duration of lamivudine treatment

may be prolonged commensurate with the degree of immu-

nosuppression. HBV naıve patients should be immunised

against hepatitis B, as should haematopoietic stem cell donors.

In summary, overt and occult HBV pose a serious, but

preventable, threat. Pre-treatment screening of patients at risk

should be practiced diligently by all clinicians that treat

patients with malignancies.

Keywords: immune suppression, leukaemia, lymphoma, anti-

viral treatment, haematopoietic stem cell transplantation.

Approximately 2 billion people worldwide have been

infected with hepatitis B virus (HBV) during their lifetime,

with >350 million remaining chronically infected (Lavanchy,

2004). The prevalence of chronic HBV infection, as deter-

mined by hepatitis B surface antigen (HBsAg) testing, ranges

between 8% and 25% in endemic countries (East Asia and

Africa) to <0Æ5% in the native populations of the Western

hemisphere (Lok et al, 1987; Lavanchy, 2004). The prevalence

of HBsAg in haemato-oncological patients is increased but

proportional to that reported in the general population: 1%

in the USA, 3Æ5% in Western Europe, 5% in Turkey and

10% in Asian Chinese (Lau et al, 1999; Takai et al, 2005).

Chronic HBV carriers, defined as persons with positive

HBsAg for >6 months, have a 15–40% lifetime risk of

developing serious complications of chronic liver disease

(including chronic hepatitis, cirrhosis and hepatocellular

carcinoma) (McMahon, 2005). Most carriers, however,

remain clinically silent for extended periods, lasting from

decades to a lifetime. Some carriers will lose HBsAg over

time but remain positive for antibodies to hepatitis B core

antigen (anti-HBc), with low levels of HBV-DNA, reflecting

occult infection.

Patients with haematological malignancies deserve special

attention regarding their hepatitis B status for several reasons.

First, in endemic countries, the incidence of HBV reactivation

is increased in this group compared with normal subjects

(Takai et al, 2005; Yim & Lok, 2006). Yet, overt and occult

HBV infections are often missed at a stage when pre-emptive

anti-viral treatment may prevent HBV reactivation. Secondly,

HBV reactivation is a common sequella of chemotherapy

occurring in 21–53% of HBsAg carriers (Yeo et al, 2000), and

when left undetected, may carry a grave prognosis despite

therapy. Thirdly, even when full recovery is achieved, reacti-

vation may reduce survival because it may require interruption

of chemotherapy.

During the past decade, new diagnostic tools and efficacious

anti-viral agents have been developed mainly for hepatitis B

but also for hepatitis C. This review discusses the clinical

presentation, diagnosis, treatment and prevention of HBV

reactivation in haemato-oncological patients.

Correspondence: Prof. Daniel Shouval, Director, Liver Unit, Hadassah-

Hebrew University Hospital, PO Box 12000, Jerusalem 91120, Israel.

E-mail: [email protected]

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ª 2007 The Authors First published online 8 January 2007Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 136, 699–712 doi:10.1111/j.1365-2141.2006.06465.x

The ‘natural’ course of hepatitis B virus infectionas relevant to patients with a haematologicalmalignancy

The evolution of chronic HBV infection often depends on the

age at infection and is affected by the balance between the host

immune response and viral replication. Vertical or perinatal

transmission of HBV frequently results in immune tolerance to

the virus. Infection during adulthood induces a neutralising

immune response in over 90% of immunocompetent individ-

uals, with spontaneous resolution of acute infection (McMa-

hon, 2005; Yim & Lok, 2006). In this case, immune memory,

comprising T helper cell type 1 (Th1) responses to nucleo-

capsid epitopes and antibodies to HBsAg (anti-HBs), persist

for decades and generally prevent reinfection (Chisari, 1997;

Bertoletti & Gehring, 2006). Patients who are unable to resolve

an acute infection have an altered natural course of HBV

infection, consisting of four phases: immune tolerance with

enhanced viral replication; immune clearance characterised by

the initial presence of hepatitis B e antigen (HBeAg) and

variable viral load; inactive carrier state frequently associated

with antibodies to HBeAg (anti-HBe) seroconversion with low

viral replication, and HBV reactivation (Yim & Lok, 2006).

Reactivation of HBV infection may occur in a known

asymptomatic HBsAg carrier or in patients with occult or

rarely with resolved hepatitis B. HBV reactivation, either

spontaneous or following chemotherapy, can resolve, persist,

recur or lead to liver failure and death (Fig 1). Such flares have

been attributed to changes in equilibrium due to an enhanced

immunological response to HBV during recovery from

immune suppression, associated with quantitative variations

in viral load. Serological recovery from HBV infection (defined

as anti-HBs antibody titre >10 IU/l, also termed resolved

HBV) usually signifies clearance of viraemia and complete

resolution of hepatocellular injury. However, even after

serological recovery, HBV may persist as an occult infection

in serum, in the liver (with intra-hepatic covalently closed

circular DNA, termed cccDNA) or in extra-hepatic sites, with

resulting risk of reactivation (Yim & Lok, 2006). This is

especially true during recovery from immunosuppression or

disease-associated immunodeficiency (Puoti et al, 2006).

Immune suppression allows enhanced viral replication with

increased viral load and reduced clearance. Immune reconsti-

tution may then lead to a vigorous host-derived inflammatory

response towards HBV, with concomitant hepatic necrosis

(Liaw, 1998).

Risk factors

Patients at risk are those with haematological malignancies (or

solid malignant tumours) who are candidates for chemother-

apy but also patients with non-malignant diseases, such as

immune thrombocytopenic purpura (ITP) or autoimmune

haemolytic anaemia, which require continuous immunosup-

pressive therapy. Most haemato-oncological patients should be

considered at risk either for HBV reactivation or acute

acquired HBV infection. Increased risk is due to increased

exposure to potentially contaminated blood products (despite

conventional screening) as well as disease- and treatment-

related factors (Yeo & Johnson, 2006).

Haemato-oncological diseases reported in association with

HBV reactivation are listed in Table I.

Studies on the clinical significance of HBV genotypes

indicate that genotypes may correlate with key clinical events

(Kao et al, 2000). Although data are scarce, the incidence of

HBV reactivation seems to correlate with distinct HBV

genotypes C and B, prevalent in East Asia, and the East

Mediterranean (Lok & Lai, 1990; Lok et al, 1991; Jazayeri et al,

2004).

Several specific risk factors for HBV reactivation have been

proposed, but few were confirmed in multivariate analysis. In

studies of 78 patients (Yeo et al, 2000, 2004a), univariate

analysis identified an increased risk in younger males who

had HBsAg positive/HBeAg positive lymphoma, while there

was no association with pre-treatment alanine amino trans-

Fig 1. Dynamics of viral load and alanine amino transferase (ALT)

during the course of hepatitis B virus (HBV) reactivation following

chemotherapy-induced immune suppression. Adapted from Xunrong

et al (2001). �John Wiley & Sons Limited with permission.

Table I. Haematological diseases reported in association with hepatitis

B virus reactivation

Group Disease

Acute leukaemia Acute myeloid leukaemia

Acute lymphoblastic leukaemia

Myeloproliferative

disorders

Chronic myeloid leukaemia

Lymphoproliferative

disorders

Chronic lymphocytic leukaemia

Non-Hodgkin lymphoma

Hodgkin disease

Plasma cell dyscrasias Multiple myeloma

Waldenstrom macroglobulinaemia

Plasmacytoma

Other Aplastic anaemia

Myelodysplastic syndrome

Haematopoietic stem cell transplantation

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ª 2007 The Authors700 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 136, 699–712

ferase (ALT), bilirubin or HBV DNA. In contrast, in a study

of patients with hepatocellular carcinoma and underlying

liver disease, pre-treatment ALT elevation was shown to be a

risk factor for HBV reactivation (Yeo et al, 2004b). In a study

of 100 patients, male sex was the only risk factor (Lok et al,

1991). In contrast, a study of 137 autologous haematopoietic

cell transplantation (HCT) patients found that pre-immune

suppression HBV DNA level >105 copies/ml was the only

significant risk factor (Lau et al, 2002a). This was also

observed in 138 cancer patients for whom HBV viral load

>3 · 105 copies/ml was a risk factor for reactivation (Yeo

et al, 2004a). Zhong et al (2004) and Hui et al (2005a)

confirmed that high titre viral DNA levels increase the risk of

HBV reactivation.

Different chemotherapeutic agents have been reported in

association with HBV reactivation (Table II), most import-

antly, corticosteroids and anthracyclines (Lok et al, 1991;

Cheng et al, 2003; Yeo & Johnson, 2006). The HBV DNA

contains a glucocorticoid responsive element that facilitates

replication (Tur-Kaspa et al, 1986), while anthracyclines have

been shown in vitro to stimulate HBV DNA secretion (Hsu

et al, 2004). Most important, corticosteroids may also induce a

flare, particularly upon abrupt withdrawal of treatment.

‘Steroid free’ chemotherapy has been proposed to minimise

the risk of HBV reactivation (Lok et al, 1992; Nakamura et al,

1996), but is of dubious benefit. In a prospective study of 50

patients with aggressive non-Hodgkin lymphoma (NHL) (75%

diffuse large B-cell NHL in both the steroid-free and the

steroid-inclusive arms), the use of ‘steroid-free’ chemotherapy

resulted in a significant decrease in the rate of HBV reactiva-

tion (73% vs. 38%, P ¼ 0Æ03). However, patients in the

‘steroid-free’ arm had a significantly lower rate of complete

remission and shorter overall survival, presumably due to

suboptimal therapy (Cheng et al, 2003).

Theoretically, any form of immune suppression, including

agents not mentioned in Table II, may lead to HBV reactiva-

tion. Standard chemotherapy has frequently been documented

to cause HBV reactivation in HBsAg negative patients with

occult HBV infection (Lok et al, 1991; Hui et al, 2006).

Immune suppression of greater intensity may be a risk factor.

One study found the incidence of HBV reactivation increased

with second or third line chemotherapy (Kumagai et al, 1997),

but this was not subsequently confirmed (Yeo et al, 2000).

In contrast, mildly immune suppressive chemotherapy, such as

Table II. Chemotherapeutic and immune modulating agents involved in hepatitis B virus reactivation and their potential for hepatotoxicity*.

Class Agents associated with HBV reactivation Potential hepatotoxicity

Alkylators Cyclophosphamide VOD, hepatocellular injury

Ifosfamide Hepatocellular injury, cholestasis

Chlorambucil Hepatocellular injury

Carboplatin, cisplatin hepatocellular injury, cholestasis, steatosis, peliosis

Antimetabolites Cytarabine VOD, hepatocellular injury

Fluorouraril Hepatocellular injury

Gemcitabine Hepatocellular injury, cholestasis

Mercaptopurine Hepatocellular injury, cholestasis

Methotrexate Hepatocellular injury, steatosis, fibrosis, hepatic neoplasm

Thioguanine VOD, hepatocellular injury, NRH, peliosis

Antitumor antibiotics Anthracyclines Hepatocellular injury, VOD

Bleomycin Steatosis

Mitomycin C VOD, steatosis

Actinomycin D VOD, steatosis

Corticosteroides Prednisone/dexamethasone etc. hepatomegaly (rare association)

Immunotherapy Rituximab (anti-CD20) Hepatocellular injury

Alemtuzumab (anti-CD52) Hepatocellular injury

Infliximab (anti-TNF) Hepatocellular injury, steatosis

Plant Alkaloids Vincristine VOD, hepatocellular injury

Vinblastine Hepatocellular injury

Others Asparginase Hepatocellular injury, steatosis

Procarbazine VOD

Docetaxel Hepatocellular injury

Etoposide Hepatocellular injury

Fludarabine Hepatocellular injury

Imatinib Mesylate Hepatocellular injury, cholestasis

Interferon alpha Hepatocellular injury

*Only predominant forms of liver injury are cited for the purpose of differential diagnosis of abnormal liver function tests.

Modified from Yeo and Johnson (2006) with permission from John Wiley & Sons, Inc.�, and Bonkovsky et al (2006) with permission from Elsevier.

VOD, veno-occlusive disease; NRH, nodular regenerative hyperplasia.

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ª 2007 The AuthorsJournal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 136, 699–712 701

5-fluorouracil, for colon cancer carried a lower risk (Liaw,

1998).

Allogeneic haematopoietic stem cell transplantation (HSCT)

frequently leads to reactivation (Chen et al, 1990, 1993; Martin

et al, 1995; Picardi et al, 1998; Strasser & McDonald, 1999;

Iwai et al, 2000; Nordbo et al, 2000; Goyama et al, 2002); the

rate of HBV reactivation varies between 14% and 50% (Chen

et al, 1990; Dhedin et al, 1998; Seth et al, 2002; Knoll et al,

2004; Onozawa et al, 2005). Suggested risk factors include

corticosteroid use, lack of anti-HBs in the donor, and graft

versus host disease (GVHD). Conversely, in autologous-HSCT,

there have been fewer reports (Webster et al, 1989; Goyama

et al, 2002). One case series showed that one of 37 patients

developed non-fulminant hepatitis B (Lau et al, 2002a).

Newer therapeutic monoclonal antibodies, such as Rituxim-

ab (anti-CD20) (Westhoff et al, 2003; Law et al, 2005; Niscola

et al, 2005; Sarrecchia et al, 2005), Alemtuzumab (anti-CD52)

(Iannitto et al, 2005) and infliximab (anti-TNF) (Calabrese

et al, 2006) have been associated with HBV reactivation in

HBsAg carriers as well as in HBsAg negative patients, which may

progress to fulminant hepatitis. These agents cause profound

and long-lasting immunosuppression (Osterburg et al, 1997;

van der Kolk et al, 2002), which may account for the risk of

HBV reactivation following treatment.

The patient’s HBV serological profile is linked to the risk of

HBV reactivation. HBsAg positive patients are at highest risk;

patients with anti-HBs levels >10 IU/l are at the lowest risk.

HBeAg positivity, previously considered to signify high level

viral replication, has been replaced by more sensitive viral load

assays (Locarnini, 2004) that have a threshold of detection of

as low as 300 copies/ml and a wide dynamic range (Gish &

Locarnini, 2006). HBV DNA assays are also useful in HBeAg

negative/anti-HBe positive patients in whom viraemia can still

be significant. Even in patients who have cleared HBsAg and

undergone seroconversion, residual HBV DNA, in the form of

cccDNA ‘hidden’ in hepatocytes, can be used as a template for

reactivation following immune suppression (Hui et al, 2005b).

Furthermore, HBV DNA has been found in peripheral blood

mononuclear cells recovered from immune suppressed trans-

planted patients with a serologic profile anti-HBc positive/

HBsAg negative/anti-HBs negative, in the absence of HBV

DNA in the serum (Mason et al, 1998; Locarnini, 2004).

A similar rule applies for patients following treatment for

HBV. Even with successful therapy, some patients remain at

lifelong risk for reactivation (Osborn & Lok, 2006). Therefore,

while anti-HBs positive patients are at low risk (Lok et al,

1991; Lau et al, 2002a; Knoll et al, 2004; Onozawa et al, 2005),

these patients are not absolutely protected against reactivation.

Subclinical changes in the immune profile of such patients may

lead to asymptomatic rise of ALT, which may progress to overt

disease. In a report of 17 patients with haematological

malignancies (Wands et al, 1975), 12 had a marked reduction

in their anti-HBs titre; five developed ‘seroreversion’, with

reappearance of HBsAg, and two remained persistently HBsAg

positive despite the cessation of chemotherapy. Others have

reported changes in the HBV serological profile following

chemotherapy (Iannitto et al, 2005; Avettand-Fenoel et al,

2006).

In summary, proven risk factors include: positive HBsAg

(especially when associated with high viral load), positive HBeAg,

positive anti-HBc in the absence of HBsAg and anti-HBs, use of

corticosteroids or anthracyclines, higher intensity chemotherapy

(suchasforHSCT),malegenderandyoungage.

Clinical manifestations and laboratory diagnosisof a hepatitis B flare in the immune suppressedpatient

Hepatitis B virus reactivation is characterised by two main

parameters: rising serum HBV DNA levels followed by rising

ALT. Monitoring of HBV DNA requires an available sensitive

assay with a wide dynamic range (Gish & Locarnini, 2006).

Reactivation may be symptomatic or remain asymptomatic.

Rising HBV DNA levels usually precede ALT elevation, which

frequently lags by several days (range 1–11 weeks) after an

increase in viral load (Lau et al, 2003). Furthermore, HBV

DNA levels may be declining or undetectable by the time a rise

in ALT is noticed (Xunrong et al, 2001; Yeo & Johnson, 2006)

(Fig 1). Therefore, there are no clear cut diagnostic criteria for

HBV reactivation. One proposed definition was a sudden rise

in serum ALT more than five times the upper limit of normal

or more than three times baseline level, whichever was higher

(Lok et al, 1987). Other definitions include a 10-fold rise in

viral load or HBV DNA levels exceeding approximately

6 log10 copies/ml (Yeo et al, 2000). Essentially, measuring

viral load (Gish & Locarnini, 2006) and ALT are the key to

diagnosing and monitoring reactivation. A liver biopsy,

although usually not imperative, can potentially yield im-

portant information, by excluding other or concomitant

factors involved in liver injury. It may also reveal a potentially

wide spectrum of histological changes associated with HBV

infection. If present, coagulopathy or thrombocytopenia may

necessitate a transjugular approach.

Reactivation most frequently follows cessation of che-

motherapy, but may occur during chemotherapy. The reported

interval ranges from 4 to 36 weeks (median, 16 weeks) from

initiation of chemotherapy (Liang et al, 1999; Lau et al, 2003).

An acute flare may also be induced by HBV genotypic

variations, such as precore or DNA polymerase mutants as well

as superinfection by other hepatotrophic viruses, such as

hepatitis D, hepatitis C and hepatitis A as well as cytomeg-

alovirus (CMV) and Epstein–Barr virus (EBV). Interaction

with HIV or hepatotoxicity of anti-HIV agents may also

contribute (Puoti et al, 2006). An acute flare may be indistin-

guishable from acute viral hepatitis B including the detection

of anti-HBc IgM, potentially leading to a misdiagnosis of acute

HBV infection in patients with previously undiagnosed

chronic disease. HBV-reactivation can easily be missed,

particularly in early stages, when salvage anti-viral therapy

could be life saving. Reactivation can also be associated with an

Review


increase in alpha-feto-protein, raising concern about the

development of hepatocellular carcinoma (Lok & Lai, 1989).

Hepatitis B virus reactivation may resolve spontaneously.

Symptomatic patients may develop the classical symptoms of

hepatitis, including fatigue, jaundice, ascites, hepatic encepha-

lopathy and coagulopathy. Patients with underlying cirrhosis

may rapidly develop liver failure; their mortality ranges from

4% to 41% (Lok et al, 1991; Kumagai et al, 1997; Liang et al,

1999; Markovic et al, 1999; Tillman et al, 2003).

Since many patients are asymptomatic, regular monitoring

of ALT and HBV DNA is essential although there is no

consensus regarding frequency of testing. As reactivation may

be transient, more frequent HBV DNA and ALT monitoring

will lead to a higher rate of diagnosis.

Differential diagnosis of a hepatitis flare

Most hepatitis flares in patients with chronic HBV are of viral

aetiology. However, there are a number of other causes for

liver dysfunction including chemotherapy or other drug-

induced toxic hepatitis, veno-occlusive disease (VOD), pelio-

sis, hepatic steatosis, hepatic fibrosis and nodular regenerative

hyperplasia (NRH). Table II lists various types of chemother-

apy agents involved in HBV reactivation that may also induce

toxic hepatocellular or cholestatic dysfunction. Hepatotoxicity

of anti-cancer agents may frequently result from an interaction

between two or more agents. ALT elevation can also be caused

by bacterial, viral or fungal infection [i.e. sepsis, CMV, EBV,

herpes or human immunodeficiency virus (HIV)]. Super-

infection with other hepatitis viruses, i.e. delta virus (HDV)

infection in HBsAg carriers, hepatitis C or even hepatitis A can

cause as many as 20–30% of flares (Perrillo, 2001). HBV-

related fibrosing cholestatic hepatitis and GVHD are reported

to be more frequent in HBsAg carriers (Lau et al, 1999). Other

causes of hepatocellular or cholestatic injury should be

considered where appropriate, such as exposure to alcohol,

total parentral nutrition, acalculous cholecystitis, tumour

infiltration, or radiation toxicity. About 12% of ALT elevations

remain unexplained (Yeo et al, 2000).

Haemato-oncological patients previously treated for HBV

are at risk for developing resistance against the antiviral agent,

such as reported for lamivudine for which 16–60% of recipients

develop a mutation known as the YMDD motif within 1–

4 years of treatment, respectively (Locarnini, 2004; Osborn &

Lok, 2006; Wong & Lok, 2006). Hepatitis flares in such patients

with a high viral load despite lamivudine treatment, must

therefore be evaluated for this mutation, followed by optional

treatment with adefovir or entecavir (see below).

Hepatitis B reactivation: screening andprevention

Prevention of HBV reactivation is superior to intervention at

the time of reactivation. Preventive measures start with proper

screening for HBV markers before initiation of chemotherapy

followed by active immunisation of all HBV susceptible

patients (also including bone-marrow and stem cell donors).

Candidate patients with overt or occult HBV must be

identified and protected against HBV by an anti-viral agent.

Screening of haemato-oncological patients prior toinitiation of chemotherapy

All patients diagnosed with a haematological disease should be

screened for HBV infection. Initial screening is based on

serological tests for anti-HBc antibodies, HBsAg and anti-HBs

antibodies (see flow chart: Fig 2). Seronegative patients should

be actively vaccinated against HBV. HBsAg positive patients

are considered carriers and should be protected pre-emptively

against HBV reactivation by an anti-viral agent before

initiation of chemotherapy (see below). Frequently, the

diagnosis of an HBsAg carrier state cannot be verified at time

of initiation of chemotherapy, as it is based on 6 months’

observation. In such a situation, the presence of a positive

HBsAg test should be interpreted as representing an HBsAg

carrier state, provided there is no evidence for acute hepatitis B

which may result in delay of cytotoxic treatment. All HBsAg

positive patients should be further tested for HBeAg, anti-HBe,

HBV DNA and if possible, anti-HBc IgM. A liver biopsy may

be considered in patients with pre-chemotherapy abnormal

liver function tests, the result of which may have implications

on the selection and dosing of chemotherapy. HBsAg negative

patients who are anti-HBc positive, require further testing. A

positive anti-HBs test in this context signifies a patient who

recovered from HBV infection; while a negative anti-HBs test

may signify either occult HBV infection, recovery from

infection with a waning antibody titre or a false positive

anti-HBc result. Differentiation between these fundamentally

different states may be accomplished by repeating the

serological profile after administration of an HBV vaccine

booster dose to anti-HBc positive patients negative for HBsAg

and anti-HBs (Fig 2). A rise in the anti-HBs antibody titre

above 10 IU/l (and preferably >100 IU/l) within 2–4 weeks is a

result of an anamnestic immune response and signifies

immunity to HBV. In anti-HBc positive non-responders to

the HBV vaccine, HBV-DNA should be measured by a

sensitive polymerase chain reaction (PCR) assay. Detectable

HBV-DNA implies occult HBV infection which will require

pre-emptive antiviral therapy before initiation of chemother-

apy (Fig 2). Since a patient’s serological profile may change

during the course of chemotherapy (i.e. seroreversion from a

state of anti-HBs positivity to HBsAg positivity) it is advised to

perform serologic re-testing before the continuation of

chemotherapy in case ALT levels rise (Wands et al, 1975;

Chen et al, 1990; Dhedin et al, 1998; Seth et al, 2002; Knoll

et al, 2004; Onozawa et al, 2005). In cases where urgent

chemotherapy treatment is required this may be accomplished

by saving an adequate blood sample for serological analysis

prior to the institution of therapy and making a decision on

anti-viral treatment once results are available.

Review


Immunisation against hepatitis B infection

The cornerstone of prevention for patients who are HBV

seronegative is immunisation. Currently available HBV vac-

cines are very safe and have an efficacy of >90% in immuno-

competent young individuals. Non-response is associated with

a number of factors including genetically determined resist-

ance, advanced age, obesity, chronic liver disease, smoking,

male gender and miscellaneous systemic diseases including

renal failure (Shouval, 2003; Yu et al, 2006). Although

universal vaccination of newborns has been implemented

worldwide according to World Health Organisation recom-

mendations, it will take several decades until the majority of

the world’s adult population will be immune. Unfortunately,

vaccination rates are low in many countries either due to lack

of funding or because of the misconception that vaccination is

only necessary in high-risk groups (Banatvala et al, 2006).

It is strongly recommended that all haemato-oncological

patients be screened for HBV markers and immunisation

against hepatitis B should be performed when appropriate (see

algorithm, Fig 2). The conventional regimen for the HBV

vaccine requires three doses at 0, 1 and 6 months. Delaying

administration of the third dose in healthy individuals (up to

1 year) may increase anti-HBs antibody levels. Frequently, in

haemato-oncological patients, urgent administration of che-

motherapy does not allow completion of the three-dose

regimen. In such cases, an effort should be made to immunise

patients with at least two doses within a 3–4 week interval. The

third dose can then be given a few months after chemotherapy

is completed.

In most countries, immunity against HBV infection is

defined as an anti-HBs titre >10 IU/l and in the UK the

recommended titre is >100 IU/l. Non-response to HBV

vaccines is not rare in haemato-oncological patients due to

disease-associated or treatment-induced immune suppression.

Thus, protection against HBV may not be achieved until all

doses have been administered. Although immune suppressed

patients have significantly lower response rates to vaccination,

successful anti-HBs seroconversion following a three dose

vaccine schedule has been reported in 57% of cancer patients,

15–68% of bone marrow transplant recipients, and in 10% in

acute lymphoblastic leukaemia (ALL) patients (Yu et al, 2006).

Documentation of post-vaccination anti-HBs seroconversion

is recommended. There are a number of means to augment the

immune response to HBV immunisation in non-responders,

including adding three additional doses; doubling the vaccine

dose; intradermal injection of the vaccine and use of new,

more immunogenic HBV vaccines (Shouval, 2003; Yu et al,

2006). Finally, after allogeneic HSCT, immunity to HBV

acquired through active immunisation may rarely be abolished

by immune suppression and/or transplantation of HBV naıve

bone marrow cells (Dhedin et al, 1998).

Fig 2. Guidelines for prevention of hepatitis B virus reactivation in haemato-oncologic patients: patients management according to status of hepatitis

B virus markers.

Review


Agents for treatment of patients with occult or overtHBV infection

Recently, new and efficacious anti-viral agents have signifi-

cantly improved our ability to intervene in and prevent HBV

reactivation in immune suppressed patients (Osborn & Lok,

2006; Wong & Lok, 2006). Standard therapy currently consists

of lamivudine, a nucleoside analogue introduced in 1995,

which inhibits the viral DNA polymerase, thus rapidly and

effectively interfering with viral replication, with minimal

toxicity.

In addition, several new potent anti-viral agents been

developed and licensed for the treatment of chronic HBV,

including adefovir dipivoxil in 2002 (Osborn & Lok, 2006),

entecavir in 2005 (Chang et al, 2006; Lai et al, 2006) and

others are awaiting approval. Both adefovir and entecavir are

effective against YMDD mutants. While adefovir and lamivu-

dine seem to suppress hepatitis B viral load equally well,

entecavir is the currently most potent agent against HBV,

leading to a 5–6 log suppression in viral load in HBsAg/HBeAg

positive patients after 48 weeks of treatment with no HBV

resistant strains reported thus far. There have been a few

reports on the successful use of adefovir for HBV reactivation

by a YMDD mutant during lamivudine therapy in haemato-

oncological and immune suppressed patients (Nunez &

Soriano, 2005; Cortelezzi et al, 2006; Fouillard et al, 2006).

Interferon alpha, used for the treatment of chronic HBV, has

been shown to control chronic HBV infection during chemo-

therapy to a certain degree (Lok et al, 1992; Kumagai et al,

1997; Leaw et al, 2004; Osborn & Lok, 2006). However,

adverse effects, such as thrombocytopenia and or leucopenia,

often limit its use during chemotherapy. A more serious

concern is the enhancement of hepatocellular injury by

augmentation of the host immune response against HBV.

Thus, the use of interferon for an HBV flare has now been

practically discontinued.

Protection and management of immunesuppressed patients with overt or occult HBVagainst HBV reactivation

There are currently two approaches in management of patients

at risk, namely intervention by treatment of HBV reactivation

when it is diagnosed, or prevention through pre-emptive

treatment prior to or upon initiation of chemotherapy.

Intervention upon diagnosis of hepatitis B reactivation

When HBV reactivation is diagnosed, prompt anti-viral

therapy is vital. In patients who develop signs of HBV

reactivation, end points of treatment include normalisation of

ALT, suppression of HBV viral load to undetectable levels and

HBeAg seroconversion to anti-HBe. In anti-HBe positive

patients, ALT normalisation and viral load suppression are the

main goals of treatment. Aggressive supportive therapy should

be instituted and cessation of chemotherapy and withdrawal of

potential hepatotoxic agents should be considered. Patients

should be monitored, closely testing liver enzymes, coagulation

function and viral load. Consultation with an expert hepato-

logist or early referral to a hepatology centre should be

considered in patients with a severe course, although liver

transplantation may not be feasible in patients with a

malignancy.

Currently lamivudine is the primary agent for treatment for

HBV reactivation in the setting of immune suppression.

Several reports have shown clinical improvement and effective

control of viral replication (Clark et al, 1998; Picardi et al,

1998; Ahmed & Keeffe, 1999; Al-Taie et al, 1999; Vento et al,

2002). The true rate of HBV reactivation in immune

suppressed patients is not known and spontaneous resolution

may occur (Table III). Thus, the reported efficacy rates of

antiviral treatment may be somewhat overestimated (Yeo &

Johnson, 2006). None of the studies reporting the success of

lamivudine for HBV reactivation in these patients is a truly

prospective, blinded, placebo controlled trial. Presently, it is

unlikely that such a study is ethically feasible. Despite this

caveat, there is no doubt that lamivudine is effective in

suppression of HBV replication and thus has dual importance,

as it may enable the continuation of chemotherapy without

risking further hepatic deterioration. Lamivudine is efficacious

for HBV reactivation but less so if hepatic decompensation has

occurred (ter Borg et al, 1998; Clark et al, 1998). Mortality

may be as high as 40% despite lamivudine (Markovic et al,

1999) if severe hepatic injury is present (Iwai et al, 2000; Yeo

et al, 2000; Yeo & Johnson, 2006). Thus, it is imperative to

begin antiviral therapy immediately once a flare is diagnosed.

As stated earlier, HBV DNA rises prior to ALT elevation

(Fig 1). Ideally, in cases where lamivudine is not administered

pre-emptively, viral load should be monitored periodically

during chemotherapy, although there is no consensus as to

how frequently. Once a rise in HBV DNA is identified, it is

strongly advised to immediately administer lamivudine, prior

to the appearance of clinical manifestations. However, this

recommendation is difficult to implement due to cost and the

time required for assessment of HBV DNA levels.

Pre-emptive anti-viral therapy against hepatitis Breactivation

Several reports have demonstrated the benefit of pre-emptive

treatment with lamivudine in patients at risk of HBV

reactivation. The rational for initiation of pre-emptive treat-

ment with lamivudine in patients at risk is based on

observations that viraemia, defined as HBV DNA >104 cop-

ies/ml, usually precedes ALT elevation by a day to several

months. Thus, early suppression of viral load prior to hepatic

injury is superior to deferred intervention. Reports on the

efficacy of pre-emptive treatment may be divided into

retrospective studies and prospective studies with historical

controls, listed in Table III. In 12 studies conducted in 208

Review


Tab

leII

I.Se

lect

edre

po

rts

on

the

ou

tco

me

of

hep

atit

isB

viru

sre

acti

vati

on

inp

atie

nts

wit

hh

aem

ato

logi

cal

mal

ign

anci

estr

eate

db

yd

efer

red

or

pre

-em

pti

vela

miv

ud

ine*

.

Th

erap

yw

ith

Lam

ivu

din

eA

uth

or

Dia

gno

sis

Stu

dy

typ

e

Inte

rval

to

reac

tiva

tio

n

To

tal

nu

mb

ero

f

pat

ien

ts

Nu

mb

ero

fp

atie

nts

inea

chgr

ou

p:

P/D

/NT

Nu

mb

ero

fac

ute

hep

atit

is

case

s(r

eso

lved

)

Nu

mb

ero

f

HB

V-r

elat

edd

eath

s

No

ne

Lia

ng

etal

(199

0)L

ymp

ho

ma

Ret

roD

uri

ng

and

afte

rC

105

NT

166

Def

erre

dY

eoet

al(1

999)

NH

L,

oth

erR

etro

Du

rin

gC

88-

D5

1-D

(2d

eath

sfr

om

mal

ign

ancy

)

Pet

rell

iet

al(2

001)

NH

L,

PC

,A

ML

,M

M,

KS,

AL

LR

etro

Du

rin

gC

105-

D/5

-NT

18

(1d

eath

fro

mm

alig

nan

cy)

Per

sico

etal

(200

2)N

HL

Ret

roD

uri

ng

C12

9-D

/3-N

T9

3-N

T

Lia

oet

al(2

002)

NH

LP

roD

uri

ng

C6

1-P

/5-D

51-

D

Sim

pso

net

al(2

003)

BC

,N

HL

Ret

roD

uri

ng

C4

4-D

22-

D

Pre

-em

pti

veR

oss

iet

al(2

001)

NH

L,

CL

L,

MM

,A

ML

Pro

2m

afte

rC

and

1m

afte

rL

AM

2019

-P/1

-D1-

P(p

ost

-LA

M

dis

con

t.)

0

Shib

ole

tet

al(2

002)

Lym

ph

om

a,o

ther

Ret

roD

uri

ng

C18

13-P

/5-D

0-P

/2-D

0

Lim

etal

(200

2)H

aem

ato

logi

cal

and

soli

dtu

mo

urs

Ret

ro10

–105

daf

ter

C35

16-P

/19-

NT�

0-P

/2-D

0-P

/5-N

T&

D

Lee

et

al(2

003)

NH

LR

etro

+H

CN

A31

11-P

/20-

NT�

1-P

/17-

NT

/5-N

T&

D0-

P/1

-NT

Lau

et

al(2

003)

NH

L,

HD

Pro

�4

m–

du

rin

gC

1–8

maf

ter

C

3015

-P/1

5-D

0-P

/7-D

0-P

/0-D

Idil

man

etal

(200

4)N

HL

,A

ML

,A

LL

,

CL

L,

HD

,M

M,

BC

Pro

§4

m–

du

rin

gC

1–

12m

afte

rC

188-

P/1

0-N

T�

0-P

/5-D

/5-N

T&

D0

Ozg

uro

glu

et

al(2

004)

NH

LR

etro

NA

124-

P/2

-D/6

-NT�

0-P

/2-D

/2-N

T0-

P/2

-D/4

-NT

Yeo

etal

(200

4c)

NH

L,

oth

erP

ro+

HC

NA

258

65P

/193

D3-

P/4

2-D

0-P

/5-D

Lea

wet

al(2

004)

Lym

ph

om

aR

etro

+H

CN

A64

11-P

/53-

NT

0-P

/10-

NT

0-P

/7-N

T

Hu

iet

al(2

005a

,b)

NH

L,

HD

,A

ML

,M

MP

ro9–

39m

afte

rC

6–36

maf

ter

LA

Md

isco

nt.

4646

-P10

-P(1

1p

atie

nts

reac

tiva

ted

po

st

LA

Md

isco

nt.

)

1-P

(po

st-L

AM

dis

con

t.)

Vas

sili

adis

etal

(200

5)N

HL

,A

LL

,C

LL

,A

ML

,W

M,

AA

Pro

NA

1010

-P0-

P0-

P

Li

etal

(200

6)N

HL

,H

DP

ro+

HC

NA

156

40P

/116

NT

7-P

/60-

NT

0-P

/6-N

T

AM

L,

acu

tem

yelo

idle

uka

emia

;A

LL

,ac

ute

lym

ph

ocy

tic

leu

kaem

ia;

CL

L,

chro

nic

lym

ph

ocy

tic

leu

kaem

ia;

NH

L,

no

n-H

od

gkin

lym

ph

om

a;H

D,

Ho

dgk

ind

isea

se;

MM

,m

ult

iple

mye

lom

a;W

M,

Wal

den

stro

mm

acro

glo

bu

lin

aem

ia;

AA

,ap

last

ican

aem

ia;

BC

,b

reas

tca

nce

r;P

C,

pla

smac

yto

ma;

KS,

Kap

osi

sarc

om

a.

Ret

ro,

retr

osp

ecti

ve;

pro

,p

rosp

ecti

ve;

d,

day

s;m

,m

on

ths;

C,

chem

oth

erap

y;D

,d

efer

red

trea

tmen

tw

ith

lam

ivu

din

e;H

C,

his

tori

cal

con

tro

ls;

LA

M,

lam

ivu

din

e;N

A,

no

tav

aila

ble

;N

T,

no

ttr

eate

d;

P,

pre

-

emp

tive

trea

tmen

tw

ith

lam

ivu

din

e;d

isco

nt.

,d

isco

nti

nu

ed.

*Sev

eral

case

rep

ort

so

fsu

cces

sfu

ld

efer

red

trea

tmen

tw

ith

lam

ivu

din

efo

rH

BV

reac

tiva

tio

nn

ot

qu

ote

d.

�So

me

pat

ien

tso

rigi

nal

lyli

sted

inN

Tgr

ou

ps

wer

esu

bse

qu

entl

ytr

eate

dw

ith

lam

ivu

din

eu

po

nre

acti

vati

on

.T

hes

ep

atie

nts

are

mar

ked

asN

T&

D.

�Ran

do

mis

edco

ntr

oll

ed.

§Co

ntr

oll

ed.

Mo

difi

edfr

om

Yeo

and

Joh

nso

n(2

006)

wit

hp

erm

issi

on

fro

mJo

hn

Wil

ey&

Son

s,In

c.

Review


patients at risk treated pre-emptively with lamivudine during

chemotherapy for various malignancies, HBV reactivation

could be reduced from 25–85% to 0–9%. Thus a large body of

clinical trials strongly supports pre-emptive therapy in patients

undergoing chemotherapy.

The optimal timing for beginning pre-emptive anti-viral

therapy has not been established and requires further study. It

is preferable to begin pre-emptive treatment 2–3 weeks prior

to chemotherapy, and we suggest no later than the first day of

chemotherapy.

The optimal duration of prophylactic anti-viral therapy in

patients at risk is unclear. Various studies have reported

lamivudine discontinuation within 1–12 months after cessa-

tion of chemotherapy (Hui et al, 2005a; Hsiao et al, 2006).

Premature discontinuation may lead to delayed HBV reacti-

vation, as shown in Fig 3. Re-treatment with lamivudine may

be successful, but delay in intervention may lead to serious

liver injury and may be life threatening (Dai et al, 2004). The

natural history of patients who stopped prophylactic therapy

has not been well-studied. Despite the absence of well

controlled trials we suggest that treatment be maintained for

at least 6 months and preferably 12 months after completion

of chemotherapy (Idilman, 2006). Extended treatment for

>12 months after chemotherapy may be advisable in patients

who initially had high serum HBV DNA levels, at the

discretion of the treating physician. More definitive recom-

mendations require a prospective controlled study.

Guidelines for screening, immunisation and pre-emptive

anti-viral treatment for patients at risk are suggested in Fig 2.

A potential concern related to the use of prophylactic

lamivudine is the development of resistant mutants. At

present, reports on lamivudine resistance in haemato-onco-

logical patients with HBV reactivation are scarce, probably

because of the relatively short duration of therapy. Newer and

more potent anti-viral agents described above will enable

effective protection despite the emergence of escape mutants.

Thus, in case of emergence of YMDD mutant-associated

hepatitis, adefovir or entecavir may be used for rescue.

It should, however, be remembered that HBV reactivation

may occur in up to 9% of patients at risk, despite pre-emptive

lamivudine treatment. The reason(s) for this breakthrough

phenomenon are still not understood.

Adoptive transfer of immunity to hepatitis Bthrough immunisation of haematopoietic celldonors

Candidates for allogeneic HSCT require special attention. They

are very poor responders to conventional vaccination against

hepatitis B. Such patients may benefit from the acquired

immune memory obtained through transplantation of HBV

immune lymphocytes from their human leucocyte antigen

(HLA) matched donors. The donors can be either immunised

against HBV or may be immune following natural HBV

infection with seroconversion (anti-HBc positive/anti-HBs

positive). Indeed, adoptive transfer of immunity to HBsAg

was shown to occur in HBV naıve bone marrow recipients and

in recipients of peripheral lymphocytes and stem-cells trans-

ferred from immunised anti-HBs positive donors (Shouval &

Ilan, 1995; Ilan et al, 2000). Immunity to HBsAg could be

boosted after transplantation by HBV vaccination. Studies in

various animals confirmed that immunity to HBV can be

adoptively transferred, even under conditions of immune

suppression (Shouval et al, 1993; Li et al, 2002; Dahmen et al,

2004).

A number of studies have provided further evidence that

immunisation of donors may induce HBV immunity in

recipients within several days to weeks of transplantation (Ilan

et al, 1993a; Lindemann et al, 2003; Shouval, 2007). Immuni-

sation of stem cell donors is simple, practically risk-free and

should be planned in advance, so that donors can be

adequately vaccinated prior to harvesting. Both donor and

recipient can then receive a booster vaccine. The optimal

timing and the number of booster doses required depends on

the immune status of the recipient and should be documented

by anti-HBs testing (Ilan et al, 1993a). Administration of the

third vaccine dose to the donor at 6 months should not be

forgotten after the primary immunisation to maximise anti-

HBs seroconversion if future cell donations are required. It is

not yet established if a booster dose is required in transplant

recipients from cell donors who had previously recovered

spontaneously from HBV infection and were anti-HBc posit-

ive/anti-HBs positive at time of donation. However, there is a

rational for administering a booster vaccine dose to such

recipients once they recover immunologically.

If an HBsAg positive patient requires haematopoietic call

transplantation (HCT) or HSCT, it may be possible to

adoptively transfer immunity to HBV by these procedures. A

number of observations suggest that this is possible. Clearance

of HBV was first documented in an HBsAg positive/anti-HBe

positive/HBV DNA positive chronic lymphocytic leukaemia

Fig 3. The effect of premature withdrawal of antiviral treatment on

hepatitis B viral load and alanine amino transferase (ALT) in a patient

with diffuse large B cell lymphoma treated pre-emptively with lami-

vudine. Reproduced from Dai et al (2004) with kind permission of

Springer Science and Business Media.

Review


(CLL) patient who received a bone marrow transplant from his

anti-HBc positive/anti-HBs positive brother (Ilan et al, 1993b).

Lau et al (1997, 2002a) confirmed and extended this observa-

tion in HBsAg positive transplant recipients in whom HBV

clearance and anti-HBs seroconversion was achieved following

receipt of an HBV immune bone-marrow, without serious

adverse events. Furthermore, donor-derived core antigen

reactive T-cells were linked to the clearance of HBV in the

recipients (Lau et al, 1999, 2002b). The probability of iden-

tifying an HLA-matched HBV immune donor with an anti-

HBc positive/anti-HBs positive serological profile for an

HBsAg positive recipient is low, albeit not negligible, especially

in HBV endemic countries. Utilisation of such donors,

together with pre-emptive lamivudine treatment may therefore

be beneficial in patients with chronic HBV infection. Finally,

there already is a report suggesting anti-HBs seroconversion in

HBsAg negative patients transplanted with livers from HBV

immune donors (Shouval, 2007).

Summary of recommendations

(1) All patients who are candidates for immune suppressive

therapy should be screened for HBV markers.

(2) All HBV naıve patients, including potential bone marrow

and stem cell donors, should be immunised against HBV

as soon as possible with preferably three doses and no less

than two. The quantitative anti-HBs response should be

documented several weeks after the last injection. Non-

responders should receive another course of three injec-

tions, when possible.

(3) Early, pre-emptive anti-viral therapy is superior to inter-

vention at time of HBV reactivation. Patients who are

HBsAg positive should be evaluated for presence of liver

disease and receive pre-emptive treatment with lamivu-

dine at 100 mg/d, regardless of their HBeAg or HBV DNA

status. Anti-viral treatment should be started preferably

within 2–3 weeks prior to initiation and no later than the

first day of chemotherapy. Lamivudine treatment should

be continued for at least 6 months after discontinuation of

chemotherapy and preferably for 12 months.

(4) Patients who are anti-HBc positive/HBsAg negative/anti-

HBs negative should receive one dose of a hepatitis B

vaccine and quantitative anti-HBs response measured

within 2–4 weeks. Those who develop an anti-HBs

response will not require pre-emptive anti-viral treat-

ment. Non-responders to the vaccine should be tested for

HBV-DNA by PCR. Patients with viraemia should be

started on pre-emptive lamivudine 100 mg/d.

(5) Patients who are anti-HBc positive/HBsAg negative/anti-

HBs negative/HBV DNA negative do not require pre-

emptive lamivudine. However, continuous monitoring

for ALT is advised. In case of ALT elevation, HBV DNA

should be tested.

(6) Antiviral treatment should be started promptly in

immune suppressed patients who demonstrate symptoms

compatible with a hepatitis flare attributed to HBV

reactivation.

In conclusion, surveillance for HBV status is an integral part

of the care of the haematology patient. By implementing good

medical practice, virtually all patients should be prevented

from contracting or reactivating HBV, in view of the

potentially serious consequences of this infection.

Acute hepatitis B – Hepatic injury that resolves within6 months after exposure to HBV or onset of symptoms. ElevatedALT and AST, HBsAg positive/anti-HBc IgM, positive.Chronic hepatitis B – Hepatic injury which continues >6 months.HBsAg positive >6 months, elevated ALT and AST, HBV-DNAin serum positive or negative.Inactive HBsAg Carrier state – ALT and AST levels persistentlynormal, HBsAg positive >6 months, HBV DNA negative or lowpositive <105 copies/ml in serum.Occult HBV – Normal or abnormal ALT levels, anti-HBcpositive/HBsAg negative, anti-HBs negative or positive, HBVDNA positive (in serum or liver tissue).Overt HBV – Clinically, biochemically and virologically apparenthepatitis B.Resolved HBV – HBsAg negative, HBV DNA negative, normalALT, history of HBV infection/anti-HBc positive/anti-HBspositive or negative.

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